Pyrethroid insecticides evoke neurotransmitter release from rabbit striatal slices

International Nuclear Information System (INIS)

Eells, J.T.; Dubocovich, M.L.

1988-01-01

The effects of the synthetic pyrethroid insecticide fenvalerate ([R,S]-alpha-cyano-3-phenoxybenzyl[R,S]-2-(4-chlorophenyl)-3- methylbutyrate) on neurotransmitter release in rabbit brain slices were investigated. Fenvalerate evoked a calcium-dependent release of [ 3 H]dopamine and [ 3 H]acetylcholine from rabbit striatal slices that was concentration-dependent and specific for the toxic stereoisomer of the insecticide. The release of [ 3 H]dopamine and [ 3 H]acetylcholine by fenvalerate was modulated by D2 dopamine receptor activation and antagonized completely by the sodium channel blocker, tetrodotoxin. These findings are consistent with an action of fenvalerate on the voltage-dependent sodium channels of the presynaptic membrane resulting in membrane depolarization, and the release of dopamine and acetylcholine by a calcium-dependent exocytotic process. In contrast to results obtained in striatal slices, fenvalerate did not elicit the release of [ 3 H]norepinephrine or [ 3 H]acetylcholine from rabbit hippocampal slices indicative of regional differences in sensitivity to type II pyrethroid actions

Characterization of the effects of serotonin on the release of [3H]dopamine from rat nucleus accumbens and striatal slices

International Nuclear Information System (INIS)

Nurse, B.; Russell, V.A.; Taljaard, J.J.

1988-01-01

The effect of serotonin agonists on the depolarization (K+)-induced, calcium-dependent, release of [ 3 H]dopamine (DA) from rat nucleus accumbens and striatal slices was investigated. Serotonin enhanced basal 3 H overflow and reduced K+-induced release of [ 3 H]DA from nucleus accumbens slices. The effect of serotonin on basal 3 H overflow was not altered by the serotonin antagonist, methysergide, or the serotonin re-uptake blocker, chlorimipramine, but was reversed by the DA re-uptake carrier inhibitors nomifensine and benztropine. With the effect on basal overflow blocked, serotonin did not modulate K+-induced release of [ 3 H]DA in the nucleus accumbens or striatum. The serotonin agonists, quipazine (in the presence of nomifensine) and 5-methoxytryptamine, did not significantly affect K+-induced release of [ 3 H]DA in the nucleus accumbens. This study does not support suggestions that serotonin receptors inhibit the depolarization-induced release of dopamine in the nucleus accumbens or striatum of the rat brain. The present results do not preclude the possibility that serotonin may affect the mesolimbic reward system at a site which is post-synaptic to dopaminergic terminals in the nucleus accumbens

Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

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Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

2013-01-01

Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

Evaluation of the effects and mechanisms of action of glufosinate, an organophosphate insecticide, on striatal dopamine release by using in vivo microdialysis in freely moving rats.

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Ferreira Nunes, Brenda V; Durán, Rafael; Alfonso, Miguel; de Oliveira, Iris Machado; Ferreira Faro, Lilian R

2010-10-01

The purpose of the present work was to assess the effects of glufosinate ammonium (GLA), an aminoacid structurally related to glutamate, on in vivo dopamine (DA) release from rat striatum, using brain microdialysis coupled to HPLC-EC. Intrastriatal administration of GLA produced significant concentration-dependent increases in DA levels. At least two mechanisms can be proposed to explain these increases: GLA could be inducing DA release from synaptic vesicles or producing an inhibition of DA transporter (DAT). Thus, we investigated the effects of GLA under Ca(++)-free condition, and after pretreatment with reserpine and TTX. It was observed that the pretreatment with Ca(++)-free Ringer, reserpine or TTX significantly reduced the DA release induced by GLA. Coinfusion of GLA and nomifensine shows that the GLA-induced DA release did not involve the DAT. These results show that GLA-induced striatal DA release is probably mediated by an exocytotic-, Ca(++)-, action potential-dependent mechanism, being independent of DAT.

Dopamine D(1) receptor-mediated control of striatal acetylcholine release by endogenous dopamine.

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Acquas, E; Di Chiara, G

1999-10-27

The role of dopamine D(1) and D(2) receptors in the control of acetylcholine release in the dorsal striatum by endogenous dopamine was investigated by monitoring with microdialysis the effect of the separate or combined administration of the dopamine D(1) receptor antagonist, SCH 39166 ¿(-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride¿ (50 microg/kg subcutaneous (s.c.)), of the dopamine D(2)/D(3) receptor agonist, quinpirole (trans-(-)-4aR, 4a,5,6,7,8,8a,9-octahydro-5-propyl-1H-pyrazolo-(3,4-g)-quinoline hydrochloride) (5 and 10 microg/kg s.c.), and of the D(3) receptor selective agonist, PD 128,907 [S(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride] (50 microg/kg s.c.), on in vivo dopamine and acetylcholine release. Microdialysis was performed with a Ringer containing low concentrations (0.01 microM) of the acetylcholinesterase inhibitor, neostigmine. Quinpirole (10 microg/kg s.c.) decreased striatal dopamine and acetylcholine release. Administration of PD 128,907 (50 microg/kg) decreased dopamine but failed to affect acetylcholine release. SCH 39166 (50 microg/kg s.c.) stimulated dopamine release and reduced acetylcholine release. Pretreatment with quinpirole reduced (5 microg/kg s.c.) or completely prevented (10 microg/kg s.c.) the stimulation of dopamine release elicited by SCH 39166 (50 microg/kg s.c.); on the other hand, pretreatment with quinpirole (5 and 10 microg/kg) potentiated the reduction of striatal acetylcholine release induced by SCH 39166 (50 microg/kg s.c.). Similarly, pretreatment with PD 128,907 (50 microg/kg) which prevented the increase of dopamine release induced by SCH 39166 (50 microg/kg), potentiated the reduction of striatal acetylcholine transmission elicited by SCH 39166. Thus, pretreatment with low doses of quinpirole or PD 128,907 influences in opposite manner the effect of SCH 39166 on striatal dopamine and

Ventricular fibrillation cardiac arrest produces a chronic striatal hyperdopaminergic state that is worsened by methylphenidate treatment.

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Nora, Gerald J; Harun, Rashed; Fine, David F; Hutchison, Daniel; Grobart, Adam C; Stezoski, Jason P; Munoz, Miranda J; Kochanek, Patrick M; Leak, Rehana K; Drabek, Tomas; Wagner, Amy K

2017-07-01

Cardiac arrest survival rates have improved with modern resuscitation techniques, but many survivors experience impairments associated with hypoxic-ischemic brain injury (HIBI). Currently, little is understood about chronic changes in striatal dopamine (DA) systems after HIBI. Given the common empiric clinical use of DA enhancing agents in neurorehabilitation, investigation evaluating dopaminergic alterations after cardiac arrest (CA) is necessary to optimize rehabilitation approaches. We hypothesized that striatal DA neurotransmission would be altered chronically after ventricular fibrillation cardiac arrest (VF-CA). Fast-scan cyclic voltammetry was used with median forebrain bundle (MFB) maximal electrical stimulations (60Hz, 10s) in rats to characterize presynaptic components of DA neurotransmission in the dorsal striatum (D-Str) and nucleus accumbens 14 days after a 5-min VF-CA when compared to Sham or Naïve. VF-CA increased D-Str-evoked overflow [DA], total [DA] released, and initial DA release rate versus controls, despite also increasing maximal velocity of DA reuptake (V max ). Methylphenidate (10 mg/kg), a DA transporter inhibitor, was administered to VF-CA and Shams after establishing a baseline, pre-drug 60 Hz, 5 s stimulation response. Methylphenidate increased initial evoked overflow [DA] more-so in VF-CA versus Sham and reduced D-Str V max in VF-CA but not Shams; these findings are consistent with upregulated striatal DA transporter in VF-CA versus Sham. Our work demonstrates that 5-min VF-CA increases electrically stimulated DA release with concomitant upregulation of DA reuptake 2 weeks after brief VF-CA insult. Future work should elucidate how CA insult duration, time after insult, and insult type influence striatal DA neurotransmission and related cognitive and motor functions. © 2017 International Society for Neurochemistry.

Stimulated serotonin release from hyperinnervated terminals subsequent to neonatal dopamine depletion regulates striatal tachykinin, but not enkephalin gene expression.

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Basura, G J; Walker, P D

2000-09-30

Dopamine (DA) depletion in neonatal rodents results in depressed tachykinin and elevated enkephalin gene expression in the adult striatum (STR). Concurrently, serotonin (5-HT) fibers sprout to hyperinnervate the DA-depleted anterior striatum (A-STR). The present study was designed to determine if increased 5-HT release from sprouted terminals influences dysregulated preprotachykinin (PPT) and preproenkephalin (PPE) mRNA expression in the DA-depleted STR. Three-day-old Sprague-Dawley rat pups received bilateral intracerebroventricular injections of vehicle or the DA neurotoxin 6-hydroxydopamine (6-OHDA, 100 microg). Two months later, rats received a single intraperitoneal injection of vehicle or the acute 5-HT releasing agent p-chloroamphetamine (PCA; 10 mg/kg). Rats were killed 4 h later and striata processed for monoamine content by HPLC-ED and mRNA expression by in situ hybridization within specific subregions of the A-STR and posterior striatum (P-STR). 6-OHDA treatment severely (>98%) reduced striatal DA levels, while 5-HT content in the A-STR was significantly elevated (doubled), indicative of 5-HT hyperinnervation. Following 6-OHDA, PPT mRNA levels were depressed 60-66% across three subregions of the A-STR and 52-59% across two subregions of the P-STR, while PPE mRNA expression was elevated in both the A-STR (50-62%) and P-STR (55-82%). PCA normalized PPT mRNA levels in all regions of the DA-depleted A-STR and P-STR, yet did not alter PPE levels in either dorsal central or medial regions from 6-OHDA alone, but reduced PPE to control levels in the dorsal lateral A-STR. These data indicate that increased 5-HT neurotransmission, following neonatal 6-OHDA treatment, primarily influences PPT-containing neurons of the direct striatal output pathway.

A Comparative study for striatal-direct and -indirect pathway neurons to DA depletion-induced lesion in a PD rat model.

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Zheng, Xuefeng; Wu, Jiajia; Zhu, Yaofeng; Chen, Si; Chen, Zhi; Chen, Tao; Huang, Ziyun; Wei, Jiayou; Li, Yanmei; Lei, Wanlong

2018-04-16

Striatal-direct and -indirect Pathway Neurons showed different vulnerability in basal ganglia disorders. Therefore, present study aimed to examine and compare characteristic changes of densities, protein and mRNA levels of soma, dendrites, and spines between striatal-direct and -indirect pathway neurons after DA depletion by using immunohistochemistry, Western blotting, real-time PCR and immunoelectron microscopy techniques. Experimental results showed that: 1) 6OHDA-induced DA depletion decreased the soma density of striatal-direct pathway neurons (SP+), but no significant changes for striatal-indirect pathway neurons (ENK+). 2) DA depletion resulted in a decline of dendrite density for both striatal-direct (D1+) and -indirect (D2+) pathway neurons, and D2+ dendritic density declined more obviously. At the ultrastructure level, the densities of D1+ and D2+ dendritic spines reduced in the 6OHDA groups compared with their control groups, but the density of D2+ dendritic spines reduced more significant than that of D1. 3) Striatal DA depletion down-regulated protein and mRNA expression levels of SP and D1, on the contrary, ENK and D2 protein and mRNA levels of indirect pathway neurons were up-regulated significantly. Present results suggested that indirect pathway neurons be more sensitive to 6OHDA-induced DA depletion. Copyright © 2018 Elsevier Ltd. All rights reserved.

Repeated cocaine administration results in supersensitivity of striatal D-2 dopamine autoreceptors to pergolide

International Nuclear Information System (INIS)

Dwoskin, L.P.; Peris, J.; Yasuda, R.P.; Philpott, K.; Zahniser, N.R.

1988-01-01

Groups of rats administered cocaine-HCl (10 mg/kg, i.p.) or saline either acutely or once daily for 8 or 14 days were killed 24 hrs after the last dose. In striatal slices prelabelled with [ 3 H]DA, modulation of [ 3 H]-overflow by pergolide was used to measure D-2 autoreceptor activity. Compared to the contemporaneous control group pergolide produced a greater inhibition only in striatal slices from rats treated repeatedly with cocaine. In radioligand binding studies using striatal membranes from control rats, pergolide had a 500-fold greater affinity for the D-2, as opposed to the D-1, dopamine (DA) receptor subtype. These results indicate that repeated treatment with cocaine produces supersensitive striatal D-2 release-modulating autoreceptors consistent with a compensatory change to diminish the effect of elevated synaptic concentrations of DA produced by cocaine. In contrast, supersensitivity of D-2 receptors was not detected in [ 3 H]spiperone binding assays. 31 references, 2 figures, 1 table

Effect of MK-801 on methamphetamine-induced dopaminergic neurotoxicity: long-term attenuation of methamphetamine-induced dopamine release

Energy Technology Data Exchange (ETDEWEB)

Kim, Sang Eun; Kim, Yu Ri; Hwang, Se Hwan [Sungkyunkwan Univ., School of Medicine, Seoul (Korea, Republic of)

2001-08-01

Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum using [{sup 3}H] WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 g/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli.

Effect of MK-801 on methamphetamine-induced dopaminergic neurotoxicity: long-term attenuation of methamphetamine-induced dopamine release

International Nuclear Information System (INIS)

Kim, Sang Eun; Kim, Yu Ri; Hwang, Se Hwan

2001-01-01

Repeated administration of methamphetamine (METH) produces high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. The effect of MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, on METH-induced changes in DA transporter (DAT) and DA release evoked by an acute METH challenge was evaluated in rodent striatum using [ 3 H] WIN 38,428 ex vivo auto-radiography and in vivo microdialysis. Four injections of METH (10 mg/kg, i.p.), each given 2 h apart, produced 71% decrease in DAT levels in mouse striatum 3 d after administration. Pretreatment with MK-801 (2.5 g/kg, i.p.) 15 min before each of the four METH injections protected completely against striatal DAT depletions. Four injections of MK-801 alone did not significantly change striatal DAT levels. Striatal DA release evoked by an acute METH challenge (4mg/kg, i.p.) at 3 d after repeated administration of METH in rats was decreased but significant compared with controls, which was attenuated by repeated pretreatment with MK-801. Also, repeated injections of MK-801 alone attenuated acute METH-induced striatal DA release 3 d after administration. These results suggest that repeated administration of MK-801 may exert a preventive effect against METH-induced DA terminal injury through long-term attenuation of DA release induced by METH and other stimuli

Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

Energy Technology Data Exchange (ETDEWEB)

Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2005-07-01

Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25{+-}2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% {+-} 1.3% and 10.6% {+-} 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% {+-} 4.5% vs. 6.6% {+-} 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release.

Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

International Nuclear Information System (INIS)

Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun

2005-01-01

Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25±2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% ± 1.3% and 10.6% ± 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% ± 4.5% vs. 6.6% ± 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release

The effect of amperozide on uptake and release of [3H]-dopamine in vitro from perfused rat striatal and limbic brain areas

International Nuclear Information System (INIS)

Eriksson, E.; Christensson, E.

1990-01-01

Amperozide, a putatively antipsychotic drug, was studied for its effects on uptake and release of [ 3 H]-dopamine in rat brain in vitro. Amperozide inhibited uptake of [ 3 H]-dopamine in striatal chopped tissue in vitro with an IC 50 of 18 μM. It also increased basal release of [ 3 H]-dopamine from perfused rat striatal and limbic tissue in vitro at concentrations above 5 μM. Release of [ 3 H]-dopamine from perfused rat striatal and limbic tissue stimulated with 5 μM amphetamine, was inhibited by 1 μM amperozide to 46%. No significant difference was found for the effect of amperozide on in vitro release of [ 3 H]-dopamine from corpus striatum compared to tissue from limbic grain regions; neither on basal release nor on amphetamine-stimulated release of dopamine. (author)

Modulation of acetylcholine release from rat striatal slices by the GABA/benzodiazepine receptor complex

Energy Technology Data Exchange (ETDEWEB)

Supavilai, P.; Karobath, M.

1985-02-04

GABA, THIP and muscimol enhance spontaneous and inhibit electrically induced release of tritium labelled compounds from rat striatal slices which have been pre-labelled with /sup 3/H-choline. Baclofen is inactive in this model. Muscimol can inhibit electrically induced release of tritiated material by approximately 75% with half maximal effects at 2 ..mu..M. The response to muscimol can be blocked by the GABA antagonists bicuculline methobromide, picrotoxin, anisatin, R 5135 and CPTBO (cyclopentylbicyclophosphate). Drugs which act on the benzodiazepine receptor (BR) require the presence of muscimol to be effective and they modulate the effects of muscimol in a bidirectional manner. Thus BR agonists enhance and inverse BR agonists attenuate the inhibitory effects of muscimol on electrically induced release. Ro15-1788, a BR antagonist, does not modulate the inhibitory effects of muscimol but antagonizes the actions of clonazepam, a BR agonist, and of DMCM, an inverse BR agonist. These results demonstrate that a GABA/benzodiazepine receptor complex can modulate acetylcholine release from rat striatal slices in vitro. 24 references, 3 figures, 5 table.

A2A-D2 receptor-receptor interaction modulates gliotransmitter release from striatal astrocyte processes.

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Cervetto, Chiara; Venturini, Arianna; Passalacqua, Mario; Guidolin, Diego; Genedani, Susanna; Fuxe, Kjell; Borroto-Esquela, Dasiel O; Cortelli, Pietro; Woods, Amina; Maura, Guido; Marcoli, Manuela; Agnati, Luigi F

2017-01-01

Evidence for striatal A2A-D2 heterodimers has led to a new perspective on molecular mechanisms involved in schizophrenia and Parkinson's disease. Despite the increasing recognition of astrocytes' participation in neuropsychiatric disease vulnerability, involvement of striatal astrocytes in A2A and D2 receptor signal transmission has never been explored. Here, we investigated the presence of D2 and A2A receptors in isolated astrocyte processes prepared from adult rat striatum by confocal imaging; the effects of receptor activation were measured on the 4-aminopyridine-evoked release of glutamate from the processes. Confocal analysis showed that A2A and D2 receptors were co-expressed on the same astrocyte processes. Evidence for A2A-D2 receptor-receptor interactions was obtained by measuring the release of the gliotransmitter glutamate: D2 receptors inhibited the glutamate release, while activation of A2A receptors, per se ineffective, abolished the effect of D2 receptor activation. The synthetic D2 peptide VLRRRRKRVN corresponding to the receptor region involved in electrostatic interaction underlying A2A-D2 heteromerization abolished the ability of the A2A receptor to antagonize the D2 receptor-mediated effect. Together, the findings are consistent with heteromerization of native striatal astrocytic A2A-D2 receptors that via allosteric receptor-receptor interactions could play a role in the control of striatal glutamatergic transmission. These new findings suggest possible new pathogenic mechanisms and/or therapeutic approaches to neuropsychiatric disorders. © 2016 International Society for Neurochemistry.

Further human evidence for striatal dopamine release induced by administration of ∆9-tetrahydrocannabinol (THC): selectivity to limbic striatum.

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Bossong, Matthijs G; Mehta, Mitul A; van Berckel, Bart N M; Howes, Oliver D; Kahn, René S; Stokes, Paul R A

2015-08-01

Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of ∆9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results. The objective of this study is to assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants. We combined human neurochemical imaging data from two previous studies that used [(11)C]raclopride positron emission tomography (PET) (n = 7 and n = 13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis. THC administration induced a significant reduction in [(11)C]raclopride binding in the limbic striatum (-3.65 %, from 2.39 ± 0.26 to 2.30 ± 0.23, p = 0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions. In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

MK-801 protection against methamphetamine-induced striatal dopamine terminal injury is associated with attenuated dopamine overflow.

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Weihmuller, F B; O'Dell, S J; Marshall, J F

1992-06-01

Repeated administrations of methamphetamine (m-AMPH) produce high extracellular levels of dopamine (DA) and subsequent striatal DA terminal damage. Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors has been shown previously to prevent m-AMPH-induced striatal DA terminal injury, but the mechanism for this protection is unclear. In the present study, in vivo microdialysis was used to determine the effects of blockade of NMDA receptors with the noncompetitive antagonist MK-801 on m-AMPH-induced striatal DA overflow. Four injections of MK-801 (0.5 mg/kg, ip) alone did not significantly change extracellular striatal DA concentrations from pretreatment values. Four treatments with m-AMPH (4.0 mg/kg, sc at 2-hr intervals) increased striatal DA overflow, and the overflow was particularly extensive following the fourth injection. This m-AMPH regimen produced a 40% reduction in striatal DA tissue content 1 week later. Treatment with MK-801 15 min before each of the four m-AMPH injections or prior to only the last two m-AMPH administrations attenuated the m-AMPH-induced increase in striatal DA overflow and protected completely against striatal DA depletions. Other MK-801 treatment regimens less effectively reduced the m-AMPH-induced striatal DA efflux and were ineffective in protecting against striatal DA depletions. Linear regression analysis indicated that cumulative DA overflow was strongly predictive (r = -.68) of striatal DA tissue levels measured one week later. These findings suggest that the extensive DA overflow seen during a neurotoxic regimen of m-AMPH is a crucial component of the subsequent neurotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Phasic dopamine release drives rapid activation of striatal D2-receptors

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Marcott, Pamela F; Mamaligas, Aphroditi A; Ford, Christopher P

2014-01-01

Summary Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G-protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory post-synaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals. PMID:25242218

Homeostatic regulation of excitatory synapses on striatal medium spiny neurons expressing the D2 dopamine receptor.

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Thibault, Dominic; Giguère, Nicolas; Loustalot, Fabien; Bourque, Marie-Josée; Ducrot, Charles; El Mestikawy, Salah; Trudeau, Louis-Éric

2016-05-01

Striatal medium spiny neurons (MSNs) are contacted by glutamatergic axon terminals originating from cortex, thalamus and other regions. The striatum is also innervated by dopaminergic (DAergic) terminals, some of which release glutamate as a co-transmitter. Despite evidence for functional DA release at birth in the striatum, the role of DA in the establishment of striatal circuitry is unclear. In light of recent work suggesting activity-dependent homeostatic regulation of glutamatergic terminals on MSNs expressing the D2 DA receptor (D2-MSNs), we used primary co-cultures to test the hypothesis that stimulation of DA and glutamate receptors regulates the homeostasis of glutamatergic synapses on MSNs. Co-culture of D2-MSNs with mesencephalic DA neurons or with cortical neurons produced an increase in spines and functional glutamate synapses expressing VGLUT2 or VGLUT1, respectively. The density of VGLUT2-positive terminals was reduced by the conditional knockout of this gene from DA neurons. In the presence of both mesencephalic and cortical neurons, the density of synapses reached the same total, compatible with the possibility of a homeostatic mechanism capping excitatory synaptic density. Blockade of D2 receptors increased the density of cortical and mesencephalic glutamatergic terminals, without changing MSN spine density or mEPSC frequency. Combined blockade of AMPA and NMDA glutamate receptors increased the density of cortical terminals and decreased that of mesencephalic VGLUT2-positive terminals, with no net change in total excitatory terminal density or in mEPSC frequency. These results suggest that DA and glutamate signaling regulate excitatory inputs to striatal D2-MSNs at both the pre- and postsynaptic level, under the influence of a homeostatic mechanism controlling functional output of the circuit.

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates.

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Singh, Arun; Jenkins, Meagan A; Burke, Kenneth J; Beck, Goichi; Jenkins, Andrew; Scimemi, Annalisa; Traynelis, Stephen F; Papa, Stella M

2018-01-23

Dopamine (DA) loss in Parkinson's disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the "on" state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice.

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Hirata, H; Ladenheim, B; Carlson, E; Epstein, C; Cadet, J L

1996-04-01

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the issue of loss of DA terminals. In the present study, we have used receptor autoradiographic studies of [(125)I]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent in the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.

Dysregulation of striatal projection neurons in Parkinson's disease.

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Beck, Goichi; Singh, Arun; Papa, Stella M

2018-03-01

The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum

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Krebs, M.O.; Trovero, F.; Desban, M.; Gauchy, C.; Glowinski, J.; Kemel, M.L. (College de France, Paris (France))

1991-05-01

Striosome- and matrix-enriched striatal zones were defined in coronal and sagittal brain sections of the rat, on the basis of {sup 3}H-naloxone binding to mu-opiate receptors (a striosome-specific marker). Then, using a new in vitro microsuperfusion device, the NMDA (50 microM)-evoked release of newly synthesized {sup 3}H-dopamine ({sup 3}H-DA) was examined in these four striatal areas under Mg(2+)-free conditions. The amplitudes of the responses were different in striosomal (171 +/- 6% and 161 +/- 5% of the spontaneous release) than in matrix areas (223 +/- 6% and 248 +/- 12%), even when glycine (1 or 100 microM) was coapplied (in the presence of 1 microM strychnine). In the four areas, the NMDA-evoked release of {sup 3}H-DA was blocked completely by Mg{sup 2}{sup +} (1 mM) or (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801; 1 microM) and almost totally abolished by kynurenate (100 microM). Because the tetrodotoxin (TTX)-resistant NMDA-evoked release of {sup 3}H-DA was similar in striosome- (148 +/- 5% and 152 +/- 6%) or matrix-enriched (161 +/- 5% and 156 +/- 7%) areas, the indirect (TTX-sensitive) component of NMDA-evoked responses, which involves striatal neurons and/or afferent fibers, seems more important in the matrix- than in the striosome-enriched areas. The modulation of DA release by cortical glutamate and/or aspartate-containing inputs through NMDA receptors in the matrix appears thus to be partly distinct from that observed in the striosomes, providing some functional basis for the histochemical striatal heterogeneity.

Effect of ginseng saponina on nicotine-induced dopamine release in the rat nucleus accumbens and striatum

International Nuclear Information System (INIS)

Kim, Sang Eun; Shim, In Sop; Chung, June Key; Lee, Myung Chul

2002-01-01

We investigated the effect of ginseng total saponin (GTS) on nicotine-induced dopamine (DA) release in the striatum and nucleus accumbens of freely moving rats using in vivo microdialysis technique. Systemic pretreatment with GTS decreased striatal DA release induced by local infusion of nicotine into the striatum. However, GTS had no effect on the resting levels of extracellular DA in the striatum. GTS also blocked nicotine-induced DA release in the nucleus accumbens. The results of the present study suggest that GTS acts on the DA terminals to prevent DA release induced by nicotine. This may reflect the blocking effect of GTS on behavioral hyperactivity induced by psychostimulants

Effect of ginseng saponina on nicotine-induced dopamine release in the rat nucleus accumbens and striatum

Energy Technology Data Exchange (ETDEWEB)

Kim, Sang Eun [Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Shim, In Sop [Kyunghee University, Seoul (Korea, Republic of); Chung, June Key; Lee, Myung Chul [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2002-10-01

We investigated the effect of ginseng total saponin (GTS) on nicotine-induced dopamine (DA) release in the striatum and nucleus accumbens of freely moving rats using in vivo microdialysis technique. Systemic pretreatment with GTS decreased striatal DA release induced by local infusion of nicotine into the striatum. However, GTS had no effect on the resting levels of extracellular DA in the striatum. GTS also blocked nicotine-induced DA release in the nucleus accumbens. The results of the present study suggest that GTS acts on the DA terminals to prevent DA release induced by nicotine. This may reflect the blocking effect of GTS on behavioral hyperactivity induced by psychostimulants.

Interactions of MK-801 with glutamate-, glutamine- and methamphetamine-evoked release of [3H]dopamine from striatal slices

International Nuclear Information System (INIS)

Bowyer, J.F.; Scallet, A.C.; Holson, R.R.; Lipe, G.W.; Slikker, W. Jr.; Ali, S.F.

1991-01-01

The interactions of MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine], glutamate and glutamine with methamphetamine (METH)-evoked release of [ 3 H]dopamine were assessed in vitro to determine whether MK-801 inhibition of METH neurotoxicity might be mediated presynaptically, and to evaluate the effects of glutamatergic stimulation on METH-evoked dopamine release. MK-801 inhibition of glutamate- or METH-evoked dopamine release might reduce synaptic dopamine levels during METH exposure and decrease the formation of 6-hydroxydopamine or other related neurotoxins. Without Mg 2+ present, 40 microM and 1 mM glutamate evoked a N-methyl-D-aspartate receptor-mediated [ 3 H]dopamine and [ 3 H]metabolite (tritium) release of 3 to 6 and 12 to 16% of total tritium stores, respectively, from striatal slices. With 1.50 mM Mg 2+ present, 10 mM glutamate alone or in combination with the dopamine uptake blocker nomifensine released only 2.1 or 4.2%, respectively, of total tritium stores, and release was only partially dependent on N-methyl-D-aspartate-type glutamate receptors. With or without 1.50 mM Mg 2+ present, 0.5 or 5 microM METH evoked a substantial release of tritium (5-8 or 12-21% of total stores, respectively). METH-evoked dopamine release was not affected by 5 microM MK-801 but METH-evoked release was additive with glutamate-evoked release. Without Mg 2+ present, 1 mM glutamine increased glutamate release and induced the release of [ 3 H]dopamine and metabolites. Both 0.5 and 5 microM METH also increased tritium release with 1 mM glutamine present. When striatal slices were exposed to 5 microM METH this glutamine-evoked release of glutamate was increased more than 50%

Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine.

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Baldwin, H A; Colado, M I; Murray, T K; De Souza, R J; Green, A R

1993-03-01

1. Administration to rats of methamphetamine (15 mg kg-1, i.p.) every 2 h to a total of 4 doses resulted in a neurotoxic loss of striatal dopamine of 36% and of 5-hydroxytryptamine (5-HT) in the cortex (43%) and hippocampus (47%) 3 days later. 2. Administration of chlormethiazole (50 mg kg-1, i.p.) 15 min before each dose of methamphetamine provided complete protection against the neurotoxic loss of monoamines while administration of dizocilpine (1 mg kg-1, i.p.) using the same dose schedule provided substantial protection. 3. Measurement of dopamine release in the striatum by in vivo microdialysis revealed that methamphetamine produced an approximate 7000% increase in dopamine release after the first injection. The enhanced release response was somewhat diminished after the third injection but still around 4000% above baseline. Dizocilpine (1 mg kg-1, i.p.) did not alter this response but chlormethiazole (50 mg kg-1, i.p.) attenuated the methamphetamine-induced release by approximately 40%. 4. Dizocilpine pretreatment did not influence the decrease in the dialysate concentration of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) produced by administration of methamphetamine while chlormethiazole pretreatment decreased the dialysate concentration of these metabolites still further. 5. The concentration of dopamine in the dialysate during basal conditions increased modestly during the course of the experiment. This increase did not occur in chlormethiazole-treated rats. HVA concentrations were unaltered by chlormethiazole administration. 6. Chlormethiazole (100-1000 microM) did not alter methamphetamine (100 microM) or K+ (35 mM)-evoked release of endogenous dopamine from striatal prisms in vitro. 7. Several NMDA antagonists prevent methamphetamine-induced neurotoxicity; however chlormethiazole is not an NMDA antagonist. Inhibition of striatal dopamine function prevents methamphetamine-induced toxicity of both dopamine and 5

Cortical Regulation of Striatal Medium Spiny Neuron Dendritic Remodeling in Parkinsonism: Modulation of Glutamate Release Reverses Dopamine Depletion–Induced Dendritic Spine Loss

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Garcia, Bonnie G.; Neely, M. Diana; Deutch, Ariel Y.

2010-01-01

Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if dec...

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

International Nuclear Information System (INIS)

Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

1988-01-01

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17β-estradiol (E 2 ) at both low (0.1 μg/kg) and high (20 μg/kg) doses confirmed its ability to increase the number of striatal 3 H-Spiperone ( 3 H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E 2 , to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity

Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes

International Nuclear Information System (INIS)

Minnema, D.J.; Greenland, R.D.; Michaelson, I.A.

1986-01-01

The effect of inorganic lead in vitro in several aspects of [ 3 H]dopamine release from superfused rat striatal synaptosomes was examined. Under conditions of spontaneous release, lead (1-30 microM) induced dopamine release in a concentration-dependent manner. The onset of the lead-induced release was delayed by approximately 15-30 sec. The magnitude of dopamine release induced by lead was increased when calcium was removed from the superfusing buffer. Lead-induced release was unaffected in the presence of putative calcium, sodium, and/or potassium channel blockers (nickel, tetrodotoxin, tetraethylammonium, respectively). Depolarization-evoked dopamine release, produced by a 1-sec exposure to 61 mM potassium, was diminished at calcium concentrations below 0.254 mM. The onset of depolarization-evoked release was essentially immediate following exposure of the synaptosomes to high potassium. The combination of lead (3 or 10 microM) with high potassium reduced the magnitude of depolarization-evoked dopamine release. This depression of depolarization-evoked release by lead was greater in the presence of 0.25 mM than 2.54 mM calcium in the superfusing buffer. These findings demonstrate multiple actions of lead on synaptosomal dopamine release. Lead can induce dopamine release by yet unidentified neuronal mechanisms independent of external calcium. Lead can also reduce depolarization-evoked dopamine release by apparent competition with calcium influx at the neuronal membrane calcium channel

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors

Energy Technology Data Exchange (ETDEWEB)

Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

1988-01-01

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding.

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Nicole Speed

Full Text Available The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt involved in insulin signaling induced by exposure to a high-fat (HF diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT. Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.Acquired disruption of brain insulin action may confer risk for and/or underlie "food-abuse" disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to "the fast food

Molecular substrates of action control in cortico-striatal circuits.

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Shiflett, Michael W; Balleine, Bernard W

2011-09-15

The purpose of this review is to describe the molecular mechanisms in the striatum that mediate reward-based learning and action control during instrumental conditioning. Experiments assessing the neural bases of instrumental conditioning have uncovered functional circuits in the striatum, including dorsal and ventral striatal sub-regions, involved in action-outcome learning, stimulus-response learning, and the motivational control of action by reward-associated cues. Integration of dopamine (DA) and glutamate neurotransmission within these striatal sub-regions is hypothesized to enable learning and action control through its role in shaping synaptic plasticity and cellular excitability. The extracellular signal regulated kinase (ERK) appears to be particularly important for reward-based learning and action control due to its sensitivity to combined DA and glutamate receptor activation and its involvement in a range of cellular functions. ERK activation in striatal neurons is proposed to have a dual role in both the learning and performance factors that contribute to instrumental conditioning through its regulation of plasticity-related transcription factors and its modulation of intrinsic cellular excitability. Furthermore, perturbation of ERK activation by drugs of abuse may give rise to behavioral disorders such as addiction. Copyright © 2011 Elsevier Ltd. All rights reserved.

Running wheel exercise before a binge regimen of methamphetamine does not protect against striatal dopaminergic damage.

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O'dell, Steven J; Marshall, John F

2014-09-01

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" dosing regimen produces long-lasting damage to forebrain dopaminergic nerve terminals as measured by decreases in tissue dopamine (DA) content and levels of the plasmalemmal DA transporter (DAT). However, the midbrain cell bodies from which the DA terminals arise survive, and previous reports show that striatal DA markers return to control levels by 12 months post-mAMPH, suggesting long-term repair or regrowth of damaged DA terminals. We previously showed that when rats engaged in voluntary aerobic exercise for 3 weeks before and 3 weeks after a binge regimen of mAMPH, exercise significantly ameliorated mAMPH-induced decreases in striatal DAT. However, these data left unresolved the question of whether exercise protected against the initial neurotoxicity from the mAMPH binge or accelerated the repair of the damaged DA terminals. The present experiments were designed to test whether exercise protects against the mAMPH-induced injury. Adult male Sprague-Dawley rats were allowed to run in wheels for 3 weeks before an acute binge regimen of mAMPH or saline, then placed into nonwheel cages for an additional week before autoradiographic determination of striatal DAT binding. The autoradiographic findings showed that prior exercise provided no protection against mAMPH-induced damage to striatal DA terminals. These results, together with analyses from our previous experiments, suggest that voluntary exercise may accelerate the repair of mAMPH-damaged DA terminals and that voluntary exercise may be useful as therapeutic adjunct in the treatment mAMPH addicts. © 2014 Wiley Periodicals, Inc.

Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens.

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Hartung, Henrike; Threlfell, Sarah; Cragg, Stephanie J

2011-08-01

Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca(2+)-activated K(+) channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals.

DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding.

Science.gov (United States)

Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2013-01-01

The default mode network (DMN) comprises a set of brain regions with "increased" activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([(123)I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

Elevated Striatal Dopamine Function in Immigrants and Their Children: A Risk Mechanism for Psychosis

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Egerton, A.; Howes, O. D.; Houle, S.; McKenzie, K.; Valmaggia, L. R.; Bagby, M. R.; Tseng, H-H; Bloomfield, M. A. P.; Kenk, M.; Bhattacharyya, S.; Suridjan, I.; Chaddock, C. A.; Winton-Brown, T. T.; Allen, P.; Rusjan, P.

2017-01-01

Migration is a major risk factor for schizophrenia but the neurochemical processes involved are unknown. One candidate mechanism is through elevations in striatal dopamine synthesis and release. The objective of this research was to determine whether striatal dopamine function is elevated in immigrants compared to nonimmigrants and the relationship with psychosis. Two complementary case–control studies of in vivo dopamine function (stress-induced dopamine release and dopamine synthesis capaci...

Histamine H3 Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

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Varaschin, Rafael Koerich; Osterstock, Guillaume; Ducrot, Charles; Leino, Sakari; Bourque, Marie-Josée; Prado, Marco A M; Prado, Vania Ferreira; Salminen, Outi; Rannanpää Née Nuutinen, Saara; Trudeau, Louis-Eric

2018-04-15

Histamine H 3 receptors are widely distributed G i -coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H 3 receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity. Acute brain slices from C57BL/6 or channelrhodopsin-2-transfected DAT-cre mice were obtained, and dopamine transients evoked either electrically or optogenetically were measured by fast-scan cyclic voltammetry. The H 3 agonist α-methylhistamine significantly reduced electrically- evoked dopamine overflow, an effect blocked by the nicotinic acetylcholine receptor antagonist dihydro-β-erythroidine, suggesting involvement of cholinergic interneurons. None of the drug treatments targeting H 3 receptors affected optogenetically evoked dopamine overflow, indicating that direct H 3 -modulation of dopaminergic axons is unlikely. Next, we used qPCR and confirmed the expression of histamine H 3 receptor mRNA in cholinergic interneurons, both in ventral and dorsal striatum. Activation of H 3 receptors by α-methylhistamine reduced spontaneous firing of cholinergic interneurons in the ventral, but not in the dorsal striatum. Resting membrane potential and number of spontaneous action potentials in ventral-striatal cholinergic interneurons were significantly reduced by α-methylhistamine. Acetylcholine release from isolated striatal synaptosomes, however, was not altered by α-methylhistamine. Together, these results indicate that histamine H 3 receptors are important modulators of dopamine release, specifically in the ventral striatum, and that they do so by decreasing the firing rate of cholinergic neurons and, consequently, reducing cholinergic tone on dopaminergic axons. Copyright © 2018 IBRO

Effect of superficial radial nerve stimulation on the activity of nigro-striatal dopaminergic neurons in the cat: role of cutaneous sensory input

International Nuclear Information System (INIS)

Nieoullon, A.; Dusticier, N.

1982-01-01

The release of 3 H-dopamine (DA) continuously synthesized from 3 H-thyrosine was measured in the caudate nucleus (CN) and in the substantia nigra (SN) in both sides of the brain during electrical stimulation of the superficial radial nerve in cats lightly anaesthetized with halothane. Use of appropriate electrophysiologically controlled stimulation led to selective activation of low threshold afferent fibers whereas high stimulation activated all cutaneous afferents. Results showed that low threshold fiber activation induced a decreased dopaminergic activity in CN contralateral to nerve stimulation and a concomitant increase in dopaminergic activity on the ipsilateral side. Stimulation of group I and threshold stimulation of group II afferent fibers induced changes in the release of 3 H-DA mainly on the contralateral CN and SN and in the ipsilateral CN. High stimulation was followed by a general increase of the neurotransmitter release in the four structures. This shows that the nigro-striatal dopaminergic neurons are mainly-if not exclusively-controlled by cutaneous sensory inputs. This control, non-specific when high threshold cutaneous fibers are also activated. Such activations could contribute to restablish sufficient release of DA when the dopaminergic function is impaired as in Parkinson's disease. (Author)

Effect of superficial radial nerve stimulation on the activity of nigro-striatal dopaminergic neurons in the cat: role of cutaneous sensory input

Energy Technology Data Exchange (ETDEWEB)

Nieoullon, A; Dusticier, N [Centre National de la Recherche Scientifique, 13 - Marseille (France). Inst. de Neurophysiologie et Psychophysiologie

1982-01-01

The release of /sup 3/H-dopamine (DA) continuously synthesized from /sup 3/H-thyrosine was measured in the caudate nucleus (CN) and in the substantia nigra (SN) in both sides of the brain during electrical stimulation of the superficial radial nerve in cats lightly anaesthetized with halothane. Use of appropriate electrophysiologically controlled stimulation led to selective activation of low threshold afferent fibers whereas high stimulation activated all cutaneous afferents. Results showed that low threshold fiber activation induced a decreased dopaminergic activity in CN contralateral to nerve stimulation and a concomitant increase in dopaminergic activity on the ipsilateral side. Stimulation of group I and threshold stimulation of group II afferent fibers induced changes in the release of /sup 3/H-DA mainly on the contralateral CN and SN and in the ipsilateral CN. High stimulation was followed by a general increase of the neurotransmitter release in the four structures. This shows that the nigro-striatal dopaminergic neurons are mainly-if not exclusively-controlled by cutaneous sensory inputs. This control, non-specific when high threshold cutaneous fibers are also activated. Such activations could contribute to reestablish sufficient release of DA when the dopaminergic function is impaired as in Parkinson's disease.

Potentiation by choline of basal and electrically evoked acetylcholine release, as studied using a novel device which both stimulates and perfuses rat corpus striatum

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Farber, S. A.; Kischka, U.; Marshall, D. L.; Wurtman, R. J.

1993-01-01

We examined the release of acetylcholine (ACh) and dopamine (DA) using a novel probe through which striatal neurons could be both superfused and stimulated electrically in both anesthetized and freely moving awake animals. Optimal stimulation parameters for eliciting ACh release from cholinergic neurons differed from those required for eliciting DA release from dopaminergic terminals: at 0.6 ms pulse duration, 20 Hz and 200 microA, ACh release increased to 357 +/- 30% (P basal release rose from 117 +/- 7% to 141 +/- 5% of initial baseline levels (P basal or evoked DA release although neostigmine (10 microM) significantly elevated basal DA release (from 36.7 fmol/10 min to 71.5 fmol/10 min; P basal (from 106 +/- 7% to 154 +/- 17%; P < 0.05) and electrically evoked (from 146 +/- 13 to 262 +/- 16%; P < 0.01) ACh release.(ABSTRACT TRUNCATED AT 250 WORDS).

Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography

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Booij, J.; Korn, P.; Linszen, D.H.; Royen, E.A. van

1997-01-01

This double-blind, placebo-controlled study assessed pharmacologically induced endogenous dopamine (DA) release in healthy male volunteers (n=12). Changes in endogenous DA release after injection of the psychostimulant drug methylphenidate were evaluated by single-photon emission tomography (SPET) and constant infusion of iodine-123 iodobenzamide ([ 123 I[IBZM), a D 2 receptor radioligand that is sensitive to endogenous DA release. Methylphenidate induced displacement of striatal [ 123 I[IBZM binding, resulting in a significantly decrease in the specific to non-specific [ 123 I[IBZM uptake ratio (average: 8.6%) in comparison with placebo (average: -1.9%). Moreover, injection of methylphenidate induced significant behavioural responses on the following items: excitement, anxiety, tension, and mannerisms and posturing. The results of this study demonstrate the feasibility of using constant infusion of [ 123 I[IBZM and SPET imaging to measure endogenous DA release after methylphenidate challenge and to investigate neurochemical aspects of behaviour. (orig.). With 2 figs., 1 tab

Differences between the release of radiolabelled and endogenous dopamine from superfused rat brain slices: effects of depolarizing stimuli, amphetamine and synthesis inhibition

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Herdon, H.; Strupish, J.; Nahorski, S.R.

1985-01-01

Direct comparisons between radiolabelled and endogenous dopamine (DA) release from superfused rat brain slices have been made. Striatal slices were prelabelled with [ 3 H]dopamine ([ 3 H]DA), then superfused at 0.5 ml/min and the released catecholamines analyzed by HPLC with electrochemical detection and radioactivity present in superfusate fractions also counted. The studies indicate that labelled and endogenous amine release do not always occur in parallel, and that major causes of discrepancy between them may include the presence of a large newly-synthesized component in endogenous release and the uneven distribution of labelled amine within endogenous releasable pools. The results also suggest that the prelabelling process itself may alter the pools contributing to subsequent endogenous release. (Auth.)

Free radical production induced by methamphetamine in rat striatal synaptosomes

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Pubill, David; Chipana, Carlos; Camins, Antonio; Pallas, Merce; Camarasa, Jordi; Escubedo, Elena

2005-01-01

The pro-oxidative effect of methamphetamine (METH) in dopamine terminals was studied in rat striatal synaptosomes. Flow cytometry analysis showed increased production of reactive oxygen species (ROS) in METH-treated synaptosomes, without reduction in the density of dopamine transporters. In synaptosomes from dopamine (DA)-depleted animals, METH did not induce ROS production. Reserpine, in vitro, completely inhibited METH-induced ROS production. These results point to endogenous DA as the main source of ROS induced by METH. Antioxidants and inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC) prevented the METH-induced oxidative effect. EGTA and the specific antagonist methyllycaconitine (MLA, 50 μM) prevented METH-induced ROS production, thus implicating calcium and α7 nicotinic receptors in such effect. Higher concentrations of MLA (>100 μM) showed nonspecific antioxidant effect. Preincubation of synaptosomes with METH (1 μM) for 30 min reduced [ 3 H]DA uptake by 60%. The METH effect was attenuated by MLA and EGTA and potentiated by nicotine, indicating that activation of α 7 nicotinic receptors and Ca 2+ entry are necessary and take place before DAT inhibition. From these findings, it can be postulated that, in our model, METH induces DA release from synaptic vesicles to the cytosol. Simultaneously, METH activates α 7 nicotinic receptors, probably inducing depolarization and an increase in intrasynaptosomal Ca 2+ . This would lead to DAT inhibition and NOS and PKC activation, initiating oxidation of cytosolic DA

Alteration of striatal dopamine levels under various partial pressure of oxygen in pre-convulsive and convulsive phases in freely-moving rats.

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Lavoute, Cécile; Weiss, Michel; Risso, Jean-Jacques; Rostain, Jean-Claude

2014-02-01

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5 ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5 ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1 week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5 ATA. DA level was monitored continuously (every 3 min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1 ATA to 4 ATA (-15 % at 1 ATA, -30 % at 2 ATA, -40 % at 3 ATA, -45 % at 4 ATA), without signs of oxygen toxicity. At 5 ATA, DA level strongly decreases (-75 %) before seizure which occurred after 27 min ± 7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.

Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers.

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Oberlin, Brandon G; Dzemidzic, Mario; Tran, Stella M; Soeurt, Christina M; O'Connor, Sean J; Yoder, Karmen K; Kareken, David A

2015-03-01

Although striatal dopamine (DA) is important in alcohol abuse, the nature of DA release during actual alcohol drinking is unclear, since drinking includes self-administration of both conditioned flavor stimuli (CS) of the alcoholic beverage and subsequent intoxication, the unconditioned stimulus (US). Here, we used a novel self-administration analog to distinguish nucleus accumbens (NAcc) DA responses specific to the CS and US. Right-handed male heavy drinkers (n = 26) received three positron emission tomography (PET) scans with the D2/D3 radioligand [(11)C]raclopride (RAC) and performed a pseudo self-administration task that separately administered a flavor CS of either a habitually consumed beer or the appetitive control Gatorade®, concomitant with the US of ethanol intoxication (0.06 g/dL intravenous (IV) administration) or IV saline. Scan conditions were Gatorade flavor + saline (Gat&Sal), Gatorade flavor + ethanol (Gat&Eth), and beer flavor + ethanol (Beer&Eth). Ethanol (US) reduced RAC binding (inferring DA release) in the left (L) NAcc [Gat&Sal > Gat&Eth]. Beer flavor (CS) increased DA in the right (R) NAcc [Gat&Eth > Beer&Eth]. The combination of beer flavor and ethanol (CS + US), [Gat&Sal > Beer&Eth], induced DA release in bilateral NAcc. Self-reported intoxication during scanning correlated with L NAcc DA release. Relative to saline, infusion of ethanol increased alcoholic drink wanting. Our findings suggest lateralized DA function in the NAcc, with L NAcc DA release most reflecting intoxication, R NAcc DA release most reflecting the flavor CS, and the conjoint CS + US producing a bilateral NAcc response.

Striatal dopamine release and genetic variation of the serotonin 2C receptor in humans.

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Mickey, Brian J; Sanford, Benjamin J; Love, Tiffany M; Shen, Pei-Hong; Hodgkinson, Colin A; Stohler, Christian S; Goldman, David; Zubieta, Jon-Kar

2012-07-04

Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT(2C)) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT(2C) receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT(2C) receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D(2)/D(3) receptor radiotracer [(11)C]raclopride. Binding potential (BP(ND)) was quantified before and after a standardized stress challenge consisting of 20 min of moderate deep muscular pain, and reduction in BP(ND) served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BP(ND). These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.

Elevated Striatal Dopamine Function in Immigrants and Their Children: A Risk Mechanism for Psychosis.

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Egerton, Alice; Howes, Oliver D; Houle, Sylvain; McKenzie, Kwame; Valmaggia, Lucia R; Bagby, Michael R; Tseng, Huai-Hsuan; Bloomfield, Michael A P; Kenk, Miran; Bhattacharyya, Sagnik; Suridjan, Ivonne; Chaddock, Chistopher A; Winton-Brown, Toby T; Allen, Paul; Rusjan, Pablo; Remington, Gary; Meyer-Lindenberg, Andreas; McGuire, Philip K; Mizrahi, Romina

2017-03-01

Migration is a major risk factor for schizophrenia but the neurochemical processes involved are unknown. One candidate mechanism is through elevations in striatal dopamine synthesis and release. The objective of this research was to determine whether striatal dopamine function is elevated in immigrants compared to nonimmigrants and the relationship with psychosis. Two complementary case-control studies of in vivo dopamine function (stress-induced dopamine release and dopamine synthesis capacity) in immigrants compared to nonimmigrants were performed in Canada and the United Kingdom. The Canadian dopamine release study included 25 immigrant and 31 nonmigrant Canadians. These groups included 23 clinical high risk (CHR) subjects, 9 antipsychotic naïve patients with schizophrenia, and 24 healthy volunteers. The UK dopamine synthesis study included 32 immigrants and 44 nonimmigrant British. These groups included 50 CHR subjects and 26 healthy volunteers. Both striatal stress-induced dopamine release and dopamine synthesis capacity were significantly elevated in immigrants compared to nonimmigrants, independent of clinical status. These data provide the first evidence that the effect of migration on the risk of developing psychosis may be mediated by an elevation in brain dopamine function. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

Effects of zoxazolamine and related centrally acting muscle relaxants on nigrostriatal dopaminergic neurons.

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Matthews, R T; McMillen, B A; Speciale, S G; Jarrah, H; Shore, P A; Sanghera, M K; Shepard, P D; German, D C

1984-05-01

The effects of zoxazolamine (ZOX) and related centrally acting muscle relaxants on striatal dopamine (DA) metabolism and turnover, and substantia nigra zona compacta DA neuronal impulse flow were studied in rats. ZOX, chlorzoxazone and mephenesin, but not meprobamate, chloral hydrate, diazepam, pentobarbital, ethanol or dantrolene, decreased striatal DA metabolism without affecting striatal DA concentrations. More specifically, ZOX, as a representative muscle relaxant, was shown to decrease striatal DA turnover without directly affecting DA synthesis, catabolism, reuptake, or release. ZOX decreased nigral DA neuronal firing rates and dramatically decreased firing rate variability (normally many of the cells fire with bursting firing patterns but after ZOX the cells often fired with a very regular pacemaker-like firing pattern). ZOX and related centrally acting muscle relaxants appear to decrease striatal DA turnover by decreasing both neuronal firing rate and firing rate variability. The possible relationships between DA neuronal activity and muscle tone are discussed.

Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.

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Woodward, Neil D; Cowan, Ronald L; Park, Sohee; Ansari, M Sib; Baldwin, Ronald M; Li, Rui; Doop, Mikisha; Kessler, Robert M; Zald, David H

2011-04-01

Schizotypal personality traits are associated with schizophrenia spectrum disorders, and individuals with schizophrenia spectrum disorders demonstrate increased dopamine transmission in the striatum. The authors sought to determine whether individual differences in normal variation in schizotypal traits are correlated with dopamine transmission in the striatum and in extrastriatal brain regions. Sixty-three healthy volunteers with no history of psychiatric illness completed the Schizotypal Personality Questionnaire and underwent positron emission tomography imaging with [(18)F]fallypride at baseline and after administration of oral d-amphetamine (0.43 mg/kg). Dopamine release, quantified by subtracting each participant's d-amphetamine scan from his or her baseline scan, was correlated with Schizotypal Personality Questionnaire total and factor scores using region-of-interest and voxel-wise analyses. Dopamine release in the striatum was positively correlated with overall schizotypal traits. The association was especially robust in the associative subdivision of the striatum. Voxel-wise analyses identified additional correlations between dopamine release and schizotypal traits in the left middle frontal gyrus and left supramarginal gyrus. Exploratory analyses of Schizotypal Personality Questionnaire factor scores revealed correlations between dopamine release and disorganized schizotypal traits in the striatum, thalamus, medial prefrontal cortex, temporal lobe, insula, and inferior frontal cortex. The association between dopamine signaling and psychosis phenotypes extends to individual differences in normal variation in schizotypal traits and involves dopamine transmission in both striatal and extrastriatal brain regions. Amphetamine-induced dopamine release may be a useful endophenotype for investigating the genetic basis of schizophrenia spectrum disorders.

Cocaine modulates allosteric D2-σ1 receptor-receptor interactions on dopamine and glutamate nerve terminals from rat striatum.

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Beggiato, Sarah; Borelli, Andrea Celeste; Borroto-Escuela, Dasiel; Corbucci, Ilaria; Tomasini, Maria Cristina; Marti, Matteo; Antonelli, Tiziana; Tanganelli, Sergio; Fuxe, Kjell; Ferraro, Luca

2017-12-01

The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D 2 -σ 1 heteroreceptor complexes and their inhibitory signaling over Gi/o, have been tested in rat striatal synaptosomes and HEK293T cells. Furthermore, the possible role of σ 1 receptors (σ 1 Rs) in the cocaine-provoked amplification of D 2 receptor (D 2 R)-induced reduction of K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes, has also been investigated. The dopamine D 2 -likeR agonist quinpirole (10nM-1μM), concentration-dependently reduced K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes. The σ 1 R antagonist BD1063 (100nM), amplified the effects of quinpirole (10 and 100nM) on K + -evoked [ 3 H]-DA, but not glutamate, release. Nanomolar cocaine concentrations significantly enhanced the quinpirole (100nM)-induced decrease of K + -evoked [ 3 H]-DA and glutamate release from rat striatal synaptosomes. In the presence of BD1063 (10nM), cocaine failed to amplify the quinpirole (100nM)-induced effects. In cotransfected σ 1 R and D 2L R HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D 2L R singly transfected cells. In the presence of cocaine (100nM), the potency of quinpirole to inhibit the CREB signal was restored. In D 2L singly transfected cells cocaine (100nM and 10μM) exerted no modulatory effects on the inhibitory potency of quinpirole to bring down the CREB signal. These results led us to hypothesize the existence of functional D 2 -σ 1 R complexes on the rat striatal DA and glutamate nerve terminals and functional D 2 -σ 1 R-DA transporter complexes on the striatal DA terminals. Nanomolar cocaine concentrations appear to alter the allosteric receptor-receptor interactions in such complexes leading to enhancement of Gi/o mediated D 2 R signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

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Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

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Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

2010-06-01

Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

Striatal and extra-striatal dopamine transporter in cannabis and tobacco addiction: a high resolution PET study

International Nuclear Information System (INIS)

Leroy, C.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Ribeiro, M.J.; Trichard, Ch.; Karila, L.; Lukasiewicz, M.; Benyamina, A.; Reynaud, M.; Martinot, J.L.; Duchesnay, E.; Artiges, E.; Comtat, C.; Artiges, E.; Trichard, Ch.

2011-01-01

The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extra-striatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 ± 5.3 cigarettes/day for 12.1 ± 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 ± 5.3 cannabis joints/day for 8.7 ± 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [ 11 C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects. (authors)

Serotonin 2A receptor regulation of striatal neuropeptide gene expression is selective for tachykinin, but not enkephalin neurons following dopamine depletion.

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Basura, G J; Walker, P D

2001-08-15

Serotonin (5-HT) 2A receptor-mediated regulation of striatal preprotachykinin (PPT) and preproenkephalin (PPE) mRNAs was studied in adult rodents that had been subjected to near-total dopamine (DA) depletion as neonates. Two months following bilateral 6-hydroxydopamine (6-OHDA) lesion, PPT mRNA levels decreased 59-73% across dorsal subregions of the rostral and caudal striatum while PPE transcripts increased 61-94%. Four hours after a single injection of the serotonin 2A/2C receptor agonist, (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 1 mg/kg), PPT mRNA expression was significantly increased in DA-depleted rats across all dorsal subregions of the rostral and caudal striatum as compared to 6-OHDA-treated animals alone. In the intact rat, DOI did not influence PPT mRNA levels in the rostral striatum, but did raise expression in the caudal striatum where 5-HT2A receptors are prominent. DOI did not regulate PPE mRNA levels in any striatal sub-region of the intact or DA-depleted rat. Prior administration of the 5-HT2A/2C receptor antagonist, ritanserin (1 mg/kg) or the 5-HT2A receptor antagonist, ketanserin (1 mg/kg) completely blocked the DOI-induced increases in striatal PPT mRNA in both lesioned and intact animals. The ability of ketanserin to produce identical results as ritanserin suggests that 5-HT2A receptor-mediated regulation is selectively strengthened within tachykinin neurons of the rostral striatum which are suppressed by DA depletion. The selectivity suggests that 5-HT2A receptor upregulation following DA depletion is capable of regulating tachykinin biosynthesis without influencing enkephalin expression in striatal output neurons.

[Effects of acupuncture stimulation of different acupoint groups on sleeping duration and serum and striatal dopamine contents in rats with gastric mucosal injury].

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Yang, Ping; Peng, Lei; Li, Jie-Ting; Ma, Hui-Fang

2014-02-01

To observe the effect of acupuncture intervention on gastric ulcer (GU) and sleeping quality from the viewpoint of brain-gut axis which plays an important role in the regulation of many vital functions in health and disease. Forty male Wistar rats were randomized into normal control, GU model, acupuncture of "Zhongwan" (CV 12)-"Zusanli" (ST 36, gastric treatment acupoints), acupuncture of "Shenmai" (BL 62)-"Zhaohai" (KI 6, sleep-promotion acupoints), and acupuncture of CV 12-ST 36-BL 62-KI 6 (combined treatment) groups, with 8 rats in each group. GU model was established by intragastric perfusion of dehydrated alcohol (1 mL/rat), and sleep model established by intraperitoneal injection of pentobarbital sodium (40 mg/kg) after the last treatment. The abovementioned acupoints were punctured with filiform needles and stimulated by manipulating the needle for about 30 s, once every 5 mm during 20 mm of needle retention. The treatment was conducted once daily for five days. Gastric mucosal lesion index was assessed by Guth's method, and the mucosal pathological changes were observed under microscope after H. E. staining. The contents of dopamine (DA) in the serum and striatal tissues were detected by ELISA kit. Compared with the normal control group, the rats' sleeping duration, and serum DA content were markedly decreased and the gastric mucosal lesion index, and the striatal DA content remarkably increased in the model group (P sleeping duration, and serum DA content were significantly increased, and the gastric mucosal lesion index, and the striatal DA content remarkably down-regulated in the CV 12-ST 36 (gastric treatment acupoints), BL 62-KI 6 (sleep-promotion acupoints) and CV 12-ST 36-BL 62-KI 6 (combined treatment) groups (P sleep promotion acupoints group in reducing mucosal lesion index and in increasing serum DA level (P sleeping duration in gastric lesion rats, which may be related to its effects in increasing blood DA and lowering striatal DA level

Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

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Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

1985-09-16

The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

Epothilone D prevents binge methamphetamine-mediated loss of striatal dopaminergic markers.

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Killinger, Bryan A; Moszczynska, Anna

2016-02-01

Exposure to binge methamphetamine (METH) can result in a permanent or transient loss of dopaminergic (DAergic) markers such as dopamine (DA), dopamine transporter, and tyrosine hydroxylase (TH) in the striatum. We hypothesized that the METH-induced loss of striatal DAergic markers was, in part, due to a destabilization of microtubules (MTs) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague-Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT-stabilizing compound, and assessed 3 days after the treatments for the levels of several DAergic markers as well as for the levels of tubulins and their post-translational modifications (PMTs). Binge METH induced a loss of stable long-lived MTs within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MTs and prevented METH-mediated deficits in several DAergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MTs and potentiated the METH-induced deficits in several DAergic markers. The low-dose EpoD also prevented the METH-induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH-induced losses of several DAergic markers in the striatum and may mediate METH-induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT-stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DAergic nerve terminals following METH exposure when administered at low doses. Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include

In vitro labelled neurotransmitters release for the study of neuro toxins

International Nuclear Information System (INIS)

Camillo, Maria A.P.; Rogero, Jose R.; Troncone, Lanfranco R.P.

1995-01-01

There is an increasing concern in the replacement of in vivo by in vitro methods in Pharmacology. Looking for a method which involves the most of the physiological aspects related to neural functions, a super fusion system designed to evaluate in vitro neurotransmitter release from brain striatal tissue is here described. The method is based on the basal and stimulated release of pre-loaded tritium-labelled neurotransmitters. This procedure bears an active uptake/release function which is fairly changed by membrane polarisation state, ion channel activation and enzymatic activity, as well as other still unknown steps involved in neurotransmission. Calcium dependency of dopamine and acetylcholine release induced by high potassium depolarization or glutamate (Glu) stimulation was demonstrated employing calcium-free (+EGTA) super fusion or lanthanum/cadmium addition. Glutamate stimulation involved NMDA receptors since magnesium or MK801 blocks stimulated release. Uptake of DA and Ach was evidenced by using bupropione or hemicolinium-3. presynaptic inhibition of Ach release was evidenced by physostigmine-induced inhibitions of acetylcholinesterase. (author). 3 refs., 6 figs

Levodopa effects on [11C]raclopride binding in the resting human brain [v1; ref status: indexed, http://f1000r.es/4oe

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Kevin J. Black

2015-01-01

Full Text Available Rationale: Synaptic dopamine (DA release induced by amphetamine or other experimental manipulations can displace [11C]raclopride (RAC* from dopamine D2-like receptors. We hypothesized that exogenous levodopa might increase dopamine release at striatal synapses under some conditions but not others, allowing a more naturalistic assessment of presynaptic dopaminergic function. Presynaptic dopaminergic abnormalities have been reported in Tourette syndrome (TS. Objective: Test whether levodopa induces measurable synaptic DA release in healthy people at rest, and gather pilot data in TS. Methods: This double-blind crossover study used RAC* and positron emission tomography (PET to measure synaptic dopamine release 4 times in each of 10 carbidopa-pretreated, neuroleptic-naïve adults: before and during an infusion of levodopa on one day and placebo on another (in random order. Five subjects had TS and 5 were matched controls. RAC* binding potential (BPND was quantified in predefined anatomical volumes of interest (VOIs. A separate analysis compared BPND voxel by voxel over the entire brain. Results: DA release declined between the first and second scan of each day (p=0.012, including on the placebo day. Levodopa did not significantly reduce striatal RAC* binding and striatal binding did not differ significantly between TS and control groups. However, levodopa’s effect on DA release differed significantly in a right midbrain region (p=0.002, corrected, where levodopa displaced RAC* by 59% in control subjects but increased BPND by 74% in TS subjects. Discussion: Decreased DA release on the second scan of the day is consistent with the few previous studies with a similar design, and may indicate habituation to study procedures. We hypothesize that mesostriatal DA neurons fire relatively little while subjects rest, possibly explaining the non-significant effect of levodopa on striatal RAC* binding. The modest sample size argues for caution in interpreting

The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

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Walters, Jennifer L., E-mail: Jennifer.l.walters@wmich.edu [Western Michigan University, Department of Psychology, 1903 W Michigan Ave, Kalamazoo, MI 49008-5439 (United States); Lansdell, Theresa A., E-mail: lansdel1@msu.edu [Michigan State University, Department of Pharmacology and Toxicology, 1355 Bogue Street, East Lansing, MI 48824 (United States); Lookingland, Keith J., E-mail: lookingl@msu.edu [Michigan State University, Department of Pharmacology and Toxicology, 1355 Bogue Street, East Lansing, MI 48824 (United States); Baker, Lisa E., E-mail: lisa.baker@wmich.edu [Western Michigan University, Department of Psychology, 1903 W Michigan Ave, Kalamazoo, MI 49008-5439 (United States)

2015-12-01

This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. - Highlights: • Male rats received gestational and chronic exposure to ATZ (10 mg/kg and 100 μg/kg). • ATZ altered locomotor activity and impaired motor coordination. • ATZ lowered striatal DA and DOPAC concentrations. • ATZ produced a potential anxiogenic effect. • ATZ did not impair performance in learning and memory assessments.

The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

International Nuclear Information System (INIS)

Walters, Jennifer L.; Lansdell, Theresa A.; Lookingland, Keith J.; Baker, Lisa E.

2015-01-01

This study sought to investigate the effects of environmentally relevant gestational followed by continued chronic exposure to the herbicide, atrazine, on motor function, cognition, and neurochemical indices of nigrostriatal dopamine (DA) activity in male rats. Dams were treated with 100 μg/kg atrazine, 10 mg/kg atrazine, or vehicle on gestational day 1 through postnatal day 21. Upon weaning, male offspring continued daily vehicle or atrazine gavage treatments for an additional six months. Subjects were tested in a series of behavioral assays, and 24 h after the last treatment, tissue samples from the striatum were analyzed for DA and 3,4-dihydroxyphenylacetic acid (DOPAC). At 10 mg/kg, this herbicide was found to produce modest disruptions in motor functioning, and at both dose levels it significantly lowered striatal DA and DOPAC concentrations. These results suggest that exposures to atrazine have the potential to disrupt nigrostriatal DA neurons and behaviors associated with motor functioning. - Highlights: • Male rats received gestational and chronic exposure to ATZ (10 mg/kg and 100 μg/kg). • ATZ altered locomotor activity and impaired motor coordination. • ATZ lowered striatal DA and DOPAC concentrations. • ATZ produced a potential anxiogenic effect. • ATZ did not impair performance in learning and memory assessments.

The role of presynaptic receptors in the release and synthesis of 3H-dopamine by slices of rat striatum

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Westfall, T.C.; Besson, M.J.; Giorguieff, M.F.; Glowinski, J.

1976-01-01

Striatal slices were continuously superfused with L-3,5- 3 H-Tyrosine(50μCi/ml) and 3 H-H 2 O [index of 3 H-dopamine ( 3 H-DA) synthesis] and 3 H-DA estimated in 0.5 ml (2.5min) superfusate fractions. Depolarization with 50 mM k + for 7.5 min induced a marked increase in 3 H-DA release and a biphasic effect on synthesis. The decrease in the rate of 3 H-H 2 O formation induced by K + was not related to modifications of the specific activity of tyrosine in tissues. The possibility that the inhibition of synthesis was due to alterations in DA concentration in the synaptic cleft was examined. On the other hand, when the powerful neuroleptic fluphenazine was added to the superfusion medium in a concentration which only weakly blocked 3 H-DA uptake (10 -6 M) it potentiated 3 H-DA release and prevented the inhibition of synthesis both in the absence or presence of benztropine. The DA inhibitory effect on synthesis was still observed in the presence of benztropine (10 -6 M) while the NA effect was prevented. This concentration of benztropine blocked both DA and NA uptake. The administration of fluphenazine (10 -6 M) significantly prevented the decrease in 3 H-DA synthesis induced by exogenous DA and partially prevented the effect of NA. The present results provide direct support for the concept that activation of presynaptic DA receptors located on DA terminals in the striatum of the rat results in an inhibition of synthesis and release of the transmitter. (orig.) [de

Prolactin releasing effect of sulpiride isomers in rats and man

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Mueller, E E; Stefanini, E; Spano, P F [Cagliari Univ. (Italy). Inst. of Pharmacology and Pharmacognosy; Camanni, F; Massara, F [Turin Univ. (Italy). Chair of Endocrinology; Locatelli, V; Cocchi, D

1979-01-01

Sulpiride, an antipsychotropic drug of the benzamide class, reportedly displaces stereospecifically (/sup 3/H)-butyrophenones from putative dopamine (DA) binding sites in rat striatum. To evaluate if sulpiride displays the same stereospecifity in the inhibition of pituitary DA receptors, the effect of the two(-)-and (+)-sulpiride isomers was tested with regard to their ability to stimulate prolactin (PRL) secretion in rats and man and to displace (/sup 3/H)-spiroperidol bound to rat anterior pituitary receptors. In male rats, (-)-sulpiride at doses of 0.1 and 0.1 mg/kg i.p., induced a maximum PRL-releasing effect, not different from that evoked by a dose of 10 mg/kg of the compound. (+)-Sulpiride was active only at the dose of 10mg/kg i.p., and its PRL-releasing effect was superimposable to that evoked by the same dose of (-)-sulpiride. Similarily, in 8 normal subjects (4 men and 4 women) only (-)-sulpiride was active as PRL releaser when the low dose of 0.25 mg i.v. was used; when the higher dose of sulpiride was used (4.0 mg i.v.), it induced a rise in plasma PRL of the same entity for both isomers at early post-injection times (15-30 min) but greater with the (-)-isomer at the following time intervals (45-120 min). (-)-Sulpiride displaced (/sup 3/H)-spiroperidol bound to rat anterior pituitary homogenates with a potency about 100 times greater as that showed by (+)-sulpiride. In all, these data indicate that sulpiride isomers display at the level of pituitary DA receptors for PRL control the same stereospecifity exhibited on a population of striatal DA receptors.

Disease-toxicant interactions in manganese exposed Huntington disease mice: early changes in striatal neuron morphology and dopamine metabolism.

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Jennifer L Madison

Full Text Available YAC128 Huntington's disease (HD transgenic mice accumulate less manganese (Mn in the striatum relative to wild-type (WT littermates. We hypothesized that Mn and mutant Huntingtin (HTT would exhibit gene-environment interactions at the level of neurochemistry and neuronal morphology. Twelve-week-old WT and YAC128 mice were exposed to MnCl(2-4H(2O (50 mg/kg on days 0, 3 and 6. Striatal medium spiny neuron (MSN morphology, as well as levels of dopamine (DA and its metabolites (which are known to be sensitive to Mn-exposure, were analyzed at 13 weeks (7 days from initial exposure and 16 weeks (28 days from initial exposure. No genotype-dependent differences in MSN morphology were apparent at 13 weeks. But at 16 weeks, a genotype effect was observed in YAC128 mice, manifested by an absence of the wild-type age-dependent increase in dendritic length and branching complexity. In addition, genotype-exposure interaction effects were observed for dendritic complexity measures as a function of distance from the soma, where only YAC128 mice were sensitive to Mn exposure. Furthermore, striatal DA levels were unaltered at 13 weeks by genotype or Mn exposure, but at 16 weeks, both Mn exposure and the HD genotype were associated with quantitatively similar reductions in DA and its metabolites. Interestingly, Mn exposure of YAC128 mice did not further decrease DA or its metabolites versus YAC128 vehicle exposed or Mn exposed WT mice. Taken together, these results demonstrate Mn-HD disease-toxicant interactions at the onset of striatal dendritic neuropathology in YAC128 mice. Our results identify the earliest pathological change in striatum of YAC128 mice as being between 13 to 16 weeks. Finally, we show that mutant HTT suppresses some Mn-dependent changes, such as decreased DA levels, while it exacerbates others, such as dendritic pathology.

Role of presynaptic receptors in the release and synthesis of /sup 3/H-dopamine by slices of rat striatum

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Westfall, T C; Besson, M J; Giorguieff, M F; Glowinski, J [Institut National de la Sante et de la Recherche Medicale (INSERM), 75 - Paris (France). Groupe de Neuropharmacologie Biochimique

1976-01-01

Striatal slices were continuously superfused with L-3,5-/sup 3/H-Tyrosine(50..mu..Ci/ml) and /sup 3/H-H/sub 2/O (index of /sup 3/H-dopamine (/sup 3/H-DA) synthesis) and /sup 3/H-DA estimated in 0.5 ml (2.5min) superfusate fractions. Depolarization with 50 mM k/sup +/ for 7.5 min induced a marked increase in /sup 3/H-DA release and a biphasic effect on synthesis. The decrease in the rate of /sup 3/H-H/sub 2/O formation induced by K/sup +/ was not related to modifications of the specific activity of tyrosine in tissues. The possibility that the inhibition of synthesis was due to alterations in DA concentration in the synaptic cleft was examined. On the other hand, when the powerful neuroleptic fluphenazine was added to the superfusion medium in a concentration which only weakly blocked /sup 3/H-DA uptake (10/sup -6/M) it potentiated /sup 3/H-DA release and prevented the inhibition of synthesis both in the absence or presence of benztropine. The DA inhibitory effect on synthesis was still observed in the presence of benztropine (10/sup -6/M) while the NA effect was prevented. This concentration of benztropine blocked both DA and NA uptake. The administration of fluphenazine (10/sup -6/M) significantly prevented the decrease in /sup 3/H-DA synthesis induced by exogenous DA and partially prevented the effect of NA. The present results provide direct support for the concept that activation of presynaptic DA receptors located on DA terminals in the striatum of the rat results in an inhibition of synthesis and release of the transmitter.

Positron emission tomography (PET) imaging of nicotine-induced dopamine release in squirrel monkeys using [18F]Fallypride.

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Naylor, Jennifer E; Hiranita, Takato; Matazel, Katelin S; Zhang, Xuan; Paule, Merle G; Goodwin, Amy K

2017-10-01

Nicotine, the principal psychoactive tobacco constituent, is thought to produce its reinforcing effects via actions within the mesolimbic dopamine (DA) system. The objective of the current study was to examine the effect of nicotine on DA D 2 /D 3 receptor availability in the nonhuman primate brain with the use of the radioligand [ 18 F]fallypride and positron emission tomography (PET). Ten adult male squirrel monkeys were used in the current study. Each subject underwent two PET scans, one with an injection (IV) of saline and subsequently one with an injection of nicotine (0.032mg/kg). The DA D 2 /D 3 antagonist, [ 18 F]fallypride, was delivered IV at the beginning of each scan, and nicotine or saline was delivered at 45min into the scan. Regions of interest (ROI) were drawn on specific brain regions and these were used to quantify standard uptake values (SUVs). The SUV is defined as the average concentration of radioactivity in the ROI x body weight/injected dose. Using the cerebellum as a reference region, SUV ratios (SUV ROI /SUV cerebellum ) were calculated to compare saline and nicotine effects in each ROI. Two-way repeated ANOVA revealed a significant decrease of SUV ratios in both striatal and extrastriatal regions following an injection of nicotine during the PET scans. Like other drugs of abuse, these results indicate that nicotine administration may produce DA release, as suggested by the decrease in [ 18 F]fallypride signal in striatal regions. These findings from a nonhuman primate model provide further evidence that the mesolimbic DA system is affected by the use of products that contain nicotine. Published by Elsevier B.V.

Extrasynaptic neurotransmission in the modulation of brain function. Focus on the striatal neuronal-glial networks

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Kjell eFuxe

2012-06-01

Full Text Available Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT and histamine striatal afferents, the cholinergic interneurons and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal

Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

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Asensio, S.; Goldstein, R.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F.; Volkow, N.D.; Goldstein, R.Z.

2010-01-01

Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with ( 11 C)raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

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Asensio, S.; Goldstein, R.; Asensio, S.; Romero, M.J.; Romero, F.J.; Wong, C.T.; Alia-Klein, N.; Tomasi, D.; Wang, G.-J.; Telang, F..; Volkow, N.D.; Goldstein, R.Z.

2010-05-01

Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [{sup 11}C]raclopride and positron emission tomography and response to monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.

Single versus multiple impulse control disorders in Parkinson's disease: an ¹¹C-raclopride positron emission tomography study of reward cue-evoked striatal dopamine release.

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Wu, Kit; Politis, Marios; O'Sullivan, Sean S; Lawrence, Andrew D; Warsi, Sarah; Bose, Subrata; Lees, Andrew J; Piccini, Paola

2015-06-01

Impulse control disorders (ICDs) are reported in Parkinson's disease (PD) in association with dopaminergic treatment. Approximately 25 % of patients with ICDs have multiple co-occurring ICDs (i.e. more than one diagnosed ICD). The extent to which dopaminergic neurotransmission in PD patients with multiple ICDs differs from those with only one diagnosed ICD is unknown. The aims of this study are: (1) to investigate dopamine neurotransmission in PD patients diagnosed with multiple ICDs, single ICDs and non-ICD controls in response to reward-related visual cues using positron emission tomography with (11)C-raclopride. (2) to compare clinical features of the above three groups. PD individuals with mulitple ICDs (n = 10), single ICD (n = 7) and no ICDs (n = 9) were recruited and underwent two positron emission tomography (PET) scans with (11)C-raclopride: one where they viewed neutral visual cues and the other where they viewed a range of visual cues related to different rewards. Individuals with both multiple ICDs and single ICDs showed significantly greater ventral striatal dopamine release compared to non-ICD PD individuals in response to reward cues, but the two ICD groups did not differ from each other in the extent of dopamine release. Subjects with multiple ICDs were, however, significantly more depressed, and had higher levels of impulsive sensation-seeking compared to subjects with single ICDs and without ICDs. This is the first study to compare dopamine neurotransmission using PET neuroimaging in PD subjects with multiple vs. single ICDs. Our results suggest that striatal dopamine neurotransmission is not directly related to the co-occurrence of ICDs in PD, potentially implicating non-dopaminergic mechanisms linked to depression; and suggest that physicians should be vigilant in managing depression in PD patients with ICDs.

Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours.

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O'Sullivan, Sean S; Wu, Kit; Politis, Marios; Lawrence, Andrew D; Evans, Andrew H; Bose, Subrata K; Djamshidian, Atbin; Lees, Andrew J; Piccini, Paola

2011-04-01

Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P = 0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive

A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

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Alexander Kurz

2010-07-01

Full Text Available Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice.Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

Independent mediation of unconditioned motor behavior by striatal D1 and D2 receptors in rats depleted of dopamine as neonates.

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Bruno, J P; Byrnes, E M; Johnson, B J

1995-11-01

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at the level of striatal DA terminals and their targets. The ability of bilateral intrastriatal injections (0.5 microliter) of DA receptor antagonists to induce motoric deficits was determined in adult rats treated with vehicle or 6-OHDA (100 micrograms, intraventricular) on postnatal day 3. Administration of the D1-like antagonist SCH 23390 (0.5-2.0 micrograms) or the D2-like antagonist clebopride (1.0-4.0 micrograms) induced dose-dependent akinesia, catalepsy, and somatosensory neglect in vehicle-treated controls. In contrast, neither antagonist produced deficits in rats depleted of forebrain DA as neonates. However, combined administration of SCH 23390 + clebopride induced similar akinesia, catalepsy, and somatosensory neglect in both controls and DA depleted animals. Animals depleted of DA were more sensitive than controls to the low doses of this combined D1 + D2 antagonism. These results demonstrate that activation of striatal DA receptors remains necessary for unconditioned motor behavior in rats depleted of DA as neonates. However, the specific contributions of D1- and D2-like receptors to these behaviors differ between intact animals and those depleted of DA as neonates. The ability of endogenous DA acting at either D1 or D2 receptors to support spontaneous motor behavior in rats depleted of DA as neonates may contribute to their relative sparing from parkinsonian deficits.

Parsing Heterogeneous Striatal Activity

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Kae Nakamura

2017-05-01

Full Text Available The striatum is an input channel of the basal ganglia and is well known to be involved in reward-based decision making and learning. At the macroscopic level, the striatum has been postulated to contain parallel functional modules, each of which includes neurons that perform similar computations to support selection of appropriate actions for different task contexts. At the single-neuron level, however, recent studies in monkeys and rodents have revealed heterogeneity in neuronal activity even within restricted modules of the striatum. Looking for generality in the complex striatal activity patterns, here we briefly survey several types of striatal activity, focusing on their usefulness for mediating behaviors. In particular, we focus on two types of behavioral tasks: reward-based tasks that use salient sensory cues and manipulate outcomes associated with the cues; and perceptual decision tasks that manipulate the quality of noisy sensory cues and associate all correct decisions with the same outcome. Guided by previous insights on the modular organization and general selection-related functions of the basal ganglia, we relate striatal activity patterns on these tasks to two types of computations: implementation of selection and evaluation. We suggest that a parsing with the selection/evaluation categories encourages a focus on the functional commonalities revealed by studies with different animal models and behavioral tasks, instead of a focus on aspects of striatal activity that may be specific to a particular task setting. We then highlight several questions in the selection-evaluation framework for future explorations.

Fronto-striatal atrophy in behavioural variant frontotemporal dementia & Alzheimer’s disease

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Maxime eBertoux

2015-07-01

Full Text Available Behavioural variant frontotemporal dementia (bvFTD has only recently been associated with significant striatal atrophy, whereas the striatum appears to be relatively preserved in Alzheimer’s disease (AD. Considering the critical role the striatum has in cognition and behaviour, striatal degeneration, together with frontal atrophy, could be responsible of some characteristic symptoms in bvFTD and emerges therefore as promising novel diagnostic biomarker to distinguish bvFTD and AD. Previous studies have, however, only taken either cortical or striatal atrophy into account when comparing the two diseases. In this study, we establish for the first time a profile of fronto-striatal atrophy in 23 bvFTD and 29 AD patients at presentation, based on the structural connectivity of striatal and cortical regions. Patients are compared to 50 healthy controls by using a novel probabilistic connectivity atlas, which defines striatal regions by their cortical white matter connectivity, allowing us to explore the degeneration of the frontal and striatal regions that are functionally linked. Comparisons with controls revealed that bvFTD showed substantial fronto-striatal atrophy affecting the ventral as well as anterior and posterior dorso-lateral prefrontal cortices and the related striatal subregions. By contrast, AD showed few fronto-striatal atrophy, despite having significant posterior dorso-lateral prefrontal degeneration. Direct comparison between bvFTD and AD revealed significantly more atrophy in the ventral striatal-ventromedial prefrontal cortex regions in bvFTD. Consequently, deficits in ventral fronto-striatal regions emerge as promising novel and efficient diagnosis biomarker for bvFTD. Future investigations into the contributions of these fronto-striatal loops on bvFTD symptomology are needed to develop simple diagnostic and disease tracking algorithms.

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

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Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

2011-02-14

Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine.

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Kharkwal, Geetika; Radl, Daniela; Lewis, Robert; Borrelli, Emiliana

2016-10-11

The psychomotor effects of cocaine are mediated by dopamine (DA) through stimulation of striatal circuits. Gabaergic striatal medium spiny neurons (MSNs) are the only output of this pivotal structure in the control of movements. The majority of MSNs express either the DA D1 or D2 receptors (D1R, D2R). Studies have shown that the motor effect of cocaine depends on the DA-mediated stimulation of D1R-expressing MSNs (dMSNs), which is mirrored at the cellular level by stimulation of signaling pathways leading to phosphorylation of ERKs and induction of c-fos Nevertheless, activation of dMSNs by cocaine is necessary but not sufficient, and D2R signaling is required for the behavioral and cellular effects of cocaine. Indeed, cocaine motor effects and activation of signaling in dMSNs are blunted in mice with the constitutive knockout of D2R (D2RKO). Using mouse lines with a cell-specific knockout of D2R either in MSNs (MSN-D2RKO) or in dopaminergic neurons (DA-D2RKO), we show that D2R signaling in MSNs is required and permissive for the motor stimulant effects of cocaine and the activation of signaling in dMSNs. MSN-D2RKO mice show the same phenotype as constitutive D2RKO mice both at the behavioral and cellular levels. Importantly, activation of signaling in dMSNs by cocaine is rescued by intrastriatal injection of the GABA antagonist, bicuculline. These results are in support of intrastriatal connections of D2R + -MSNs (iMSNs) with dMSNs and indicate that D2R signaling in MSNs is critical for the function of intrastriatal circuits.

Decreased dopamine activity predicts relapse in methamphetamine abusers

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Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

2011-01-20

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Decreased dopamine activity predicts relapse in methamphetamine abusers

International Nuclear Information System (INIS)

Wang, G.J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

2011-01-01

Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and ( 11 C)raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Distinctive Modulation of Dopamine Release in the Nucleus Accumbens Shell Mediated by Dopamine and Acetylcholine Receptors.

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Shin, Jung Hoon; Adrover, Martin F; Alvarez, Veronica A

2017-11-15

Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals in vivo and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, in vitro fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals in vivo SIGNIFICANCE STATEMENT The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is

Membrane properties of striatal direct and indirect pathway neurons in mouse and rat slices and their modulation by dopamine.

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Henrike Planert

Full Text Available D1 and D2 receptor expressing striatal medium spiny neurons (MSNs are ascribed to striatonigral ("direct" and striatopallidal ("indirect" pathways, respectively, that are believed to function antagonistically in motor control. Glutamatergic synaptic transmission onto the two types is differentially affected by Dopamine (DA, however, less is known about the effects on MSN intrinsic electrical properties. Using patch clamp recordings, we comprehensively characterized the two pathways in rats and mice, and investigated their DA modulation. We identified the direct pathway by retrograde labeling in rats, and in mice we used transgenic animals in which EGFP is expressed in D1 MSNs. MSNs were subjected to a series of current injections to pinpoint differences between the populations, and in mice also following bath application of DA. In both animal models, most electrical properties were similar, however, membrane excitability as measured by step and ramp current injections consistently differed, with direct pathway MSNs being less excitable than their counterparts. DA had opposite effects on excitability of D1 and D2 MSNs, counteracting the initial differences. Pronounced changes in AP shape were seen in D2 MSNs. In direct pathway MSNs, excitability increased across experimental conditions and parameters, and also when applying DA or the D1 agonist SKF-81297 in presence of blockers of cholinergic, GABAergic, and glutamatergic receptors. Thus, DA induced changes in excitability were D1 R mediated and intrinsic to direct pathway MSNs, and not a secondary network effect of altered synaptic transmission. DAergic modulation of intrinsic properties therefore acts in a synergistic manner with previously reported effects of DA on afferent synaptic transmission and dendritic processing, supporting the antagonistic model for direct vs. indirect striatal pathway function.

Global actions of nicotine on the striatal microcircuit.

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Plata, Víctor; Duhne, Mariana; Pérez-Ortega, Jesús; Hernández-Martinez, Ricardo; Rueda-Orozco, Pavel; Galarraga, Elvira; Drucker-Colín, René; Bargas, José

2013-01-01

what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.

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Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-11-01

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. Copyright © 2011 Wiley-Liss, Inc.

Protection but maintained dysfunction of nigral dopaminergic nerve cell bodies and striatal dopaminergic terminals in MPTP-lesioned mice after acute treatment with the mGluR5 antagonist MPEP.

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Aguirre, Jose A; Kehr, Jan; Yoshitake, Takashi; Liu, Fang-Ling; Rivera, Alicia; Fernandez-Espinola, Sergio; Andbjer, Beth; Leo, Giuseppina; Medhurst, Andrew D; Agnati, Luigi F; Fuxe, Kjell

2005-02-08

The mGluR5 antagonist MPEP was used to study the role of mGluR5 in MPTP-induced injury of the nigrostriatal DA neurons. The findings indicate that acute blockade of mGluR5 may result in neuroprotective actions against MPTP neurotoxicity on nigral DA cell bodies and striatal DA terminals using stereological analysis of TH immunoreactivity and microdensitometry. Biochemical analysis showed no restoration of DA levels and metabolism indicating a maintained reduction of DA transmission.

Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response.

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Peciña, Marta; Sikora, Magdalena; Avery, Erich T; Heffernan, Joseph; Peciña, Susana; Mickey, Brian J; Zubieta, Jon-Kar

2017-10-01

Dopamine (DA) neurotransmission within the brain's reward circuit has been implicated in the pathophysiology of depression and in both, cognitive and pharmacological mechanisms of treatment response. Still, a direct relationship between measures of DA neurotransmission and reward-related deficits in patients with depression has not been demonstrated. To gain insight into the symptom-specific alterations in the DA system in patients with depression, we used positron emission tomography (PET) and the D 2/3 receptor-selective radiotracer [ 11 C]raclopride in twenty-three non-smoking un-medicated Major Depressive Disorder (MDD) patients and sixteen healthy controls (HC). We investigated the relationship between D 2/3 receptor availability and baseline measures of depression severity, anxiety, anhedonia, and cognitive and pharmacological mechanisms of treatment response. We found that, compared to controls, patients with depression showed greater D 2/3 receptor availability in several striatal regions, including the bilateral ventral pallidum/nucleus accumbens (vPAL/NAc), and the right ventral caudate and putamen. In the depressed sample, D 2/3 receptor availability in the caudal portion of the ventral striatum (NAc/vPAL) correlated with higher anxiety symptoms, whereas D 2/3 receptor availability in the rostral area of the ventral striatum correlated negatively with the severity of motivational anhedonia. Finally, MDD non-remitters showed greater baseline anxiety, greater D 2/3 availability in the NAc/vPAL, and greater placebo-induced DA release in the bilateral NAc. Our results demonstrate abnormally high D 2/3 receptor availability in the ventral striatum of patients with MDD, which seem to be associated with comorbid anxiety symptoms and lack of response to antidepressants. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats, as determined by in vivo brain microdialysis

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Hara, Shuichi; Kurosaki, Kunihiko; Kuriiwa, Fumi; Endo, Takahiko [Department of Forensic Medicine, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402 (Japan); Mukai, Toshiji [Department of Legal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-0015 (Japan)

2002-10-01

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na{sup +} channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na{sup +}-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species

Global actions of nicotine on the striatal microcircuit

Directory of Open Access Journals (Sweden)

Victor E Plata

2013-11-01

Full Text Available The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA, the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

Interaction of structural analogs of dopamine, chlorpromazine and sulpiride with striatal dopamine receptors

International Nuclear Information System (INIS)

Wallace, R.A.

1987-01-01

The objectives of these studies were to determine if the nitrogen atom of dopaminergic agonists and antagonists drugs is required for interaction with the D-1 and D-2 dopamine receptors and whether the positively charged or uncharged molecular species interacts with these receptors. To address these issues, permanently charged analogs of dopamine, chlorpromazine and sulpiride were synthesized in which a dimethylsulfonium, dimethylselenonium or quaternary ammonium group replaced the amine group. Permanently uncharged analogs which contained a methylsulfide, methylselenide and sulfoxide group instead of an amine group were also synthesized. The interactions of these compounds with striatal dopamine receptors were studied. We found that the permanently charged dopamine analogs bound to the D-2 receptor of striatal membranes like conventional dopaminergic agonists and displayed agonist activity at the D-2 receptor regulating potassium-evoked [ 3 H] acetylcholine release. In contrast, the permanently uncharged analogs bound only to the high affinity state of the D-2 receptor and had neither agonist or antagonist activity

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels.

Science.gov (United States)

Voon, Valerie; Rizos, Alexandra; Chakravartty, Riddhika; Mulholland, Nicola; Robinson, Stephanie; Howell, Nicholas A; Harrison, Neil; Vivian, Gill; Ray Chaudhuri, K

2014-02-01

Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [(11)C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [(123)I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. The [(123)I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications.

Striatal dysfunction in attention deficit and hyperkinetic disorder

International Nuclear Information System (INIS)

Lou, H.C.; Henriksen, L.; Bruhn, P.; Borner, H.; Nielsen, J.B.

1989-01-01

We have previously reported that periventricular structures are hypoperfused in attention deficit and hyperactivity disorder (ADHD). This study has expanded the number of patients, who were divided into two groups: six patients with pure ADHD, and 13 patients with ADHD in combination with other neurologic symptoms. By using xenon 133 inhalation and emission tomography, the regional cerebral blood flow distribution was determined and compared with a control group. Striatal regions were found to be hypoperfused and, by inference, hypofunctional in both groups. This hypoperfusion was statistically significant in the right striatum in ADHD, and in both striatal regions in ADHD with other neuropsychologic and neurologic symptoms. The primary sensory and sensorimotor cortical regions were highly perfused. Methylphenidate increased flow to striatal and posterior periventricular regions, and tended to decrease flow to primary sensory regions. Low striatal activity, partially reversible with methylphenidate, appears to be a cardinal feature in ADHD

Striatal dysfunction in attention deficit and hyperkinetic disorder

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Lou, H.C.; Henriksen, L.; Bruhn, P.; Borner, H.; Nielsen, J.B.

1989-01-01

We have previously reported that periventricular structures are hypoperfused in attention deficit and hyperactivity disorder (ADHD). This study has expanded the number of patients, who were divided into two groups: six patients with pure ADHD, and 13 patients with ADHD in combination with other neurologic symptoms. By using xenon 133 inhalation and emission tomography, the regional cerebral blood flow distribution was determined and compared with a control group. Striatal regions were found to be hypoperfused and, by inference, hypofunctional in both groups. This hypoperfusion was statistically significant in the right striatum in ADHD, and in both striatal regions in ADHD with other neuropsychologic and neurologic symptoms. The primary sensory and sensorimotor cortical regions were highly perfused. Methylphenidate increased flow to striatal and posterior periventricular regions, and tended to decrease flow to primary sensory regions. Low striatal activity, partially reversible with methylphenidate, appears to be a cardinal feature in ADHD.

Local application of SCH 39166 reversibly and dose-dependently decreases acetylcholine release in the rat striatum.

Science.gov (United States)

Acquas, E; Di Chiara, G

1999-11-03

The effect of local application by reverse dialysis of the dopamine D(1) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride (SCH 39166) on acetylcholine release was studied in awake, freely moving rats implanted with concentric microdialysis probes in the dorsal striatum. In these experiments, the reversible acetylcholine esterase inhibitor, neostigmine, was added to the perfusion solution at two different concentrations, 0.01 and 0.1 microM. SCH 39166 (1, 5 and 10 microM), in the presence of 0.01 microM neostigmine, reversibly decreased striatal acetylcholine release (1 microM SCH 39166 by 8+/-4%; 5 microM SCH 39166 by 24+/-5%; 10 microM SCH 39166 by 27+/-7%, from basal). Similarly, SCH 39166, applied in the presence of a higher neostigmine concentration (0.1 microM), decreased striatal acetylcholine release by 14+/-4% at 1 microM, by 28+/-8% at 5 microM and by 30+/-5% at 10 microM, in a dose-dependent and time-dependent manner. These results are consistent with the existence of a facilitatory tone of dopamine on striatal acetylcholine transmission mediated by dopamine D(1) receptors located on striatal cholinergic interneurons.

Age-dependent changes in 24-hour rhythms of catecholamine content and turnover in hypothalamus, corpus striatum and pituitary gland of rats injected with Freund's adjuvant

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Reyes Toso Carlos A

2001-11-01

Full Text Available Abstract Background Little information is available on the circadian sequela of an immune challenge in the brain of aged rats. To assess them, we studied 24-hour rhythms in hypothalamic and striatal norepinephrine (NE content, hypothalamic and striatal dopamine (DA turnover and hypophysial NE and DA content, in young (2 months and aged (18–20 months rats killed at 6 different time intervals, on day 18th after Freund's adjuvant or adjuvant's vehicle administration. Results Aging decreased anterior and medial hypothalamic NE content, medial and posterior hypothalamic DA turnover, and striatal NE concentration and DA turnover. Aging also decreased NE and DA content in pituitary neurointermediate lobe and augmented DA content in the anterior pituitary lobe. Immunization by Freund's adjuvant injection caused: (i reduction of DA turnover in anterior hypothalamus and corpus striatum; (ii acrophase delay of medial hypothalamic DA turnover in old rats, and of striatal NE content in young rats; (iii abolition of 24-h rhythm in NE and DA content of neurointermediate pituitary lobe, and in DA content of anterior lobe, of old rats. Conclusions The decline in catecholamine neurotransmission with aging could contribute to the decrease of gonadotropin and increase of prolactin release reported in similar groups of rats. Some circadian responses to immunization, e.g. suppression of 24-h rhythms of neurointermediate lobe NE and DA and of anterior lobe DA were seen only in aged rats.

THE EFFECT OF INTRASTRIATAL APPLICATION OF DIRECTLY AND INDIRECTLY ACTING DOPAMINE AGONISTS AND ANTAGONISTS ON THE INVIVO RELEASE OF ACETYLCHOLINE MEASURED BY BRAIN MICRODIALYSIS - THE IMPORTANCE OF THE POSTSURGERY INTERVAL

NARCIS (Netherlands)

DEBOER, P; DAMSMA, G; SCHRAM, Q; STOOF, JC; ZAAGSMA, J; WESTERINK, BHC

The effect of intrastriatal application of D-1, D-2 and indirect dopaminergic drugs on the release of striatal acetylcholine as a function of the post-implantation intervals was studied using in vivo microdialysis. The dopamine D-2 agonists LY 171555 and (-)N0437 inhibited the release of striatal

Behavioral sensitivity of temporally modulated striatal neurons

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George ePortugal

2011-07-01

Full Text Available Recent investigations into the neural mechanisms that underlie temporal perception have revealed that the striatum is an important contributor to interval timing processes, and electrophysiological recording studies have shown that the firing rates of striatal neurons are modulated by the time in a trial at which an operant response is made. However, it remains unclear whether striatal firing rate modulations are related to the passage of time alone (i.e., whether temporal information is represented in an abstract manner independent of other attributes of biological importance, or whether this temporal information is embedded within striatal activity related to co-occurring contextual information, such as motor behaviors. This study evaluated these two hypotheses by recording from striatal neurons while rats performed a temporal production task. Rats were trained to respond at different nosepoke apertures for food reward under two simultaneously active reinforcement schedules: a variable-interval (VI-15 sec schedule and a fixed-interval (FI-15 sec schedule of reinforcement. Responding during a trial occurred in a sequential manner composing 3 phases; VI responding, FI responding, VI responding. The vast majority of task-sensitive striatal neurons (95% varied their firing rates associated with equivalent behaviors (e.g., periods in which their snout was held within the nosepoke across these behavioral phases, and 96% of cells varied their firing rates for the same behavior within a phase, thereby demonstrating their sensitivity to time. However, in a direct test of the abstract timing hypothesis, 91% of temporally modulated hold cells were further modulated by the overt motor behaviors associated with transitioning between nosepokes. As such, these data are inconsistent with the striatum representing time in an abstract’ manner, but support the hypothesis that temporal information is embedded within contextual and motor functions of the

No association between striatal dopamine transporter binding and body mass index

DEFF Research Database (Denmark)

van de Giessen, Elsmarieke; Hesse, Swen; Caan, Matthan W A

2013-01-01

Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine...... transporter (DAT) availability is also decreased. In this study, we tested whether BMI and striatal DAT availability are associated....

Alterations in Striatal Circuits Underlying Addiction-Like Behaviors.

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Kim, Hyun Jin; Lee, Joo Han; Yun, Kyunghwa; Kim, Joung-Hun

2017-06-30

Drug addiction is a severe psychiatric disorder characterized by the compulsive pursuit of drugs of abuse despite potential adverse consequences. Although several decades of studies have revealed that psychostimulant use can result in extensive alterations of neural circuits and physiology, no effective therapeutic strategies or medicines for drug addiction currently exist. Changes in neuronal connectivity and regulation occurring after repeated drug exposure contribute to addiction-like behaviors in animal models. Among the involved brain areas, including those of the reward system, the striatum is the major area of convergence for glutamate, GABA, and dopamine transmission, and this brain region potentially determines stereotyped behaviors. Although the physiological consequences of striatal neurons after drug exposure have been relatively well documented, it remains to be clarified how changes in striatal connectivity underlie and modulate the expression of addiction-like behaviors. Understanding how striatal circuits contribute to addiction-like behaviors may lead to the development of strategies that successfully attenuate drug-induced behavioral changes. In this review, we summarize the results of recent studies that have examined striatal circuitry and pathway-specific alterations leading to addiction-like behaviors to provide an updated framework for future investigations.

Inflammation alters AMPA-stimulated calcium responses in dorsal striatal D2 but not D1 spiny projection neurons.

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Winland, Carissa D; Welsh, Nora; Sepulveda-Rodriguez, Alberto; Vicini, Stefano; Maguire-Zeiss, Kathleen A

2017-11-01

Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium-permeable versus impermeable AMPARs can result in disruptions of [Ca 2+ ] i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca 2+ ] i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, this study sought to determine whether a proinflammatory environment alters AMPA-stimulated [Ca 2+ ] i through calcium-permeable AMPARs and/or L-type VGCCs in dopamine-2- and dopamine-1-expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum. Mice expressing the calcium indicator protein, GCaMP in D2 or D1 SPNs, were utilized for calcium imaging. Microglial activation was assessed by morphology analyses. To induce inflammation, acute mouse striatal slices were incubated with lipopolysaccharide (LPS). Here we report that LPS treatment potentiated AMPA responses only in D2 SPNs. When a nonspecific VGCC blocker was included, we observed a decrease of AMPA-stimulated calcium fluorescence in D2 but not D1 SPNs. The remaining agonist-induced [Ca 2+ ] i was mediated by calcium-permeable AMPARs because the responses were completely blocked by a selective calcium-permeable AMPAR antagonist. We used isradipine, the highly selective L-type VGCC antagonist to determine the role of L-type VGCCs in SPNs treated with LPS. Isradipine decreased AMPA-stimulated responses selectively in D2 SPNs after LPS treatment. Our findings suggest that dorsal striatal D2 SPNs are specifically targeted in proinflammatory conditions and that L-type VGCCs and calcium-permeable AMPARs are important mediators of this effect. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Does human presynaptic striatal dopamine function predict social conformity?

Science.gov (United States)

Stokes, Paul R A; Benecke, Aaf; Puraite, Julita; Bloomfield, Michael A P; Shotbolt, Paul; Reeves, Suzanne J; Lingford-Hughes, Anne R; Howes, Oliver; Egerton, Alice

2014-03-01

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one's own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D₂/₃ receptor availability. This may reflect an association between SDR and D₂/₃ receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [¹⁸F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [¹⁸F]-DOPA uptake, (k(i)(cer), min⁻¹), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [¹⁸F]-DOPA k(i)(cer). These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D₂/₃ receptor expression rather than with synaptic dopamine levels.

Adversity in childhood linked to elevated striatal dopamine function in adulthood

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Egerton, A.; Valmaggia, L. R.; Howes, O. D.; Day, F.; Chaddock, C. A.; Allen, P.; Winton-Brown, T. T.; Bloomfield, M. A. P.; Bhattacharyya, S.; Chilcott, J.; Lappin, J. M.; Murray, R. M.; McGuire, P.

2016-01-01

Childhood adversity increases the risk of psychosis in adulthood. Theoretical and animal models suggest that this effect may be mediated by increased striatal dopamine neurotransmission. The primary objective of this study was to examine the relationship between adversity in childhood and striatal dopamine function in early adulthood. Secondary objectives were to compare exposure to childhood adversity and striatal dopamine function in young people at ultra high risk (UHR) of psychosis and he...

Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington's disease.

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Carmela Giampà

2010-10-01

Full Text Available Huntington's disease is a devastating neurodegenerative condition for which there is no therapy to slow disease progression. The particular vulnerability of striatal medium spiny neurons to Huntington's pathology is hypothesized to result from transcriptional dysregulation within the cAMP and CREB signaling cascades in these neurons. To test this hypothesis, and a potential therapeutic approach, we investigated whether inhibition of the striatal-specific cyclic nucleotide phosphodiesterase PDE10A would alleviate neurological deficits and brain pathology in a highly utilized model system, the R6/2 mouse.R6/2 mice were treated with the highly selective PDE10A inhibitor TP-10 from 4 weeks of age until euthanasia. TP-10 treatment significantly reduced and delayed the development of the hind paw clasping response during tail suspension, deficits in rotarod performance, and decrease in locomotor activity in an open field. Treatment prolonged time to loss of righting reflex. These effects of PDE10A inhibition on neurological function were reflected in a significant amelioration in brain pathology, including reduction in striatal and cortical cell loss, the formation of striatal neuronal intranuclear inclusions, and the degree of microglial activation that occurs in response to the mutant huntingtin-induced brain damage. Striatal and cortical levels of phosphorylated CREB and BDNF were significantly elevated.Our findings provide experimental support for targeting the cAMP and CREB signaling pathways and more broadly transcriptional dysregulation as a therapeutic approach to Huntington's disease. It is noteworthy that PDE10A inhibition in the R6/2 mice reduces striatal pathology, consistent with the localization of the enzyme in medium spiny neurons, and also cortical pathology and the formation of neuronal nuclear inclusions. These latter findings suggest that striatal pathology may be a primary driver of these secondary pathological events. More

Smoking-induced dopamine release studied with [11C]raclopride PET

International Nuclear Information System (INIS)

Kim, Yu Kyeong; Cho, Sang Soo; Lee, Do Hoon

2005-01-01

It has been postulated that dopamine release in the striatum underlies the reinforcing properties of nicotine. Substantial evidence in the animal studies demonstrates that nicotine interacts with and regulates the activation of the dopaminergic neuron. The aim of this study was to visualize the dopamine release by smoking in human brain using PET scan with [ 11 C]raclopride. Four male non-smokers or ex-smokers with an abstinence period longer than 1 year (mean age of 24.3±2.6 years) were enrolled in this study. Dopamine D2 receptor radioligand, [ 11 C]raclopride was administrated with bolus-plus-constant infusion. Dynamic PET was performed during 120 minutes (3x20s, 2x60s, 2x120s, 1x180s and 22x300s). Following the 50 minute-scanning, subjects smoked a cigarette containing 1 mg of nicotine while in the scanner. Blood samples for the measurements of plasma nicotine levels were collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, and 90 minute after smoking. Regions for striatal structures were drawn on the coronal summed PET images guided with co-registered MRI. Binding potential, calculated as striatal-cerebellar/cerebellar activity, was measured under equilibrium condition at baseline and smoking session. The mean change in binding potential between the baseline and smoking in caudate, Putamen and ventral striatum was 3.7 % , 4.0 % and 8.6 %, respectively. This indicated the striatal dopamine release by smoking. The reduction in binding potential in the ventral striatum was significantly correlated with the cumulated plasma level of the nicotine (r 2 =0.91, p=0.04). These data demonstrate that in vivo imaging with [ 11 C]raclopride PET could measure nicotine-induced dopamine release in the human brain, which has a significant positive correlation with the amount of nicotine administered by smoking

Levodopa administration modulates striatal processing of punishment-associated items in healthy participants.

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Wittmann, Bianca C; D'Esposito, Mark

2015-01-01

Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions. In this pharmacological functional magnetic resonance imaging study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans. Two groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks. Levodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared with neutral cues in participants scoring higher on the novelty-seeking dimension. These data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing.

Striatal volume predicts level of video game skill acquisition.

Science.gov (United States)

Erickson, Kirk I; Boot, Walter R; Basak, Chandramallika; Neider, Mark B; Prakash, Ruchika S; Voss, Michelle W; Graybiel, Ann M; Simons, Daniel J; Fabiani, Monica; Gratton, Gabriele; Kramer, Arthur F

2010-11-01

Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.

Aspects of dopamine and acetylcholine release induced by glutamate receptors

International Nuclear Information System (INIS)

Paes, Paulo Cesar de Arruda

2002-01-01

The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

Combined DaT imaging and olfactory testing for differentiating parkinsonian disorders

DEFF Research Database (Denmark)

Borghammer, Per; Knudsen, K; Østergaard, K

2014-01-01

ObjectiveDopamine transporter (DaT) imaging with single photon emission computed tomography (SPECT) detects loss of striatal dopaminergic innervation with very high sensitivity. It cannot readily distinguish idiopathic Parkinson's disease (iPD) and dementia with Lewy bodies (DLB) from atypical...... predicted a dopamine-deficient diagnosis with 98% sensitivity and 98% specificity. The combined DaT/olfactory testing correctly classified 91% of patients as iPD/DLB (PPV 91%). The PPV rose to 97% or greater in anosmic patients. In contrast, only 45% of aPD patients were categorised correctly by combined Da...

Smoking-induced dopamine release studied with [{sup 11}C]raclopride PET

Energy Technology Data Exchange (ETDEWEB)

Kim, Yu Kyeong; Cho, Sang Soo; Lee, Do Hoon [Seoul National University College of Medicine, Seoul (Korea, Republic of)] (and others)

2005-07-01

It has been postulated that dopamine release in the striatum underlies the reinforcing properties of nicotine. Substantial evidence in the animal studies demonstrates that nicotine interacts with and regulates the activation of the dopaminergic neuron. The aim of this study was to visualize the dopamine release by smoking in human brain using PET scan with [{sup 11}C]raclopride. Four male non-smokers or ex-smokers with an abstinence period longer than 1 year (mean age of 24.3{+-}2.6 years) were enrolled in this study. Dopamine D2 receptor radioligand, [{sup 11}C]raclopride was administrated with bolus-plus-constant infusion. Dynamic PET was performed during 120 minutes (3x20s, 2x60s, 2x120s, 1x180s and 22x300s). Following the 50 minute-scanning, subjects smoked a cigarette containing 1 mg of nicotine while in the scanner. Blood samples for the measurements of plasma nicotine levels were collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, and 90 minute after smoking. Regions for striatal structures were drawn on the coronal summed PET images guided with co-registered MRI. Binding potential, calculated as striatal-cerebellar/cerebellar activity, was measured under equilibrium condition at baseline and smoking session. The mean change in binding potential between the baseline and smoking in caudate, Putamen and ventral striatum was 3.7 % , 4.0 % and 8.6 %, respectively. This indicated the striatal dopamine release by smoking. The reduction in binding potential in the ventral striatum was significantly correlated with the cumulated plasma level of the nicotine (r{sup 2}=0.91, p=0.04). These data demonstrate that in vivo imaging with [{sup 11}C]raclopride PET could measure nicotine-induced dopamine release in the human brain, which has a significant positive correlation with the amount of nicotine administered by smoking.

β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

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Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

2010-01-01

Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

Reduced striatal D2 receptor binding in myoclonus-dystonia

International Nuclear Information System (INIS)

Beukers, R.J.; Weisscher, N.; Tijssen, M.A.J.; Booij, J.; Zijlstra, F.; Amelsvoort, T.A.M.J. van

2009-01-01

To study striatal dopamine D 2 receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus-dystonia (M-D). Fifteen DYT11 mutation carriers (11 clinically affected) and 15 age- and sex-matched controls were studied using 123 I-IBZM SPECT. Specific striatal binding ratios were calculated using standard templates for striatum and occipital areas. Multivariate analysis with corrections for ageing and smoking showed significantly lower specific striatal to occipital IBZM uptake ratios (SORs) both in the left and right striatum in clinically affected patients and also in all DYT11 mutation carriers compared to control subjects. Our findings are consistent with the theory of reduced dopamine D 2 receptor (D2R) availability in dystonia, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. (orig.)

An inquiry into the semiquantitative parameters of striatal dopamine receptor imaging

International Nuclear Information System (INIS)

Cao Guoxiang; Tan Tianzhi; Kuang Anren; Liang Zhenglu

1998-01-01

Purpose: To inquire into the optimal striatal reference region for nonspecific IBZM uptake in brain dopamine receptor imaging. Methods: Using in vivo data from rats, the authors compared the results of 125 I-iodobenzamide ( 125 I-IBZM) striatal specific binding that were respectively obtained taking cerebellum and frontal cortex as striatal reference region of nonspecific uptake of ligand. Results: Radioiodination labelled IBZM bound stereoselectively and reversibly to striatal D2 receptors. Frontal cortex and cerebellum showed rapid uptake and rapid washout of ligand. When cerebellar uptake was used as a reference of nonspecific uptake in striatum, IBZM saturation could not be demonstrated. But when the frontal cortex was used as reference region, saturation could be demonstrated with B max = 44 pmol/g striatum tissue. The percentage of haloperidol replacement and the percentage of uptake difference between striatum and other brain regions which were derived from competitive inhibition experiments with a large does of spiperone or haloperidol, suggested that the cerebellar uptake underestimated nonspecific uptake in the striatum while frontal cortex was an appropriate reference region for nonspecific uptake of ligand in striatum. Conclusions: For the calculation of specific IBZM binding and other semiquantitative parameters of striatal dopamine D2 receptor imaging, frontal cortex would be the nonspecific reference region of choice

Alterations in Ca2+-dependent and Ca2+-independent release of catecholamines in preparations of rat brain produced by ethanol treatment in vivo

International Nuclear Information System (INIS)

Lynch, M.A.; Pagonis, C.; Samuel, D.; Littleton, J.M.

1985-01-01

Compared to preparations from control animals, superfused striatal slice preparations from brains of rats treated chronically with ethanol released a significantly greater fraction of stored [ 3 H] dopamine on depolarisation in 40 mM K + . Similarly, the electrically-evoked release of [ 3 H]-norepinephrine from cortical slices and of [ 3 H]-dopamine from striatal slices is also increased, although with this mechanism of depolarisation the change is significant only in the case of [ 3 H] norepinephrine release. In contrast to this tendency to enhancement of Ca 2+ -dependent depolarisation-induced release, a reduced fraction of stored [ 3 H]-catecholamines was released from these preparations by the indirect sympathomimetics tyramine and (+)-amphetamine. The catecholamine release induced by these indirect sympathomimetics is largely independent of external Ca 2+ and the results are interpreted as suggesting that chronic alcohol treatment changes the distribution of catecholamine neurotransmitters between storage pools in the nerve terminal which do or do not require Ca 2+ entry for release

Modulation of neurotransmitter release in the region of the caudate nucleus by diet and neurotoxins

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Kurstjens, N P

1987-01-01

In this thesis the effects of dietary manipulation, ethanol and neurotoxins on the basal and electrically evoked release of dopamine and acetylcholine from the caudate nucleus of mature animals are presented together with an evaluation of the presynaptic acetylcholine and dopamine receptors controlling acetylcholine and dopamine release. A standardised superfusion technique was used to monitor the effect of apomorphine, in the presence of (R-S)- sulpiride or haloperidol, on the electrically induced release of (/sup 3/ H)-acetylcholine in slices of rat corpus striatum. The effect of ethanol and dietary manipulation on the basal and electrically evoke release of (/sup 3/H)-acetylfholine from rat striatal slices, in the presence of specific agonists and antagonists was evaluated. From this study it is possible to deduce that diet and neurotoxins exerted a measurable effect on the mechanisms controlling release of neurotransmitters in the region of the caudate nucleus. These changes were determined in mature animals previously considered to have cerebral activity, which was not subject to dietary fluctuaations. No changes in the activity of the presynaptic dopamine receptor of the acetylcholine nerve terminals of the striatal slice could be measured.

The role of adenosine A1 and A2A receptors in the caffeine effect on MDMA-induced DA and 5-HT release in the mouse striatum.

Science.gov (United States)

Górska, A M; Gołembiowska, K

2015-04-01

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a role in the effect of caffeine by investigating the effect of the selective adenosine A1 and A2A receptor antagonists, DPCPX and KW 6002 on DA and 5-HT release induced by MDMA. Mice were treated with caffeine (10 mg/kg) and MDMA (20 or 40 mg/kg) alone or in combination. DA and 5-HT release in the mouse striatum was measured using in vivo microdialysis. Caffeine exacerbated the effect of MDMA on DA and 5-HT release. DPCPX or KW 6002 co-administered with MDMA had similar influence as caffeine, but KW 6002 was more potent than caffeine or DPCPX. To exclude the contribution of MAO inhibition by caffeine in the caffeine effect on MDMA-induced increase in DA and 5-HT, we also tested the effect of the nonxanthine adenosine receptor antagonist CGS 15943A lacking properties of MAO activity modification. Our findings indicate that adenosine A1 and A2A receptor blockade may account for the caffeine-induced exacerbation of the MDMA effect on DA and 5-HT release and may aggravate MDMA toxicity.

Abnormal Striatal BOLD Responses to Reward Anticipation and Reward Delivery in ADHD

Science.gov (United States)

Furukawa, Emi; Bado, Patricia; Tripp, Gail; Mattos, Paulo; Wickens, Jeff R.; Bramati, Ivanei E.; Alsop, Brent; Ferreira, Fernanda Meireles; Lima, Debora; Tovar-Moll, Fernanda; Sergeant, Joseph A.; Moll, Jorge

2014-01-01

Altered reward processing has been proposed to contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The neurobiological mechanism underlying this alteration remains unclear. We hypothesize that the transfer of dopamine release from reward to reward-predicting cues, as normally observed in animal studies, may be deficient in ADHD. Functional magnetic resonance imaging (fMRI) was used to investigate striatal responses to reward-predicting cues and reward delivery in a classical conditioning paradigm. Data from 14 high-functioning and stimulant-naïve young adults with elevated lifetime symptoms of ADHD (8 males, 6 females) and 15 well-matched controls (8 males, 7 females) were included in the analyses. During reward anticipation, increased blood-oxygen-level-dependent (BOLD) responses in the right ventral and left dorsal striatum were observed in controls, but not in the ADHD group. The opposite pattern was observed in response to reward delivery; the ADHD group demonstrated significantly greater BOLD responses in the ventral striatum bilaterally and the left dorsal striatum relative to controls. In the ADHD group, the number of current hyperactivity/impulsivity symptoms was inversely related to ventral striatal responses during reward anticipation and positively associated with responses to reward. The BOLD response patterns observed in the striatum are consistent with impaired predictive dopamine signaling in ADHD, which may explain altered reward-contingent behaviors and symptoms of ADHD. PMID:24586543

Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia.

Science.gov (United States)

Horga, Guillermo; Cassidy, Clifford M; Xu, Xiaoyan; Moore, Holly; Slifstein, Mark; Van Snellenberg, Jared X; Abi-Dargham, Anissa

2016-08-01

Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographic organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of antidopaminergic medication. To examine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. In this multimodal, case-control study, we obtained resting-state functional magnetic resonance imaging data from 18 unmedicated patients with schizophrenia and 24 matched healthy controls from the New York State Psychiatric Institute. A subset of these (12 and 17, respectively) underwent positron emission tomography with the dopamine D2 receptor radiotracer carbon 11-labeled FLB457 before and after amphetamine administration. Data were acquired between June 16, 2011, and February 25, 2014. Data analysis was performed from September 1, 2014, to January 11, 2016. Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, the association between the multivariate striatal connectivity pattern and extrastriatal baseline D2 receptor binding potential and its change after amphetamine administration, and the association between the multivariate connectivity pattern and the severity of positive symptoms evaluated with the Positive and Negative Syndrome Scale. Of the patients with schizophrenia (mean [SEM] age, 35.6 [11.8] years), 9 (50%) were male and 9

Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2 R binding and reduces striatal D1 R binding in male hemiparkinsonian rats.

Science.gov (United States)

Wedekind, Franziska; Oskamp, Angela; Lang, Markus; Hawlitschka, Alexander; Zilles, Karl; Wree, Andreas; Bauer, Andreas

2018-01-01

Cerebral administration of botulinum neurotoxin A (BoNT-A) has been shown to improve disease-specific motor behavior in a rat model of Parkinson disease (PD). Since the dopaminergic system of the basal ganglia fundamentally contributes to motor function, we investigated the impact of BoNT-A on striatal dopamine receptor expression using in vitro and in vivo imaging techniques (positron emission tomography and quantitative autoradiography, respectively). Seventeen male Wistar rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and assigned to two treatment groups 7 weeks later: 10 rats were treated ipsilaterally with an intrastriatal injection of 1 ng BoNT-A, while the others received vehicle (n = 7). All animals were tested for asymmetric motor behavior (apomorphine-induced rotations and forelimb usage) and for striatal expression of dopamine receptors and transporters (D 1 R, D 2 R, and DAT). The striatal D 2 R availability was also quantified longitudinally (1.5, 3, and 5 months after intervention) in 5 animals per treatment group. The 6-OHDA lesion alone induced a unilateral PD-like phenotype and a 13% increase of striatal D 2 R. BoNT-A treatment reduced the asymmetry in both apomorphine-induced rotational behavior and D 2 R expression, with the latter returning to normal values 5 months after intervention. D 1 R expression was significantly reduced, while DAT concentrations showed no alteration. Independent of the treatment, higher interhemispheric symmetry in raclopride binding to D 2 R was generally associated with reduced forelimb akinesia. Our findings indicate that striatal BoNT-A treatment diminishes motor impairment and induces changes in D 1 and D 2 binding site density in the 6-OHDA rat model of PD. © 2017 Wiley Periodicals, Inc.

Fronto-striatal atrophy correlates of neuropsychiatric dysfunction in frontotemporal dementia (FTD and Alzheimer's disease (AD

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Dong Seok Yi

Full Text Available ABSTRACT Behavioural disturbances in frontotemporal dementia (FTD are thought to reflect mainly atrophy of cortical regions. Recent studies suggest that subcortical brain regions, in particular the striatum, are also significantly affected and this pathology might play a role in the generation of behavioural symptoms. Objective: To investigate prefrontal cortical and striatal atrophy contributions to behavioural symptoms in FTD. Methods: One hundred and eighty-two participants (87 FTD patients, 39 AD patients and 56 controls were included. Behavioural profiles were established using the Cambridge Behavioural Inventory Revised (CBI-R and Frontal System Behaviour Scale (FrSBe. Atrophy in prefrontal (VMPFC, DLPFC and striatal (caudate, putamen regions was established via a 5-point visual rating scale of the MRI scans. Behavioural scores were correlated with atrophy rating scores. Results: Behavioural and atrophy ratings demonstrated that patients were significantly impaired compared to controls, with bvFTD being most severely affected. Behavioural-anatomical correlations revealed that VMPFC atrophy was closely related to abnormal behaviour and motivation disturbances. Stereotypical behaviours were associated with both VMPFC and striatal atrophy. By contrast, disturbance of eating was found to be related to striatal atrophy only. Conclusion: Frontal and striatal atrophy contributed to the behavioural disturbances seen in FTD, with some behaviours related to frontal, striatal or combined fronto-striatal pathology. Consideration of striatal contributions to the generation of behavioural disturbances should be taken into account when assessing patients with potential FTD.

The pan-Kv7 (KCNQ) Channel Opener Retigabine Inhibits Striatal Excitability by Direct Action on Striatal Neurons In Vivo

DEFF Research Database (Denmark)

Hansen, Henrik H; Weikop, Pia; Mikkelsen, Maria D

2017-01-01

Central Kv7 (KCNQ) channels are voltage-dependent potassium channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 channel opener ...... by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 channels play a direct role in regulating striatal excitability in vivo....

Measurement of striatal dopamine metabolism with 6-[18F]-fluoro-L-dopa and PET

International Nuclear Information System (INIS)

Kuwabara, Y.; Otsuka, M.; Ichiya, Y.; Yoshikai, T.; Fukumura, T.; Masuda, K.; Kato, M.; Taniwaki, T.

1992-01-01

Striatal dopamine metabolism was studied with 6-[ 18 F]-fluoro-L-dopa ( 18 F-DOPA) and PET. The subjects were normal controls, and patients with Parkinson's disease (PD), parkinsonism, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Alzheimer's disease (AD), Huntington's disease (HD) and other cerebral disorders. Cerebral glucose metabolism (CMRGlc) was also measured in these patients. Striatal dopamine metabolism was evaluated by the relative striatal uptake of 18 F-DOPA referring cerebellum (S/C ratio). In normal controls, the S/C ratio was 2.82 ± 0.32 (n = 6, mean ± SD) at 120 min after injection of 18 F-DOPA. The S/C ratio was low in patients with PD, parkinsonism, MSA and PSP compared to the normal controls and thus coincident with the symptoms of parkinsonism due to decrease in striatal dopamine concentration. The decrease in the striatal CMRGlc was also observed in patients with parkinsonism and PSP, and it was preserved in patients with PD, thus representing that more neurons were damaged in patients with parkinsonism and PSP than in patients with PD. A patient with AD having symptoms of parkinsonism also showed a decrease in S/C ratio. In a patient with HD, the striatal CMRGlc sharply decreased, but the S/C ratio was normal. The measurements of striatal dopamine and glucose metabolism with PET may be useful for studying the pathophysiological mechanism in patients with cerebral disorders. (author)

Control of striatal signaling by G protein regulators

Directory of Open Access Journals (Sweden)

Keqiang eXie

2011-08-01

Full Text Available Signaling via heterotrimeric G proteins plays a crucial role in modulating the responses of striatal neurons that ultimately shape core behaviors mediated by the basal ganglia circuitry, such as reward valuation, habit formation and movement coordination. Activation of G-protein-coupled receptors (GPCRs by extracellular signals activates heterotrimeric G proteins by promoting the binding of GTP to their α subunits. G proteins exert their effects by influencing the activity of key effector proteins in this region, including ion channels, second messenger enzymes and protein kinases. Striatal neurons express a staggering number of GPCRs whose activation results in the engagement of downstream signaling pathways and cellular responses with unique profiles but common molecular mechanisms. Studies over the last decade have revealed that the extent and duration of GPCR signaling are controlled by a conserved protein family named Regulator of G protein Signaling (RGS. RGS proteins accelerate GTP hydrolysis by the α subunits of G proteins, thus promoting deactivation of GPCR signaling. In this review, we discuss the progress made in understanding the roles of RGS proteins in controlling striatal G protein signaling and providing integration and selectivity of signal transmission. We review evidence on the formation of a macromolecular complex between RGS proteins and other components of striatal signaling pathways, their molecular regulatory mechanisms and impacts on GPCR signaling in the striatum obtained from biochemical studies and experiments involving genetic mouse models. Special emphasis is placed on RGS9-2, a member of the RGS family that is highly enriched in the striatum and plays critical roles in drug addiction and motor control.

Fractal analysis of striatal dopamine re-uptake sites

International Nuclear Information System (INIS)

Kuikka, J.T.; Bergstroem, K.A.; Tiihonen, J.; Raesaenen, P.; Karhu, J.

1997-01-01

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123 I]β-CIT). The mean fractal dimension was 1.15±0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19±0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab

Fractal analysis of striatal dopamine re-uptake sites

Energy Technology Data Exchange (ETDEWEB)

Kuikka, J.T.; Bergstroem, K.A. [Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Finland); Tiihonen, J.; Raesaenen, P. [Department of Forensic Psychiatry, University of Kuopio and Niuvanniemi Hospital, Kuopio (Finland); Karhu, J. [Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio (Finland)

1997-09-01

Spatial variation in regional blood flow, metabolism and receptor density within the brain and in other organs is measurable even with a low spatial resolution technique such as emission tomography. It has been previously shown that the observed variance increases with increasing number of subregions in the organ/tissue studied. This resolution-dependent variance can be described by fractal analysis. We studied striatal dopamine re-uptake sites in 39 healthy volunteers with high-resolution single-photon emission tomography using iodine-123 labelled 2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane ([{sup 123}I]{beta}-CIT). The mean fractal dimension was 1.15{+-}0.07. The results indicate that regional striatal dopamine re-uptake sites involve considerable spatial heterogeneity which is higher than the uniform density (dimension=1.00) but much lower than complete randomness (dimension=1.50). There was a gender difference, with females having a higher heterogeneity in both the left and the right striatum. In addition, we found striatal asymmetry (left-to-right heterogeneity ratio of 1.19{+-}0.15; P<0.001), suggesting functional hemispheric lateralization consistent with the control of motor behaviour and integrative functions. (orig.). With 5 figs., 1 tab.

Smoking-induced dopamine release studied with [{sup 11}C]Raclopride PET

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Kim, Yu Kyeong; Cho, Sang Soo [Seoul National University College of Medicine, Seoul (Korea, Republic of); Lee, Do Hoon [Center for Clinical Services, National Cancer Certer, Goyang (Korea, Republic of)] (and others)

2005-10-15

It has been postulated that dopamine release in the striatum underlies the reinforcing properties of nicotine. Substantial evidence in the animal studies demonstrates that nicotine interacts with dopaminergic neuron and regulates the activation of the dopaminergic system. The aim of this study was to visualize the dopamine release by smoking in human brain using PET scan with [{sup 11}C]raclopride. Five male non-smokers or ex-smokers with an abstinence period longer than 1 year (mean age of 24.4 {+-} 1.7 years) were enrolled in this study. [{sup 1C}]raclopride, a dopamine D2 receptor radioligand, was administrated with bolus-plus-constant infusion. Dynamic PET was performed during 120 minutes (3 x 20s, 2 x 60s, 2 x 120s, 1 x 180s and 22 x 300s). Following the 50 minute-scanning, subjects smoked a cigarette containing 1 mg of nicotine while in the scanner. Blood samples for the measurement of plasma nicotine level were collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, and 90 minute after smoking. Regions for striatal structures were drawn on the coronal summed PET images guided with co-registered MRI. Binding potential, calculated as (striatal-cerebellar)/cerebellar activity, was measured under equilibrium condition at baseline and smoking session. The mean decrease in binding potential of [{sup 1C}]raclopride between the baseline and smoking in caudate head, anterior putamen and ventral striatum was 4.7%, 4.0% and 7.8%, respectively. This indicated the striatal dopamine release by smoking. Of these, the reduction in binding potential in the ventral striatum was significantly correlated with the cumulated plasma level of the nicotine (Spearman's rho=0.9, {rho} =0.4). These data demonstrate that in vivo imaging with [{sup 11}C]raclopride PET could measure nicotine-induced dopamine release in the human brain, which has a significant positive correlation with the amount of nicotine administered by smoking.

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using (123I)FP-CIT (DaTSCAN) and SPECT

DEFF Research Database (Denmark)

Thomsen, G; Knudsen, Gitte Moos; Jensen, PS

2013-01-01

BACKGROUND: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like...... receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy...... controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers. METHODS: A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present...

Gender Differences in Age-Related Striatal Dopamine Depletion in Parkinson’s Disease

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Jae Jung Lee

2015-09-01

Full Text Available Objective Gender differences are a well-known clinical characteristic of Parkinson’s disease (PD. In-vivo imaging studies demonstrated that women have greater striatal dopamine transporter (DAT activity than do men, both in the normal population and in PD patients. We hypothesize that women exhibit more rapid aging-related striatal DAT reduction than do men, as the potential neuroprotective effect of estrogen wanes with age. Methods This study included 307 de novo PD patients (152 men and 155 women who underwent DAT scans for an initial diagnostic work-up. Gender differences in age-related DAT decline were assessed in striatal sub-regions using linear regression analysis. Results Female patients exhibited greater DAT activity compared with male patients in all striatal sub-regions. The linear regression analysis revealed that age-related DAT decline was greater in the anterior and posterior caudate, and the anterior putamen in women compared with men; we did not observe this difference in other sub-regions. Conclusions This study demonstrated the presence of gender differences in age-related DAT decline in striatal sub-regions, particularly in the antero-dorsal striatum, in patients with PD, presumably due to aging-related decrease in estrogen. Because this difference was not observed in the sensorimotor striatum, this finding also suggests that women may not have a greater capacity to tolerate PD pathogenesis than do men.

Differential involvement of dopamine D-1 and D-2 receptors in the circling behaviour induced by apomorphine, SK & F 38393, pergolide and LY 171555 in 6-hydroxydopamine-lesioned rats.

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Arnt, J; Hyttel, J

1985-01-01

The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Human interleukin for DA cells or leukemia inhibitory factor is released by Vero cells in human embryo coculture.

Science.gov (United States)

Papaxanthos-Roche, A; Taupin, J L; Mayer, G; Daniel, J Y; Moreau, J F

1994-09-01

In the light of the newly discovered implications of human interleukin for DA cells and leukemia inhibitory factor in embryology, we searched for the presence of this soluble cytokine in the supernatant of Vero cell coculture systems. Using a bioassay as well as a specific ELISA, we demonstrated that Vero cells are able to release large quantities of human interleukin for DA cells and leukemia inhibitory factor in the embryo-growing medium of such cocultures.

Functional connectivity modeling of consistent cortico-striatal degeneration in Huntington's disease

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Imis Dogan

2015-01-01

Full Text Available Huntington's disease (HD is a progressive neurodegenerative disorder characterized by a complex neuropsychiatric phenotype. In a recent meta-analysis we identified core regions of consistent neurodegeneration in premanifest HD in the striatum and middle occipital gyrus (MOG. For early manifest HD convergent evidence of atrophy was most prominent in the striatum, motor cortex (M1 and inferior frontal junction (IFJ. The aim of the present study was to functionally characterize this topography of brain atrophy and to investigate differential connectivity patterns formed by consistent cortico-striatal atrophy regions in HD. Using areas of striatal and cortical atrophy at different disease stages as seeds, we performed task-free resting-state and task-based meta-analytic connectivity modeling (MACM. MACM utilizes the large data source of the BrainMap database and identifies significant areas of above-chance co-activation with the seed-region via the activation-likelihood-estimation approach. In order to delineate functional networks formed by cortical as well as striatal atrophy regions we computed the conjunction between the co-activation profiles of striatal and cortical seeds in the premanifest and manifest stages of HD, respectively. Functional characterization of the seeds was obtained using the behavioral meta-data of BrainMap. Cortico-striatal atrophy seeds of the premanifest stage of HD showed common co-activation with a rather cognitive network including the striatum, anterior insula, lateral prefrontal, premotor, supplementary motor and parietal regions. A similar but more pronounced co-activation pattern, additionally including the medial prefrontal cortex and thalamic nuclei was found with striatal and IFJ seeds at the manifest HD stage. The striatum and M1 were functionally connected mainly to premotor and sensorimotor areas, posterior insula, putamen and thalamus. Behavioral characterization of the seeds confirmed that experiments

Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.

Science.gov (United States)

Singh, Arun; Mewes, Klaus; Gross, Robert E; DeLong, Mahlon R; Obeso, José A; Papa, Stella M

2016-08-23

Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.

The impact of reconstruction method on the quantification of DaTSCAN images

Energy Technology Data Exchange (ETDEWEB)

Dickson, John C.; Erlandsson, Kjell; Hutton, Brian F. [UCLH NHS Foundation Trust and University College London, Institute of Nuclear Medicine, London (United Kingdom); Tossici-Bolt, Livia [Southampton University Hospitals NHS Trust, Department of Medical Physics, Southampton (United Kingdom); Sera, Terez [University of Szeged, Department of Nuclear Medicine and Euromedic Szeged, Szeged (Hungary); Varrone, Andrea [Psychiatry Section and Stockholm Brain Institute, Karolinska Institute, Department of Clinical Neuroscience, Stockholm (Sweden); Tatsch, Klaus [EANM/European Network of Excellence for Brain Imaging, Vienna (Austria)

2010-01-15

Reconstruction of DaTSCAN brain studies using OS-EM iterative reconstruction offers better image quality and more accurate quantification than filtered back-projection. However, reconstruction must proceed for a sufficient number of iterations to achieve stable and accurate data. This study assessed the impact of the number of iterations on the image quantification, comparing the results of the iterative reconstruction with filtered back-projection data. A striatal phantom filled with {sup 123}I using striatal to background ratios between 2:1 and 10:1 was imaged on five different gamma camera systems. Data from each system were reconstructed using OS-EM (which included depth-independent resolution recovery) with various combinations of iterations and subsets to achieve up to 200 EM-equivalent iterations and with filtered back-projection. Using volume of interest analysis, the relationships between image reconstruction strategy and quantification of striatal uptake were assessed. For phantom filling ratios of 5:1 or less, significant convergence of measured ratios occurred close to 100 EM-equivalent iterations, whereas for higher filling ratios, measured uptake ratios did not display a convergence pattern. Assessment of the count concentrations used to derive the measured uptake ratio showed that nonconvergence of low background count concentrations caused peaking in higher measured uptake ratios. Compared to filtered back-projection, OS-EM displayed larger uptake ratios because of the resolution recovery applied in the iterative algorithm. The number of EM-equivalent iterations used in OS-EM reconstruction influences the quantification of DaTSCAN studies because of incomplete convergence and possible bias in areas of low activity due to the nonnegativity constraint in OS-EM reconstruction. Nevertheless, OS-EM using 100 EM-equivalent iterations provides the best linear discriminatory measure to quantify the uptake in DaTSCAN studies. (orig.)

Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study

Science.gov (United States)

Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

2013-01-01

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions. PMID:23093224

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

Science.gov (United States)

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-02-22

Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

Directory of Open Access Journals (Sweden)

Alessandro Bertolino

2010-02-01

Full Text Available Variation of the gene coding for D2 receptors (DRD2 has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560 predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic and D2L (mainly post-synaptic. However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.Thirty-seven healthy subjects were genotyped for rs1076560 (G>T and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors, as well as BOLD fMRI during N-Back working memory.Subjects carrying the T allele (previously associated with reduced D2S expression had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

HIV infection results in ventral-striatal reward system hypo-activation during cue processing

NARCIS (Netherlands)

Plessis, Stéfan du; Vink, Matthijs; Joska, John A; Koutsilieri, Eleni; Bagadia, Asif; Stein, Dan J; Emsley, Robin

2015-01-01

OBJECTIVE: Functional MRI has thus far demonstrated that HIV has an impact on frontal-striatal systems involved in executive functioning. The potential impact of HIV on frontal-striatal systems involved in reward processing has yet to be examined by functional MRI. This study therefore aims to

No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [I-123]FP-CIT (DaTSCAN) and SPECT

NARCIS (Netherlands)

Thomsen, Gerda; Knudsen, Gitte Moos; Jensen, Peter S.; Ziebell, Morten; Holst, Klaus K.; Asenbaum, Susanne; Booij, Jan; Darcourt, Jacques; Dickson, John C.; Kapucu, Ozlem L.; Nobili, Flavio; Sabri, Osama; Sera, Terez; Tatsch, Klaus; Tossici-Bolt, Livia; van Laere, Koen; Borght, Thierry Vander; Varrone, Andrea; Pagani, Marco; Pinborg, Lars Hageman

2013-01-01

Background: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D-2-like

Reward system and addiction: what dopamine does and doesn't do.

Science.gov (United States)

Di Chiara, Gaetano; Bassareo, Valentina

2007-02-01

Addictive drugs share with palatable food the property of increasing extracellular dopamine (DA), preferentially in the nucleus accumbens shell rather than in the core. However, by acting directly on the brain, drugs bypass the adaptive mechanisms (habituation) that constrain the responsiveness of accumbens shell DA to food reward, abnormally facilitating Pavlovian incentive learning and promoting the acquisition of abnormal DA-releasing properties by drug conditioned stimuli. Thus, whereas Pavlovian food conditioned stimuli release core but not shell DA, drug conditioned stimuli do the opposite, releasing shell but not core DA. This process, which results in the acquisition of excessive incentive-motivational properties by drug conditioned stimuli, initiates the drug addiction process. Neuroadaptive processes related to the chronic influence of drugs on subcortical DA might secondarily impair the function of prefronto-striatal loops, resulting in impairments in impulse control and decision making that form the basis for the compulsive feature of drug seeking and its relapsing character.

Motor tics evoked by striatal disinhibition in the rat

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Bronfeld, Maya; Yael, Dorin; Belelovsky, Katya; Bar-Gad, Izhar

2013-01-01

Motor tics are sudden, brief, repetitive movements that constitute the main symptom of Tourette syndrome (TS). Multiple lines of evidence suggest the involvement of the cortico-basal ganglia system, and in particular the basal ganglia input structure—the striatum in tic formation. The striatum receives somatotopically organized cortical projections and contains an internal GABAergic network of interneurons and projection neurons' collaterals. Disruption of local striatal GABAergic connectivity has been associated with TS and was found to induce abnormal movements in model animals. We have previously described the behavioral and neurophysiological characteristics of motor tics induced in monkeys by local striatal microinjections of the GABAA antagonist bicuculline. In the current study we explored the abnormal movements induced by a similar manipulation in freely moving rats. We targeted microinjections to different parts of the dorsal striatum, and examined the effects of this manipulation on the induced tic properties, such as latency, duration, and somatic localization. Tics induced by striatal disinhibition in monkeys and rats shared multiple properties: tics began within several minutes after microinjection, were expressed solely in the contralateral side, and waxed and waned around a mean inter-tic interval of 1–4 s. A clear somatotopic organization was observed only in rats, where injections to the anterior or posterior striatum led to tics in the forelimb or hindlimb areas, respectively. These results suggest that striatal disinhibition in the rat may be used to model motor tics such as observed in TS. Establishing this reliable and accessible animal model could facilitate the study of the neural mechanisms underlying motor tics, and the testing of potential therapies for tic disorders. PMID:24065893

Neuroglial plasticity at striatal glutamatergic synapses in Parkinson's disease

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Rosa M Villalba

2011-08-01

Full Text Available Striatal dopamine denervation is the pathological hallmark of Parkinson’s disease (PD. Another major pathological change described in animal models and PD patients is a significant reduction in the density of dendritic spines on medium spiny striatal projection neurons. Simultaneously, the ultrastructural features of the neuronal synaptic elements at the remaining corticostriatal and thalamostriatal glutamatergic axo-spinous synapses undergo complex ultrastructural remodeling consistent with increased synaptic activity (Villalba et al., 2011. The concept of tripartite synapses (TS was introduced a decade ago, according to which astrocytes process and exchange information with neuronal synaptic elements at glutamatergic synapses (Araque et al., 1999a. Although there has been compelling evidence that astrocytes are integral functional elements of tripartite glutamatergic synaptic complexes in the cerebral cortex and hippocampus, their exact functional role, degree of plasticity and preponderance in other CNS regions remain poorly understood. In this review, we discuss our recent findings showing that neuronal elements at cortical and thalamic glutamatergic synapses undergo significant plastic changes in the striatum of MPTP-treated parkinsonian monkeys. We also present new ultrastructural data that demonstrate a significant expansion of the astrocytic coverage of striatal TS synapses in the parkinsonian state, providing further evidence for ultrastructural compensatory changes that affect both neuronal and glial elements at TS. Together with our limited understanding of the mechanisms by which astrocytes respond to changes in neuronal activity and extracellular transmitter homeostasis, the role of both neuronal and glial components of excitatory synapses must be considered, if one hopes to take advantage of glia-neuronal communication knowledge to better understand the pathophysiology of striatal processing in parkinsonism, and develop new PD

The role of striatal NMDA receptors in drug addiction.

Science.gov (United States)

Ma, Yao-Ying; Cepeda, Carlos; Cui, Cai-Lian

2009-01-01

The past decade has witnessed an impressive accumulation of evidence indicating that the excitatory amino acid glutamate and its receptors, in particular the N-methyl-D-aspartate (NMDA) receptor subtype, play an important role in drug addiction. Various lines of research using animal models of drug addiction have demonstrated that drug-induced craving is accompanied by significant upregulation of NR2B subunit expression. Furthermore, selective blockade of NR2B-containing NMDA receptors in the striatum, especially in the nucleus accumbens (NAc) can inhibit drug craving and reinstatement. The purpose of this review is to examine the role of striatal NMDA receptors in drug addiction. After a brief description of glutamatergic innervation and NMDA receptor subunit distribution in the striatum, we discuss potential mechanisms to explain the role of striatal NMDA receptors in drug addiction by elucidating signaling cascades involved in the regulation of subunit expression and redistribution, phosphorylation of receptor subunits, as well as activation of intracellular signals triggered by drug experience. Understanding the mechanisms regulating striatal NMDA receptor changes in drug addiction will provide more specific and rational targets to counteract the deleterious effects of drug addiction.

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

Science.gov (United States)

Yamamoto, Dorothy J.; Nelson, Anna M.; Mandt, Bruce H.; Larson, Gaynor A.; Rorabaugh, Jacki M.; Ng, Christopher M.C.; Barcomb, Kelsey M.; Richards, Toni L.; Allen, Richard M.; Zahniser, Nancy R.

2013-01-01

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine’s discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors. PMID:23850581

Striatal pre- and postsynaptic profile of adenosine A(2A receptor antagonists.

Directory of Open Access Journals (Sweden)

Marco Orru

2011-01-01

Full Text Available Striatal adenosine A(2A receptors (A(2ARs are highly expressed in medium spiny neurons (MSNs of the indirect efferent pathway, where they heteromerize with dopamine D(2 receptors (D(2Rs. A(2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1 receptors (A(1Rs. It has been hypothesized that postsynaptic A(2AR antagonists should be useful in Parkinson's disease, while presynaptic A(2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261 showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2AR-D(2R and A(1R-A(2AR heteromers to determine possible differences in the affinity of these compounds for different A(2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2AR when co-expressed with D(2R than with A(1R. KW-6002 showed the best relative affinity for A(2AR co-expressed with D(2R than co-expressed with A(1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile

Role of contingency in striatal response to incentive in adolescents with anxiety.

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Benson, Brenda E; Guyer, Amanda E; Nelson, Eric E; Pine, Daniel S; Ernst, Monique

2015-03-01

This study examines the effect of contingency on reward function in anxiety. We define contingency as the aspect of a situation in which the outcome is determined by one's action-that is, when there is a direct link between one's action and the outcome of the action. Past findings in adolescents with anxiety or at risk for anxiety have revealed hypersensitive behavioral and neural responses to higher value rewards with correct performance. This hypersensitivity to highly valued (salient) actions suggests that the value of actions is determined not only by outcome magnitude, but also by the degree to which the outcome is contingent on correct performance. Thus, contingency and incentive value might each modulate reward responses in unique ways in anxiety. Using fMRI with a monetary reward task, striatal response to cue anticipation is compared in 18 clinically anxious and 20 healthy adolescents. This task manipulates orthogonally reward contingency and incentive value. Findings suggest that contingency modulates the neural response to incentive magnitude differently in the two groups. Specifically, during the contingent condition, right-striatal response tracks incentive value in anxious, but not healthy, adolescents. During the noncontingent condition, striatal response is bilaterally stronger to low than to high incentive in anxious adolescents, while healthy adolescents exhibit the expected opposite pattern. Both contingency and reward magnitude differentiate striatal activation in anxious versus healthy adolescents. These findings may reflect exaggerated concern about performance and/or alterations of striatal coding of reward value in anxious adolescents. Abnormalities in reward function in anxiety may have treatment implications.

Adversity in childhood linked to elevated striatal dopamine function in adulthood.

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Egerton, Alice; Valmaggia, Lucia R; Howes, Oliver D; Day, Fern; Chaddock, Christopher A; Allen, Paul; Winton-Brown, Toby T; Bloomfield, Michael A P; Bhattacharyya, Sagnik; Chilcott, Jack; Lappin, Julia M; Murray, Robin M; McGuire, Philip

2016-10-01

Childhood adversity increases the risk of psychosis in adulthood. Theoretical and animal models suggest that this effect may be mediated by increased striatal dopamine neurotransmission. The primary objective of this study was to examine the relationship between adversity in childhood and striatal dopamine function in early adulthood. Secondary objectives were to compare exposure to childhood adversity and striatal dopamine function in young people at ultra high risk (UHR) of psychosis and healthy volunteers. Sixty-seven young adults, comprising 47 individuals at UHR for psychosis and 20 healthy volunteers were recruited from the same geographic area and were matched for age, gender and substance use. Presynaptic dopamine function in the associative striatum was assessed using 18F-DOPA positron emission tomography. Childhood adversity was assessed using the Childhood Experience of Care and Abuse questionnaire. Within the sample as a whole, both severe physical or sexual abuse (T63=2.92; P=0.005), and unstable family arrangements (T57=2.80; P=0.007) in childhood were associated with elevated dopamine function in the associative striatum in adulthood. Comparison of the UHR and volunteer subgroups revealed similar incidence of childhood adverse experiences, and there was no significant group difference in dopamine function. This study provides evidence that childhood adversity is linked to elevated striatal dopamine function in adulthood. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

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Wiltschko, Alexander B; Pettibone, Jeffrey R; Berke, Joshua D

2010-01-01

Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by di...

Striatal dopaminergic reward response relates to age of first drunkenness and feedback response in at-risk youth.

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Weiland, Barbara J; Zucker, Robert A; Zubieta, Jon-Kar; Heitzeg, Mary M

2017-03-01

Dopamine receptor concentrations, primarily in the striatum, are hypothesized to contribute to a developmental imbalance between subcortical and prefrontal control systems in emerging adulthood potentially biasing motivation and increasing risky behaviors. Positron emission tomography studies have found significant reductions in striatal dopamine D2 receptors, and blunted amphetamine-induced dopamine release, in substance users compared with healthy controls. Extant literature is limited and inconsistent concerning vulnerability associated with having a family history of substance abuse (FH+). Some studies have reported familial liability associated with higher dopamine receptor levels, reduced dopamine response to stimulant challenges and decreased response to oral alcohol. However, other reports have failed to find group differences based on family history. We explored the interaction of familial liability and behavioral risk with multi-modal molecular and neural imaging of the dopaminergic system. Forty-four young adult male subjects performed monetary incentive delay tasks during both [ 11 C]raclopride positron emission tomography and functional magnetic resonance imaging scans. FH+ subjects were identified as low (n = 24) or high risk (n = 9) based on early initiation of drunkenness. FH+ high-risk subjects exhibited heightened striatal dopamine response to monetary reward but did not differ in neural activations compared with FH+ low risk subjects and controls with no familial loading (n = 11). Across all subjects, a negative relationship was found between dopamine release and age of first drunkenness and a positive relationship with neural response to reward receipt. These results suggest that in at-risk individuals, higher dopamine transmission associated with monetary reward may represent a particularly useful neurobiological phenotype. © 2016 Society for the Study of Addiction.

Striatal pre-enkephalin overexpression improves Huntington's disease symptoms in the R6/2 mouse model of Huntington's disease.

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Stéphanie Bissonnette

Full Text Available The reduction of pre-enkephalin (pENK mRNA expression might be an early sign of striatal neuronal dysfunction in Huntington's disease (HD, due to mutated huntingtin protein. Indeed, striatopallidal (pENK-containing neurodegeneration occurs at earlier stage of the disease, compare to the loss of striatonigral neurons. However, no data are available about the functional role of striatal pENK in HD. According to the neuroprotective properties of opioids that have been recognized recently, the objective of this study was to investigate whether striatal overexpression of pENK at early stage of HD can improve motor dysfunction, and/or reduce striatal neuronal loss in the R6/2 transgenic mouse model of HD. To achieve this goal recombinant adeno-associated-virus (rAAV2-containing green fluorescence protein (GFP-pENK was injected bilaterally in the striatum of R6/2 mice at 5 weeks old to overexpress opioid peptide pENK. Striatal injection of rAAV2-GFP was used as a control. Different behavioral tests were carried out before and/or after striatal injections of rAAV2. The animals were euthanized at 10 weeks old. Our results demonstrate that striatal overexpression of pENK had beneficial effects on behavioral symptoms of HD in R6/2 by: delaying the onset of decline in muscular force; reduction of clasping; improvement of fast motor activity, short-term memory and recognition; as well as normalization of anxiety-like behavior. The improvement of behavioral dysfunction in R6/2 mice having received rAAV2-GFP-pENK associated with upregulation of striatal pENK mRNA; the increased level of enkephalin peptide in the striatum, globus pallidus and substantia nigra; as well as the slight increase in the number of striatal neurons compared with other groups of R6/2. Accordingly, we suggest that at early stage of HD upregulation of striatal enkephalin might play a key role at attenuating illness symptoms.

Adrenergic receptor-mediated modulation of striatal firing patterns.

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Ohta, Hiroyuki; Kohno, Yu; Arake, Masashi; Tamura, Risa; Yukawa, Suguru; Sato, Yoshiaki; Morimoto, Yuji; Nishida, Yasuhiro; Yawo, Hiromu

2016-11-01

Although noradrenaline and adrenaline are some of the most important neurotransmitters in the central nervous system, the effects of noradrenergic/adrenergic modulation on the striatum have not been determined. In order to explore the effects of adrenergic receptor (AR) agonists on the striatal firing patterns, we used optogenetic methods which can induce continuous firings. We employed transgenic rats expressing channelrhodopsin-2 (ChR2) in neurons. The medium spiny neuron showed a slow rising depolarization during the 1-s long optogenetic striatal photostimulation and a residual potential with 8.6-s half-life decay after the photostimulation. As a result of the residual potential, five repetitive 1-sec long photostimulations with 20-s onset intervals cumulatively increased the number of spikes. This 'firing increment', possibly relating to the timing control function of the striatum, was used to evaluate the AR modulation. The β-AR agonist isoproterenol decreased the firing increment between the 1st and 5th stimulation cycles, while the α 1 -AR agonist phenylephrine enhanced the firing increment. Isoproterenol and adrenaline increased the early phase (0-0.5s of the photostimulation) firing response. This adrenergic modulation was inhibited by the β-antagonist propranolol. Conversely, phenylephrine and noradrenaline reduced the early phase response. β-ARs and α 1 -ARs work in opposition controlling the striatal firing initiation and the firing increment. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice.

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Browne, Caleb J; Ji, Xiaodong; Higgins, Guy A; Fletcher, Paul J; Harvey-Lewis, Colin

2017-10-01

Converging lines of behavioral, electrophysiological, and biochemical evidence suggest that 5-HT 2C receptor signaling may bidirectionally influence reward-related behavior through an interaction with the mesolimbic dopamine (DA) system. Here we directly test this hypothesis by examining how modulating 5-HT 2C receptor activity affects DA-dependent behaviors and relate these effects to changes in nucleus accumbens (NAc) DA release. In C57BL/6 mice, locomotor activity and responding for a conditioned reinforcer (CRf), a measure of incentive motivation, were examined following treatment with three 5-HT 2C receptor ligands: the agonist CP809101 (0.25-3 mg/kg), the antagonist SB242084 (0.25-1 mg/kg), or the antagonist/inverse agonist SB206553 (1-5 mg/kg). We further tested whether doses of these compounds that changed locomotor activity and responding for a CRf (1 mg/kg CP809101, 0.5 mg/kg SB242084, or 2.5 mg/kg SB206553) also altered NAc DA release using in vivo microdialysis in anesthetized mice. CP809101 reduced locomotor activity, responding for a CRf, and NAc DA release. In contrast, both SB242084 and SB206553 enhanced locomotor activity, responding for a CRf, and NAc DA release, although higher doses of SB206553 produced opposite behavioral effects. Pretreatment with the non-selective DA receptor antagonist α-flupenthixol prevented SB242084 from enhancing responding for a CRf. Thus blocking tonic 5-HT 2C receptor signaling can release serotonergic inhibition of mesolimbic DA activity and enhance reward-related behavior. The observed bidirectional effects of 5-HT 2C receptor ligands may have important implications when considering the 5-HT 2C receptor as a therapeutic target for psychiatric disorders, particularly those presenting with motivational dysfunctions.

Adenosine A2A receptors and A2A receptor heteromers as key players in striatal function

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Sergi eFerre

2011-06-01

Full Text Available A very significant density of adenosine adenosine A2A receptors (A2ARs is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs. In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs. In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striato-pallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl-cyclase (AC. Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striato-pallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders.

Brain Pharmacokinetics and the Pharmacological Effects on Striatal Neurotransmitter Levels of Pueraria lobata Isoflavonoids in Rat

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Bingxin Xiao

2017-09-01

Full Text Available Isoflavonoids are putatively active components of Pueraria lobata and has been demonstrated prominent neuro-protection effect against cerebrovascular disorders, hypertension or Parkinson's disease (PD. However, the molecular basis for the beneficial effect of Pueraria lobata on nervous systems has not been well revealed. The present study aims to assess striatum exposure to main active isoflavonoids and changes of striatal extracellular neurotransmitters levels in rat brain after intravenous administration of Pueraria lobata isoflavonoids extracts (PLF, to further elucidate its' substantial bases for neuro activities. Fifteen rats were divided into 3 groups (five rats in each group to receive a dose of PLF at 80 or 160 mg/kg or normal saline (vehicle, respectively. An LC-MS/MS method was employed to determine the concentrations of five main isoflavonoids and multiple neurotransmitters in microdialysate from striatal extracellular fluid (ECF of the rats. The exposed quantities of puerarin (PU, 3′-methoxypuerarin (MPU, daidzein-8-C-apiosyl-(1-6-glucoside (DAC, and 3′-hydroxypuerarin (HPU in striatum were dose-dependent. The content of daidzein (DAZ was too low to be detected in all dialysate samples through the experiment. Optimal dose PLF (80 mg/kg promoted DA metabolism and inhibited 5-HT metabolism. No obvious change in the level of GLu was determined. The concentration of GABA presented a temporary decline firstly and then a gradual uptrend followed by a further downtrend. Higher dose (160 mg/kg PLF could enhance the metabolism of both DA and 5-HT, and lower the extracellular level of GLu, without changing GABA concentrations, which might result in alleviation on excitatory toxicity under conditions, such as ischemia. The results infer that different dose of PLF should be chosen to achieve appropriate neurochemical modulation effects under conditions, such as hypertension or ischemia/stroke. These findings may significantly contribute to a

Influences of Dietary Added Sugar Consumption on Striatal Food-Cue Reactivity and Postprandial GLP-1 Response

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Hilary M. Dorton

2018-01-01

. Added sugar intake was negatively associated with GLP-1 response to glucose. Post hoc analysis revealed a negative correlation between GLP-1 response to glucose and BOLD response to food cues in the dorsal striatum. Our findings suggest that habitual added sugar intake is related to increased striatal response to food cues and decreased GLP-1 release following glucose intake, which could contribute to susceptibility to overeating.

4-[[sup 123]I]iodospiperone as a ligand for dopamine DA receptors: in vitro and in vivo experiments in a rat model

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Krogt, J.A. van der; Valkenburg, C F.M. van; Pauwels, E K.J.; Buruma, O J.S. [Rijksuniversiteit Leiden (Netherlands); Reiffers, S [Hospital De Weezenlanden, Zwolle (Netherlands); Doremalen, P.A.P.M. van; Wijnhoven, G [Cygne, Eindhoven (Netherlands)

1992-10-01

Radioiodinated spiperone is of interest for dopamine (DA) receptor studies in the living human brain by single photon emission computed tomography (SPECT). Simulated by data obtained with [[sup 11]C]-N-methyl-spiperone, we synthesized 4-[[sup 123]I]iodospiperone and investigated the in vitro binding characteristics of this ligand to the striatal membrane of the rat and the in vivo distribution over various rat brain regions. The in vitro binding experiments showed that this radioligand displays about 10 times less affinity for the DA receptor than spiperone and specific binding, as shown with [[sup 3]H]spiperone, was not observed. Displacement by butaclamol was not observed. The in vivo studies demonstrated that both 4-[[sup 123]I]iodospiperone and [[sup 3]H]spiperone concentrate in striatal tissue, respectively, 1.9 and 3.5 times as high as in cerebellar tissue. Haloperidol pretreatment largely prevented this accumulation. In view of the obtained target-to-non-target ratios we believe, however, that this accumulation in brain areas rich DA-receptors does not offer prospects for clinical receptor imaging with SPECT. (Author).

Transient and steady-state selection in the striatal microcircuit

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Adam eTomkins

2014-01-01

Full Text Available Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role the striatal microcircuit plays in action selection in the basal ganglia-thalamo-cortical loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-thalamo-cortical loop, to asses the computational role the striatum plays in action selection. We identify a robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's Disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. Thus our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients.

Altered resting state cortico-striatal connectivity in mild to moderate stage Parkinson’s disease

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Youngbin Kwak

2010-09-01

Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI (fcMRI in mild to moderate stage Parkinson’s patients on and off L-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off L-DOPA compared to controls. This enhanced connectivity was down-regulated by L-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off L-DOPA exhibited increased power in the frequency band 0.02 – 0.05 Hz compared to controls and to PD on L-DOPA. The L-DOPA associated decrease in the power of this frequency range modulated the L-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the L-DOPA associated decrease in power in this frequency band also correlated with the L-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and L-DOPA modulate striatal resting state BOLD signal oscillations and corticostriatal network coherence.

Striatal lesions produce distinctive impairments in reaction time performance in two different operant chambers.

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Brasted, P J; Döbrössy, M D; Robbins, T W; Dunnett, S B

1998-08-01

The dorsal striatum plays a crucial role in mediating voluntary movement. Excitotoxic striatal lesions in rats have previously been shown to impair the initiation but not the execution of movement in a choice reaction time task in an automated lateralised nose-poke apparatus (the "nine-hole box"). Conversely, when a conceptually similar reaction time task has been applied in a conventional operant chamber (or "Skinner box"), striatal lesions have been seen to impair the execution rather than the initiation of the lateralised movement. The present study was undertaken to compare directly these two results by training the same group of rats to perform a choice reaction time task in the two chambers and then comparing the effects of a unilateral excitotoxic striatal lesion in both chambers in parallel. Particular attention was paid to adopting similar parameters and contingencies in the control of the task in the two test chambers. After striatal lesions, the rats showed predominantly contralateral impairments in both tasks. However, they showed a deficit in reaction time in the nine-hole box but an apparent deficit in response execution in the Skinner box. This finding confirms the previous studies and indicates that differences in outcome are not simply attributable to procedural differences in the lesions, training conditions or tasks parameters. Rather, the pattern of reaction time deficit after striatal lesions depends critically on the apparatus used and the precise response requirements for each task.

Neuroinflammation alters voltage-dependent conductance in striatal astrocytes.

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Karpuk, Nikolay; Burkovetskaya, Maria; Kielian, Tammy

2012-07-01

Neuroinflammation has the capacity to alter normal central nervous system (CNS) homeostasis and function. The objective of the present study was to examine the effects of an inflammatory milieu on the electrophysiological properties of striatal astrocyte subpopulations with a mouse bacterial brain abscess model. Whole cell patch-clamp recordings were performed in striatal glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP)(+) astrocytes neighboring abscesses at postinfection days 3 or 7 in adult mice. Cell input conductance (G(i)) measurements spanning a membrane potential (V(m)) surrounding resting membrane potential (RMP) revealed two prevalent astrocyte subsets. A1 and A2 astrocytes were identified by negative and positive G(i) increments vs. V(m), respectively. A1 and A2 astrocytes displayed significantly different RMP, G(i), and cell membrane capacitance that were influenced by both time after bacterial exposure and astrocyte proximity to the inflammatory site. Specifically, the percentage of A1 astrocytes was decreased immediately surrounding the inflammatory lesion, whereas A2 cells were increased. These changes were particularly evident at postinfection day 7, revealing increased cell numbers with an outward current component. Furthermore, RMP was inversely modified in A1 and A2 astrocytes during neuroinflammation, and resting G(i) was increased from 21 to 30 nS in the latter. In contrast, gap junction communication was significantly decreased in all astrocyte populations associated with inflamed tissues. Collectively, these findings demonstrate the heterogeneity of striatal astrocyte populations, which experience distinct electrophysiological modifications in response to CNS inflammation.

Prolonged striatal disinhibition as a chronic animal model of tic disorders.

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Vinner, Esther; Israelashvili, Michal; Bar-Gad, Izhar

2017-12-01

Experimental findings and theoretical models have associated Tourette syndrome with abnormal striatal inhibition. The expression of tics, the hallmark symptom of this disorder, has been transiently induced in non-human primates and rodents by the injection of GABA A antagonists into the striatum, leading to temporary disinhibition. The novel chronic model of tic expression utilizes mini-osmotic pumps implanted subcutaneously in the rat's back for prolonged infusion of bicuculline into the dorsolateral striatum. Tics were expressed on the contralateral side to the infusion over a period of multiple days. Tic expression was stable, and maintained similar properties throughout the infusion period. Electrophysiological recordings revealed the existence of tic-related local field potential spikes and individual neuron activity changes that remained stable throughout the infusion period. The striatal disinhibition model provides a unique combination of face validity (tic expression) and construct validity (abnormal striatal inhibition) but is limited to sub-hour periods. The new chronic model extends the period of tic expression to multiple days and thus enables the study of tic dynamics and the effects of behavior and pharmacological agents on tic expression. The chronic model provides similar behavioral and neuronal correlates of tics as the acute striatal disinhibition model but over prolonged periods of time, thus providing a unique, basal ganglia initiated model of tic expression. Chronic expression of symptoms is the key to studying the time varying properties of Tourette syndrome and the effects of multiple internal and external factors on this disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

Elevated Striatal Reactivity Across Monetary and Social Rewards in Bipolar I Disorder

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Dutra, Sunny J.; Cunningham, William A.; Kober, Hedy; Gruber, June

2016-01-01

Bipolar disorder (BD) is associated with increased reactivity to rewards and heightened positive affectivity. It is less clear to what extent this heightened reward sensitivity is evident across contexts and what the associated neural mechanisms might be. The present investigation employed both a monetary and social incentive delay task among adults with remitted BD type I (N=24) and a healthy non-psychiatric control group (HC; N=25) using fMRI. Both whole-brain and region-of-interest analyses revealed elevated ventral and dorsal striatal reactivity across monetary and social reward receipt, but not anticipation, in the BD group. Post-hoc analyses further suggested that greater striatal reactivity to reward receipt across monetary and social reward tasks predicted decreased self-reported positive affect when anticipating subsequent rewards in the HC, but not BD, group. Results point toward elevated striatal reactivity to reward receipt as a potential neural mechanism of reward reactivity. PMID:26390194

Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility

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Cherubini, Marta; Ginés, Silvia

2017-01-01

Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disorder that primarily affects medium spiny neurons within the striatum. HD is caused by inheritance of an expanded CAG repeat in the HTT gene, resulting in a mutant huntingtin (mHtt) protein containing extra glutamine residues. Despite the advances in understanding the molecular mechanisms involved in HD the preferential vulnerability of the striatum remains an intriguing question. This review discusses current knowledge that links altered mitochondrial dynamics with striatal susceptibility in HD. We also highlight how the modulation of mitochondrial function may constitute an attractive therapeutic approach to reduce mHtt-induced toxicity and therefore prevent the selective striatal neurodegeneration. - Highlights: • Mitochondrial dynamics is unbalanced towards fission in HD. • Excessive mitochondrial fragmentation plays a critical role in the selective vulnerability of the striatum in HD. • Therapeutic approaches aimed to inhibit mitochondrial fission could contribute to prevent striatal neurodegeneration in HD.

Distinctive striatal dopamine signaling after dieting and gastric bypass.

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Hankir, Mohammed K; Ashrafian, Hutan; Hesse, Swen; Horstmann, Annette; Fenske, Wiebke K

2015-05-01

Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

A new framework for cortico-striatal plasticity: behavioural theory meets in vitro data at the reinforcement-action interface.

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Kevin N Gurney

2015-01-01

Full Text Available Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem-action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and

Development of striatal patch/matrix organization in organotypic co-cultures of perinatal striatum, cortex and substantia nigra.

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Snyder-Keller, A; Costantini, L C; Graber, D J

2001-01-01

Organotypic cultures of fetal or early postnatal striatum were used to assess striatal patch formation and maintenance in the presence or absence of dopaminergic and glutamatergic influences. Vibratome-cut slices of the striatum prepared from embryonic day 19 to postnatal day 4 rat pups were maintained in static culture on clear membrane inserts in Dulbecco's modified Eagle's medium/F12 (1:1) with 20% horse serum. Some were co-cultured with embryonic day 12-16 ventral mesencephalon and/or embryonic day 19 to postnatal day 4 cortex, which produced a dense dopaminergic innervation and a modest cortical innervation. Donors of striatal and cortical tissue were previously injected with bromo-deoxyuridine (BrdU) on embryonic days 13 and 14 in order to label striatal neurons destined to populate the patch compartment of the striatum. Patches of BrdU-immunoreactive cells were maintained in organotypic cultures of late prenatal (embryonic days 20-22) or early postnatal striatum in the absence of nigral dopaminergic or cortical glutamatergic influences. In slices taken from embryonic day 19 fetuses prior to the time of in vivo patch formation, patches were observed to form after 10 days in vitro, in 39% of nigral-striatal co-cultures compared to 6% of striatal slices cultured alone or in the presence of cortex only. Patches of dopaminergic fibers, revealed by tyrosine hydroxylase immunoreactivity, were observed in the majority of nigral-striatal co-cultures. Immunostaining for the AMPA-type glutamate receptor GluR1 revealed a dense patch distribution in nearly all cultures, which developed in embryonic day 19 cultures after at least six days in vitro. These findings indicate that striatal patch/matrix organization is maintained in organotypic culture, and can be induced to form in vitro in striatal slices removed from fetuses prior to the time of in vivo patch formation. Furthermore, dopaminergic innervation from co-cultured pieces of ventral mesencephalon enhances patch

Striatal hypometabolism in premanifest and manifest Huntington's disease patients

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Lopez-Mora, Diego Alfonso; Camacho, Valle; Fernandez, Alejandro; Montes, Alberto; Carrio, Ignasi [Autonomous University of Barcelona, Nuclear Medicine Department, Hospital Sant Pau, Barcelona (Spain); Perez-Perez, Jesus; Martinez-Horta, Sauel; Kulisevsky, Jaime [Autonomous University of Barcelona, Movement Disorders Unit, Neurology Department, Hospital Sant Pau, Barcelona (Spain); Sampedro, Frederic [University of Barcelona, Barcelona (Spain); Lozano-Martinez, Gloria Andrea; Gomez-Anson, Beatriz [Autonomous University of Barcelona, Neuroradiology, Radiology Department, Hospital Sant Pau, Barcelona (Spain)

2016-11-15

To assess metabolic changes in cerebral {sup 18}F-FDG PET/CT in premanifest and manifest Huntington's disease (HD) subjects compared to a control group and to correlate {sup 18}F-FDG uptake patterns with different disease stages. Thirty-three gene-expanded carriers (Eight males; mean age: 43 y/o; CAG > 39) were prospectively included. Based on the Unified Huntington's Disease Rating Scale Total Motor Score and the Total Functional Capacity, subjects were classified as premanifest (preHD = 15) and manifest (mHD = 18). Estimated time disease-onset was calculated using the Langbehn formula, which allowed classifying preHD as far-to (preHD-A) and close-to (PreHD-B) disease-onset. Eighteen properly matched participants were included as a control group (CG). All subjects underwent brain {sup 18}F-FDG PET/CT and MRI. {sup 18}F-FDG PET/CT were initially assessed by two nuclear medicine physicians identifying qualitative metabolic changes in the striatum. Quantitative analysis was performed using SPM8 with gray matter atrophy correction using the BPM toolbox. Visual analysis showed a marked striatal hypometabolism in mHD. A normal striatal distribution of {sup 18}F-FDG uptake was observed for most of the preHD subjects. Quantitative analysis showed a significant striatal hypometabolism in mHD subjects compared to CG (p < 0.001 uncorrected, k = 50 voxels). In both preHD groups we observed a significant striatal hypometabolism with respect to CG (p < 0.001 uncorrected, k = 50 voxels). In mHD subjects we observed a significant striatal hypometabolism with respect to both preHD groups (p < 0.001 uncorrected, k = 50 voxels). {sup 18}F-FDG PET/CT might be a helpful tool to identify patterns of glucose metabolism in the striatum across the stages of HD and might be relevant in assessing the clinical status of gene-expanded HD carriers due to the fact that dysfunctional glucose metabolism begins at early preHD stages of the disease. {sup 18}F-FDG PET/CT appears as a

Centrality of striatal cholinergic transmission in basal ganglia function

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Paola eBonsi

2011-02-01

Full Text Available Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction.Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson’s disease and dystonia.Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders.

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.

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Rebecca Kuepper

Full Text Available Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and (18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ(9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis. In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ(9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder, 8 patients with psychotic disorder (high risk psychotic disorder and 7 un-related first-degree relatives (intermediate risk psychotic disorder. PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM, which accounts for time-dependent changes in (18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ(9-THC administration, reflecting dopamine release. While Δ(9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ(9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ(9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.

AN IMPROVED SPECTROSCOPIC ANALYSIS OF DA WHITE DWARFS FROM THE SLOAN DIGITAL SKY SURVEY DATA RELEASE 4

International Nuclear Information System (INIS)

Tremblay, P.-E.; Bergeron, P.; Gianninas, A.

2011-01-01

We present an improved spectroscopic and photometric analysis of hydrogen-line DA white dwarfs from the Sloan Digital Sky Survey Data Release 4 (SDSS DR4) based on model atmospheres that include improved Stark broadening profiles with non-ideal gas effects. We also perform a careful visual inspection of all spectroscopic fits with high signal-to-noise ratios (S/Ns > 12) and present improved atmospheric parameters (T eff and log g) for each white dwarf. Through a comparison of spectroscopic and photometric temperatures, we report the discovery of 35 DA+DB/DC double degenerate candidates and two helium-rich DA stars. We also determine that a cutoff at S/N = 15 optimizes the size and quality of the sample for computing the mean mass of DA white dwarfs, for which we report a value of 0.613 M sun . We compare our results to previous analyses of the SDSS DR4 and find a good agreement if we account for the shift produced by the improved Stark profiles. Finally, the properties of DA white dwarfs in the SDSS are weighed against those of the Villanova White Dwarf Catalog sample of Gianninas et al. We find systematically lower masses (by about 3% on average), a difference that we trace back to the data reduction procedure of the SDSS. We conclude that a better understanding of these differences will be important to determine the absolute temperature scale and mean mass of DA white dwarfs.

Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

Science.gov (United States)

Kaasinen, Valtteri; Vahlberg, Tero

2017-12-01

A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882. © 2017 American Neurological Association.

Striatal [[sup 11]C]-N-methyl-spiperone binding in patients with focal dystonia (torticollis) using positron emission tomography

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Leenders, K [Paul Scherrer Inst. (PSI), Villigen (Switzerland); Hartvig, P [Hospital Pharmacy, Univ. Hospital, Uppsala (Sweden); Forsgren, L; Holmgren, G; Almay, B [Dept. of Neurology, Umeaa Univ., Umeaa (Sweden); Eckernaes, S A [Dept. of Neurology, Univ. Hospital, Uppsala (Sweden); Lundqvist, H; Laangstroem, B [Uppsala Univ. PET-Center, Uppsala (Sweden)

1993-01-01

Specific binding of [[sup 11]C]-N-methyl-spiperone to striatal dopamine D2 receptors was assessed using positron emission tomography (PET) in 6 patients with adult-onset focal dystonia (predominantly spasmodic torticollis) and in 5 healthy subjects. No significant difference in average specific striatal tracer uptake between patients and healthy subjects was found. However, in the 5 patients showing lateralisation of clinical signs a trend to higher striatal tracer uptake in the contralateral hemisphere was observed. (authors).

Abnormal fronto-striatal activation as a marker of threshold and subthreshold Bulimia Nervosa.

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Cyr, Marilyn; Yang, Xiao; Horga, Guillermo; Marsh, Rachel

2018-04-01

This study aimed to determine whether functional disturbances in fronto-striatal control circuits characterize adolescents with Bulimia Nervosa (BN) spectrum eating disorders regardless of clinical severity. FMRI was used to assess conflict-related brain activations during performance of a Simon task in two samples of adolescents with BN symptoms compared with healthy adolescents. The BN samples differed in the severity of their clinical presentation, illness duration and age. Multi-voxel pattern analyses (MVPAs) based on machine learning were used to determine whether patterns of fronto-striatal activation characterized adolescents with BN spectrum disorders regardless of clinical severity, and whether accurate classification of less symptomatic adolescents (subthreshold BN; SBN) could be achieved based on patterns of activation in adolescents who met DSM5 criteria for BN. MVPA classification analyses revealed that both BN and SBN adolescents could be accurately discriminated from healthy adolescents based on fronto-striatal activation. Notably, the patterns detected in more severely ill BN compared with healthy adolescents accurately discriminated less symptomatic SBN from healthy adolescents. Deficient activation of fronto-striatal circuits can characterize BN early in its course, when clinical presentations are less severe, perhaps pointing to circuit-based disturbances as useful biomarker or risk factor for the disorder, and a tool for understanding its developmental trajectory, as well as the development of early interventions. © 2018 Wiley Periodicals, Inc.

The basal ganglia matching tools package for striatal uptake semi-quantification: description and validation

International Nuclear Information System (INIS)

Calvini, Piero; Rodriguez, Guido; Nobili, Flavio; Inguglia, Fabrizio; Mignone, Alessandro; Guerra, Ugo P.

2007-01-01

To design a novel algorithm (BasGan) for automatic segmentation of striatal 123 I-FP-CIT SPECT. The BasGan algorithm is based on a high-definition, three-dimensional (3D) striatal template, derived from Talairach's atlas. A blurred template, obtained by convolving the former with a 3D Gaussian kernel (FWHM = 10 mm), approximates striatal activity distribution. The algorithm performs translations and scale transformation on the bicommissural aligned image to set the striatal templates with standard size in an appropriate initial position. An optimization protocol automatically performs fine adjustments in the positioning of blurred templates to best match the radioactive counts, and locates an occipital ROI for background evaluation. Partial volume effect correction is included in the process of uptake computation of caudate, putamen and background. Experimental validation was carried out by means of six acquisitions of an anthropomorphic striatal phantom. The BasGan software was applied to a first set of patients with Parkinson's disease (PD) versus patients affected by essential tremor. A highly significant correlation was achieved between true binding potential and measured 123 I activity from the phantom. 123 I-FP-CIT uptake was significantly lower in all basal ganglia in the PD group versus controls with both BasGan and a conventional ROI method used for comparison, but particularly with the former. Correlations with the motor UPDRS score were far more significant with the BasGan. The novel BasGan algorithm automatically performs the 3D segmentation of striata. Because co-registered MRI is not needed, it can be used by all nuclear medicine departments, since it is freely available on the Web. (orig.)

Assessment of striatal & postural deformities in patients with Parkinson's disease

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Sanjay Pandey

2016-01-01

Interpretation & conclusions: Our results showed that striatal and postural deformities were common and present in about half of the patients with PD. These deformities we more common in patients with advanced stage of PD.

A Bacoside containing Bacopa monnieri extract reduces both morphine hyperactivity plus the elevated striatal dopamine and serotonin turnover.

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Rauf, Khalid; Subhan, Fazal; Sewell, Robert D E

2012-05-01

Bacopa monnieri (BM) has been used in Ayurvedic medicine as a nootropic, anxiolytic, antiepileptic and antidepressant. An n-butanol extract of the plant (nBt-ext BM) was analysed and found to contain Bacoside A (Bacoside A3, Bacopaside II and Bacopasaponin C). The effects of the BM extract were then studied on morphine-induced hyperactivity as well as dopamine and serotonin turnover in the striatum since these parameters have a role in opioid sensitivity and dependence. Mice were pretreated with saline or nBt-ext BM (5, 10 and 15 mg/kg, orally), 60 min before morphine administration and locomotor activity was subsequently recorded. Immediately after testing, striatal tissues were analysed for dopamine (DA), serotonin (5HT) and their metabolites using HPLC coupled with electrochemical detection. The results indicated that nBt-ext BM significantly (p < 0.001) decreased locomotor activity in both the saline and morphine treated groups. Additionally, nBt-ext BM significantly lowered morphine-induced dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-H1AA) upsurges in the striatum but failed to affect DA, 5-HT and their metabolites in the saline treated group. These findings suggest that nBt-ext BM has an antidopaminergic/serotonergic effect and may have potential beneficial effects in the treatment of morphine dependence. Copyright © 2011 John Wiley & Sons, Ltd.

Real Time Imaging of Biomarkers in the Parkinson's Brain Using Mini-Implantable Biosensors. II. Pharmaceutical Therapy with Bromocriptine

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Patricia A. Broderick

2009-12-01

Full Text Available We used Neuromolecular Imaging (NMI and trademarked BRODERICK PROBE® mini-implantable biosensors, to selectively and separately detect neurotransmitters in vivo, on line, within seconds in the dorsal striatal brain of the Parkinson’s Disease (PD animal model. We directly compared our results derived from PD to the normal striatal brain of the non-Parkinson’s Disease (non-PD animal. This advanced biotechnology enabled the imaging of dopamine (DA, serotonin (5-HT, homovanillic acid (HVA a metabolite of DA, L-tryptophan (L-TP a precursor to 5-HT and peptides, dynorphin A 1-17 (Dyn A and somatostatin (somatostatin releasing inhibitory factor (SRIF. Each neurotransmitter and neurochemical was imaged at a signature electroactive oxidation/half-wave potential in dorsal striatum of the PD as compared with the non-PD animal. Both endogenous and bromocriptine-treated neurochemical profiles in PD and non-PD were imaged using the same experimental paradigm and detection sensitivities. Results showed that we have found significant neurotransmitter peptide biomarkers in the dorsal striatal brain of endogenous and bromocriptine-treated PD animals. The peptide biomarkers were not imaged in dorsal striatal brain of non-PD animals, either endogenously or bromocriptine-treated. These findings provide new pharmacotherapeutic strategies for PD patients. Thus, our findings are highly applicable to the clinical treatment of PD.

A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder

OpenAIRE

Herbort, Maike C.; Soch, Joram; W?stenberg, Torsten; Krauel, Kerstin; Pujara, Maia; Koenigs, Michael; Gallinat, J?rgen; Walter, Henrik; Roepke, Stefan; Schott, Bj?rn H.

2016-01-01

Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BP...

Effect of Exercise Training on Striatal Dopamine D2/D3 Receptors in Methamphetamine Users during Behavioral Treatment.

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Robertson, Chelsea L; Ishibashi, Kenji; Chudzynski, Joy; Mooney, Larissa J; Rawson, Richard A; Dolezal, Brett A; Cooper, Christopher B; Brown, Amira K; Mandelkern, Mark A; London, Edythe D

2016-05-01

Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

Blunted striatal response to monetary reward anticipation during smoking abstinence predicts lapse during a contingency-managed quit attempt.

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Sweitzer, Maggie M; Geier, Charles F; Denlinger, Rachel; Forbes, Erika E; Raiff, Bethany R; Dallery, Jesse; McClernon, F J; Donny, Eric C

2016-03-01

Tobacco smoking is associated with dysregulated reward processing within the striatum, characterized by hypersensitivity to smoking rewards and hyposensitivity to non-smoking rewards. This bias toward smoking reward at the expense of alternative rewards is further exacerbated by deprivation from smoking, which may contribute to difficulty maintaining abstinence during a quit attempt. We examined whether abstinence-induced changes in striatal processing of rewards predicted lapse likelihood during a quit attempt supported by contingency management (CM), in which abstinence from smoking was reinforced with money. Thirty-six non-treatment-seeking smokers participated in two functional MRI (fMRI) sessions, one following 24-h abstinence and one following smoking as usual. During each scan, participants completed a rewarded guessing task designed to elicit striatal activation in which they could earn smoking and monetary rewards delivered after the scan. Participants then engaged in a 3-week CM-supported quit attempt. As previously reported, 24-h abstinence was associated with increased striatal activation in anticipation of smoking reward and decreased activation in anticipation of monetary reward. Individuals exhibiting greater decrements in right striatal activation to monetary reward during abstinence (controlling for activation during non-abstinence) were more likely to lapse during CM (p reward. These results are consistent with a growing number of studies indicating the specific importance of disrupted striatal processing of non-drug reward in nicotine dependence and highlight the importance of individual differences in abstinence-induced deficits in striatal function for smoking cessation.

Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia.

Science.gov (United States)

Grimm, Oliver; Heinz, Andreas; Walter, Henrik; Kirsch, Peter; Erk, Susanne; Haddad, Leila; Plichta, Michael M; Romanczuk-Seiferth, Nina; Pöhland, Lydia; Mohnke, Sebastian; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Schäfer, Axel; Cichon, Sven; Nöthen, Markus; Rietschel, Marcella; Tost, Heike; Meyer-Lindenberg, Andreas

2014-05-01

Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice.

Science.gov (United States)

Ossato, Andrea; Uccelli, Licia; Bilel, Sabrine; Canazza, Isabella; Di Domenico, Giovanni; Pasquali, Micol; Pupillo, Gaia; De Luca, Maria Antonietta; Boschi, Alessandra; Vincenzi, Fabrizio; Rimondo, Claudia; Beggiato, Sarah; Ferraro, Luca; Varani, Katia; Borea, Pier Andrea; Serpelloni, Giovanni; De-Giorgio, Fabio; Marti, Matteo

2017-01-01

JWH-018 and AKB48 are two synthetic cannabinoids (SCBs) belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB 1 receptor blockade and dopamine (DA) D 1/5 and D 2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT) revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [ 123 I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc) shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [ 3 H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.

Psychostimulant Effect of the Synthetic Cannabinoid JWH-018 and AKB48: Behavioral, Neurochemical, and Dopamine Transporter Scan Imaging Studies in Mice

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Andrea Ossato

2017-08-01

Full Text Available JWH-018 and AKB48 are two synthetic cannabinoids (SCBs belonging to different structural classes and illegally marketed as incense, herbal preparations, or chemical supply for theirs psychoactive cannabis-like effects. Clinical reports from emergency room reported psychomotor agitation as one of the most frequent effects in people assuming SCBs. This study aimed to investigate the psychostimulant properties of JWH-018 and AKB48 in male CD-1 mice and to compare their behavioral and biochemical effects with those caused by cocaine and amphetamine. In vivo studies showed that JWH-018 and AKB48, as cocaine and amphetamine, facilitated spontaneous locomotion in mice. These effects were prevented by CB1 receptor blockade and dopamine (DA D1/5 and D2/3 receptors inhibition. SPECT-CT studies on dopamine transporter (DAT revealed that, as cocaine and amphetamine, JWH-018 and AKB48 decreased the [123I]-FP-CIT binding in the mouse striatum. Conversely, in vitro competition binding studies revealed that, unlike cocaine and amphetamine, JWH-018 and AKB48 did not bind to mouse or human DAT. Moreover, microdialysis studies showed that the systemic administration of JWH-018, AKB48, cocaine, and amphetamine stimulated DA release in the nucleus accumbens (NAc shell of freely moving mice. Finally, unlike amphetamine and cocaine, JWH-018 and AKB48 did not induce any changes on spontaneous [3H]-DA efflux from murine striatal synaptosomes. The present results suggest that SCBs facilitate striatal DA release possibly with different mechanisms than cocaine and amphetamine. Furthermore, they demonstrate, for the first time, that JWH-018 and AKB48 induce a psychostimulant effect in mice possibly by increasing NAc DA release. These data, according to clinical reports, outline the potential psychostimulant action of SCBs highlighting their possible danger to human health.

Motor and cortico-striatal-thalamic connectivity alterations in intrauterine growth restriction.

Science.gov (United States)

Eixarch, Elisenda; Muñoz-Moreno, Emma; Bargallo, Nuria; Batalle, Dafnis; Gratacos, Eduard

2016-06-01

Intrauterine growth restriction is associated with short- and long-term neurodevelopmental problems. Structural brain changes underlying these alterations have been described with the use of different magnetic resonance-based methods that include changes in whole structural brain networks. However, evaluation of specific brain circuits and its correlation with related functions has not been investigated in intrauterine growth restriction. In this study, we aimed to investigate differences in tractography-related metrics in cortico-striatal-thalamic and motor networks in intrauterine growth restricted children and whether these parameters were related with their specific function in order to explore its potential use as an imaging biomarker of altered neurodevelopment. We included a group of 24 intrauterine growth restriction subjects and 27 control subjects that were scanned at 1 year old; we acquired T1-weighted and 30 directions diffusion magnetic resonance images. Each subject brain was segmented in 93 regions with the use of anatomical automatic labeling atlas, and deterministic tractography was performed. Brain regions included in motor and cortico-striatal-thalamic networks were defined based in functional and anatomic criteria. Within the streamlines that resulted from the whole brain tractography, those belonging to each specific circuit were selected and tractography-related metrics that included number of streamlines, fractional anisotropy, and integrity were calculated for each network. We evaluated differences between both groups and further explored the correlation of these parameters with the results of socioemotional, cognitive, and motor scales from Bayley Scale at 2 years of age. Reduced fractional anisotropy (cortico-striatal-thalamic, 0.319 ± 0.018 vs 0.315 ± 0.015; P = .010; motor, 0.322 ± 0.019 vs 0.319 ± 0.020; P = .019) and integrity cortico-striatal-thalamic (0.407 ± 0.040 vs 0.399 ± 0.034; P = .018; motor, 0.417 ± 0.044 vs 0

Postural & striatal deformities in Parkinson`s disease: Are these rare?

Directory of Open Access Journals (Sweden)

Sanjay Pandey

2016-01-01

Full Text Available Parkinson`s disease (PD is the most common neurodegenerative disease and is characterized by tremor, rigidity and akinesia. Diagnosis is clinical in the majority of the patients. Patients with PD may have stooped posture but some of them develop different types of postural and striatal deformities. Usually these deformities are more common in atypical parkinsonian disorders such as progressive supranuclear palsy and multisystem atrophy. But in many studies it has been highlighted that these may also be present in approximately one third of PD patients leading to severe disability. These include antecollis or dropped head, camptocormia, p0 isa syndrome, scoliosis, striatal hands and striatal toes. The pathogenesis of these deformities is a complex combination of central and peripheral influences such as rigidity, dystonia and degenerative skeletal changes. Duration of parkinsonism symptoms is an important risk factor and in majority of the patients these deformities are seen in advanced statge of the disease. The patients with such symptoms may initially respond to dopaminergic medications but if not intervened they may become fixed and difficult to treat. Pain and restriction of movement are most common clinical manifestations and these may mimick symptoms of musculoskeletal disorders like rheumatoid arthritis. Early diagnosis is important as the patients may respond to adjustment in dopaminergic medications. Recent advances such as deep brain stimulation (DBS and ultrasound guided botulinum toxin injection are helpful in management of these deformities in patients with PD.

Aspects of dopamine and acetylcholine release induced by glutamate receptors; Aspectos das liberacoes de dopamina e acetilcolina mediadas por receptores de glutamato

Energy Technology Data Exchange (ETDEWEB)

Paes, Paulo Cesar de Arruda

2002-07-01

The basal ganglia play an important role in the motor control of rats and humans. This control involves different neurotransmitters and the mutual control of these key elements has been subject to several studies. In this work we determined the role of glutamate on the release of radioactively labelled dopamine and acetylcholine from chopped striatal tissue in vitro. The values of Effective Concentration 50% for glutamate, NMDA, kainic, quisqualic acids and AMPA on the release of dopamine and acetylcholine were obtained. The inhibitory effects of magnesium, tetrodotoxin, MK-801, AP5 and MCPG, as well as the effects of glycin were evaluated. The results suggested that dopamine is influenced by the NMDA type glutamate receptor while acetylcholine seems to be influenced by NMDA, kainate and AMPA receptors. Tetrodotoxin experiments suggested that kainate receptors are both present in cholinergic terminals and cell bodies while AMPA and NMDA receptors are preferentially distributed in cell bodies. Magnesium effectively blocked the NMDA stimulation and unexpectedly also AMPA- and quisqualate-induced acetylcholine release. The latter could not be blocked by MCPG ruling out the participation of methabotropic receptors. MK-801 also blocked NMDA-receptors. Results point out the importance of the glutamic acid control of dopamine and acetylcholine release in striatal tissue. (author)

Striatal structure and its association with N-Acetylaspartate and glutamate in autism spectrum disorder and obsessive compulsive disorder

NARCIS (Netherlands)

Naaijen, Jilly; Zwiers, Marcel P.; Forde, Natalie J.; Williams, Steven C. R.; Durston, Sarah; Brandeis, Daniel; Glennon, Jeffrey C.; Franke, Barbara; Lythgoe, David J.; Buitelaar, Jan K.

Autism spectrum disorders (ASD) and obsessive compulsive disorder (OCD) are often comorbid and are associated with changes in striatal volumes and N-Acetylaspartate (NAA) and glutamate levels. Here, we investigated the relation between dorsal striatal volume and NAA and glutamate levels. We

DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons.

Science.gov (United States)

Engmann, Olivia; Giralt, Albert; Gervasi, Nicolas; Marion-Poll, Lucile; Gasmi, Laila; Filhol, Odile; Picciotto, Marina R; Gilligan, Diana; Greengard, Paul; Nairn, Angus C; Hervé, Denis; Girault, Jean-Antoine

2015-12-07

Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.

Prefrontal cortex and striatal activation by feedback in Parkinson's disease

NARCIS (Netherlands)

Keitz, Martijn; Koerts, Janneke; Kortekaas, Rudie; Renken, Remco; de Jong, Bauke M.; Leenders, Klaus L.

2008-01-01

Positive feedbacks reinforce goal-directed behavior and evoke pleasure. in Parkinson's disease (PD) the striatal dysfunction impairs motor performance, but also may lead to decreased positive feedback (reward) processing. This study investigates two types of positive feedback processing (monetary

Striatal dopamine D2/3 receptor availability in treatment resistant depression.

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Bart P de Kwaasteniet

Full Text Available Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3 receptor (D2/3R binding has not been investigated in TRD subjects. We used [(123I]IBZM single photon emission computed tomography (SPECT to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group and 15 matched healthy controls. Results showed no significant difference (p = 0.75 in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics relative to TRD patients and healthy controls (p<0.001 but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.

Ventral striatal activity correlates with memory confidence for old- and new-responses in a difficult recognition test.

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Ulrike Schwarze

Full Text Available Activity in the ventral striatum has frequently been associated with retrieval success, i.e., it is higher for hits than correct rejections. Based on the prominent role of the ventral striatum in the reward circuit, its activity has been interpreted to reflect the higher subjective value of hits compared to correct rejections in standard recognition tests. This hypothesis was supported by a recent study showing that ventral striatal activity is higher for correct rejections than hits when the value of rejections is increased by external incentives. These findings imply that the striatal response during recognition is context-sensitive and modulated by the adaptive significance of "oldness" or "newness" to the current goals. The present study is based on the idea that not only external incentives, but also other deviations from standard recognition tests which affect the subjective value of specific response types should modulate striatal activity. Therefore, we explored ventral striatal activity in an unusually difficult recognition test that was characterized by low levels of confidence and accuracy. Based on the human uncertainty aversion, in such a recognition context, the subjective value of all high confident decisions is expected to be higher than usual, i.e., also rejecting items with high certainty is deemed rewarding. In an accompanying behavioural experiment, participants rated the pleasantness of each recognition response. As hypothesized, ventral striatal activity correlated in the current unusually difficult recognition test not only with retrieval success, but also with confidence. Moreover, participants indicated that they were more satisfied by higher confidence in addition to perceived oldness of an item. Taken together, the results are in line with the hypothesis that ventral striatal activity during recognition codes the subjective value of different response types that is modulated by the context of the recognition test.

Amphetamine-induced dopamine release and neurocognitive function in treatment-naive adults with ADHD.

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Cherkasova, Mariya V; Faridi, Nazlie; Casey, Kevin F; O'Driscoll, Gillian A; Hechtman, Lily; Joober, Ridha; Baker, Glen B; Palmer, Jennifer; Dagher, Alain; Leyton, Marco; Benkelfat, Chawki

2014-05-01

Converging evidence from clinical, preclinical, neuroimaging, and genetic research implicates dopamine neurotransmission in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The in vivo neuroreceptor imaging evidence also suggests alterations in the dopamine system in ADHD; however, the nature and behavioral significance of those have not yet been established. Here, we investigated striatal dopaminergic function in ADHD using [(11)C]raclopride PET with a d-amphetamine challenge. We also examined the relationship of striatal dopamine responses to ADHD symptoms and neurocognitive function. A total of 15 treatment-free, noncomorbid adult males with ADHD (age: 29.87 ± 8.65) and 18 healthy male controls (age: 25.44 ± 6.77) underwent two PET scans: one following a lactose placebo and the other following d-amphetamine (0.3 mg/kg, p.o.), administered double blind and in random order counterbalanced across groups. In a separate session without a drug, participants performed a battery of neurocognitive tests. Relative to the healthy controls, the ADHD patients, as a group, showed greater d-amphetamine-induced decreases in striatal [(11)C]raclopride binding and performed more poorly on measures of response inhibition. Across groups, a greater magnitude of d-amphetamine-induced change in [(11)C]raclopride binding potential was associated with poorer performance on measures of response inhibition and ADHD symptoms. Our findings suggest an augmented striatal dopaminergic response in treatment-naive ADHD. Though in contrast to results of a previous study, this finding appears consistent with a model proposing exaggerated phasic dopamine release in ADHD. A susceptibility to increased phasic dopamine responsivity may contribute to such characteristics of ADHD as poor inhibition and impulsivity.

Imaging of striatal dopamine transporters in rat brain with single pinhole SPECT and co-aligned MRI is highly reproducible

International Nuclear Information System (INIS)

Booij, Jan; Bruin, Kora de; Win, Maartje M.L. de; Lavini, Cristina Mphil; Heeten, Gerard J. den; Habraken, Jan

2003-01-01

A recently developed pinhole high-resolution SPECT system was used to measure striatal to non-specific binding ratios in rats (n = 9), after injection of the dopamine transporter ligand 123 I-FP-CIT, and to assess its test/retest reproducibility. For co-alignment purposes, the rat brain was imaged on a 1.5 Tesla clinical MRI scanner using a specially developed surface coil. The SPECT images showed clear striatal uptake. On the MR images, cerebral and extra-cerebral structures could be easily delineated. The mean striatal to non-specific [ 123 I]FP-CIT binding ratios of the test/retest studies were 1.7 ± 0.2 and 1.6 ± 0.2, respectively. The test/retest variability was approximately 9%. We conclude that the assessment of striatal [ 123 I]FP-CIT binding ratios in rats is highly reproducible

DISC1 and striatal volume: a potential risk phenotype for mental illness

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M. Mallar eChakravarty

2012-06-01

Full Text Available Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2 receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans to our knowledge. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281 and Ser704Cys (rs821618 single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in fifty-four healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p=0.017; right striatum: p=0.016. From the exploratory analyses we found that Phe carriers also had larger right hemisphere volumes and right occipital lobe surface area (p=0.014 compared to LeuLeu homozygotes (p=0.0074. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1’s effects on the striatum .

Contribution of vesicular and cytosolic dopamine to the increased striatal dopamine efflux elicited by intrastriatal injection of SKF38393.

NARCIS (Netherlands)

Saigusa, T.; Aono, Y.; Sekino, R.; Uchida, T.; Takada, K.; Oi, Y.; Koshikawa, N.; Cools, A.R.

2009-01-01

Like dexamphetamine, SKF38393 induces an increase in striatal dopamine efflux which is insensitive for tetrodotoxin, Ca(2+) independent and prevented by a dopamine transporter inhibitor. The dexamphetamine-induced striatal dopamine efflux originates from both the reserpine-sensitive vesicular

Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers.

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Oberlin, Brandon G; Albrecht, Daniel S; Herring, Christine M; Walters, James W; Hile, Karen L; Kareken, David A; Yoder, Karmen K

2015-06-01

Dopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood. To determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD). NTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [(11)C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND. Across all subjects, greater impulsive choice for $20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST. Preference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.

Suppression of serotonin hyperinnervation does not alter the dysregulatory influences of dopamine depletion on striatal neuropeptide gene expression in rodent neonates.

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Basura, G J; Walker, P D

1999-10-15

Sixty days following neonatal dopamine depletion (>98%) with 6-hydroxydopamine, preprotachykinin and preprodynorphin mRNA levels were significantly reduced (67 and 78% of vehicle controls, respectively) in the anterior striatum as determined by in situ hybridization while preproenkephalin mRNA expression was elevated (133% of vehicle controls). Suppression of the serotonin hyperinnervation phenomenon in the dopamine-depleted rat with 5,7-dihydroxytryptamine yielded no significant alterations in reduced striatal preprotachykinin (66%) or preprodynorphin (64%) mRNA levels, while preproenkephalin mRNA expression remained significantly elevated (140%). These data suggest that striatal serotonin hyperinnervation does not contribute to the development of dysregulated striatal neuropeptide transmission in either direct or indirect striatal output pathways following neonatal dopamine depletion.

Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia.

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Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A; Quik, Maryka

2016-12-01

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos + D2 MSNs and decreased c-Fos + non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired development of cortico-striatal synaptic connectivity in a cell culture model of Huntington's disease.

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Buren, Caodu; Parsons, Matthew P; Smith-Dijak, Amy; Raymond, Lynn A

2016-03-01

Huntington's disease (HD) is a genetically inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein. This mutation results in progressive cell death that is particularly striking in the striatum. Recent evidence indicates that early HD is initially a disease of the synapse, in which subtle alterations in synaptic neurotransmission, particularly at the cortico-striatal (C-S) synapse, can be detected well in advance of cell death. Here, we used a cell culture model in which striatal neurons are co-cultured with cortical neurons, and monitored the development of C-S connectivity up to 21days in vitro (DIV) in cells cultured from either the YAC128 mouse model of HD or the background strain, FVB/N (wild-type; WT) mice. Our data demonstrate that while C-S connectivity in WT co-cultures develops rapidly and continuously from DIV 7 to 21, YAC128 C-S connectivity shows no significant growth from DIV 14 onward. Morphological and electrophysiological data suggest that a combination of pre- and postsynaptic mechanisms contribute to this effect, including a reduction in both the postsynaptic dendritic arborization and the size and replenishment rate of the presynaptic readily releasable pool of excitatory vesicles. Moreover, a chimeric culture strategy confirmed that the most robust impairment in C-S connectivity was only observed when mutant huntingtin was expressed both pre- and postsynaptically. In all, our data demonstrate a progressive HD synaptic phenotype in this co-culture system that may be exploited as a platform for identifying promising therapeutic strategies to prevent early HD-associated synaptopathy. Copyright © 2015 Elsevier Inc. All rights reserved.

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

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Calipari, Erin S; Sun, Haiguo; Eldeeb, Khalil; Luessen, Deborah J; Feng, Xin; Howlett, Allyn C; Jones, Sara R; Chen, Rong

2014-01-01

Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [35S]GTPγS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gαi2, whereas striatal D2/D3 receptors were coupled equally to Gαi2 and Gαo for signaling. Importantly, AMPH abolished the interaction between Gαi2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gαi2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction. PMID:24513972

Enhanced striatal sensitivity to aversive reinforcement in adolescents versus adults.

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Galván, Adriana; McGlennen, Kristine M

2013-02-01

Neurodevelopmental changes in mesolimbic regions are associated with adolescent risk-taking behavior. Numerous studies have shown exaggerated activation in the striatum in adolescents compared with children and adults during reward processing. However, striatal sensitivity to aversion remains elusive. Given the important role of the striatum in tracking both appetitive and aversive events, addressing this question is critical to understanding adolescent decision-making, as both positive and negative factors contribute to this behavior. In this study, human adult and adolescent participants performed a task in which they received squirts of appetitive or aversive liquid while undergoing fMRI, a novel approach in human adolescents. Compared with adults, adolescents showed greater behavioral and striatal sensitivity to both appetitive and aversive stimuli, an effect that was exaggerated in response to delivery of the aversive stimulus. Collectively, these findings contribute to understanding how neural responses to positive and negative outcomes differ between adolescents and adults and how they may influence adolescent behavior.

Decreased spontaneous eye blink rates in chronic cannabis users: evidence for striatal cannabinoid-dopamine interactions.

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Mikael A Kowal

Full Text Available Chronic cannabis use has been shown to block long-term depression of GABA-glutamate synapses in the striatum, which is likely to reduce the extent to which endogenous cannabinoids modulate GABA- and glutamate-related neuronal activity. The current study aimed at investigating the effect of this process on striatal dopamine levels by studying the spontaneous eye blink rate (EBR, a clinical marker of dopamine level in the striatum. 25 adult regular cannabis users and 25 non-user controls matched for age, gender, race, and IQ were compared. Results show a significant reduction in EBR in chronic users as compared to non-users, suggesting an indirect detrimental effect of chronic cannabis use on striatal dopaminergic functioning. Additionally, EBR correlated negatively with years of cannabis exposure, monthly peak cannabis consumption, and lifetime cannabis consumption, pointing to a relationship between the degree of impairment of striatal dopaminergic transmission and cannabis consumption history.

Age related changes in striatal resting state functional connectivity in autism

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Aarthi ePadmanabhan

2013-11-01

Full Text Available Characterizing the nature of developmental change is critical to understanding the mechanisms that are impaired in complex neurodevelopment disorders such as autism spectrum disorder (ASD and, pragmatically, may allow us to pinpoint periods of plasticity when interventions are particularly useful. Although aberrant brain development has long been theorized as a characteristic feature of ASD, the neural substrates have been difficult to characterize, in part due to a lack of developmental data and to performance confounds. To address these issues, we examined the development of intrinsic functional connectivity with resting state fMRI from late childhood to early adulthood (8-36 years, using a seed based functional connectivity method with the striatum. Overall, we found that both groups show decreases in cortico-striatal circuits over age. However, when controlling for age, ASD participants showed increased connectivity with parietal cortex and decreased connectivity with prefrontal cortex relative to TD participants. In addition, ASD participants showed aberrant age-related changes in connectivity with anterior aspects of cerebellum, and posterior temporal regions (e.g. fusiform gyrus, inferior and superior temporal gyri. In sum, we found prominent differences in the development of striatal connectivity in ASD, most notably, atypical development of connectivity in striatal networks that may underlie cognitive and social reward processing. Our findings highlight the need to identify the biological mechanisms of perturbations in brain reorganization over development, which also may help clarify discrepant findings in the literature.

Transgenic mice expressing a Huntington s disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity

OpenAIRE

Hansson, Oskar; Petersén, Åsa; Leist, Marcel; Nicotera, Pierluigi; Castilho, Roger F.; Brundin, Patrik

1999-01-01

Huntington’s disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R...

Direct effect of nicotine on mesolimbic dopamine release in rat nucleus accumbens shell

NARCIS (Netherlands)

Kleijn, J.; Folgering, J. H. A.; van der Hart, M. C. G.; Rollema, H.; Cremers, T. I. F. H.; Westerink, B. H. C.

2011-01-01

Nicotine stimulates dopamine (DA) cell firing via a local action at somatodendritic sites in the ventral tegmental area (VTA), increasing DA release in the nucleus accumbens (NAcc). Additionally, nicotine may also modulate DA release via a direct effect in the NAcc. This study examined the

64 kDa protein is a candidate for a thyrotropin-releasing hormone receptor in prolactin-producing rat pituitary tumor cells (GH4C1 cells)

International Nuclear Information System (INIS)

Wright, M.; Hogset, A.; Alestrom, P.; Gautvik, K.M.

1988-01-01

A thyrotropin-releasing hormone (TRH) binding protein of 64 kDa has been identified by covalently crosslinking [ 3 H]TRH to GH4C1 cells by ultraviolet illumination. The crosslinkage of [ 3 H]TRH is UV-dose dependent and is inhibited by an excess of unlabeled TRH. A 64 kDa protein is also detected on immunoblots using an antiserum raised against GH4C1 cell surface epitopes. In a closely related cell line (GH12C1) which does not bind [ 3 H]TRH, the 64 kDa protein cannot be demonstrated by [ 3 H]TRH crosslinking nor by immunoblotting. These findings indicate that the 64 kDa protein is a candidate for a TRH-receptor protein in GH4C1 cells

Reduced striatal dopamine D2/3 receptor availability in Body Dysmorphic Disorder.

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Vulink, Nienke C; Planting, Robin S; Figee, Martijn; Booij, Jan; Denys, Damiaan

2016-02-01

Though the dopaminergic system is implicated in Obsessive Compulsive and Related Disorders (OCRD), the dopaminergic system has never been investigated in-vivo in Body Dysmorphic Disorder (BDD). In line with consistent findings of reduced striatal dopamine D2/3 receptor availability in Obsessive Compulsive Disorder (OCD), we hypothesized that the dopamine D2/3 receptor availability in the striatum will be lower in patients with BDD in comparison to healthy subjects. Striatal dopamine D2/3 receptor Binding Potential (BPND) was examined in 12 drug-free BDD patients and 12 control subjects pairwise matched by age, sex, and handedness using [(123)I]iodobenzamide Single Photon Emission Computed Tomography (SPECT; bolus/constant infusion technique). Regions of interest were the caudate nucleus and the putamen. BPND was calculated as the ratio of specific striatal to binding in the occipital cortex (representing nonspecific binding). Compared to controls, dopamine D2/3 receptor BPND was significantly lower in BDD, both in the putamen (p=0.017) and caudate nucleus (p=0.022). This study provides the first evidence of a disturbed dopaminergic system in BDD patients. Although previously BDD was classified as a separate disorder (somatoform disorder), our findings give pathophysiological support for the recent reclassification of BDD to the OCRD in DSM-5. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Increased coherence among striatal regions in the theta range during attentive wakefulness

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G. Lepski

2012-08-01

Full Text Available The striatum, the largest component of the basal ganglia, is usually subdivided into associative, motor and limbic components. However, the electrophysiological interactions between these three subsystems during behavior remain largely unknown. We hypothesized that the striatum might be particularly active during exploratory behavior, which is presumably associated with increased attention. We investigated the modulation of local field potentials (LFPs in the striatum during attentive wakefulness in freely moving rats. To this end, we implanted microelectrodes into different parts of the striatum of Wistar rats, as well as into the motor, associative and limbic cortices. We then used electromyograms to identify motor activity and analyzed the instantaneous frequency, power spectra and partial directed coherence during exploratory behavior. We observed fine modulation in the theta frequency range of striatal LFPs in 92.5 ± 2.5% of all epochs of exploratory behavior. Concomitantly, the theta power spectrum increased in all striatal channels (P 0.7 between the primary motor cortex and the rostral part of the caudatoputamen nucleus, as well as among all striatal channels (P < 0.001. Conclusively, we observed a pattern of strong theta band activation in the entire striatum during attentive wakefulness, as well as a strong coherence between the motor cortex and the entire striatum. We suggest that this activation reflects the integration of motor, cognitive and limbic systems during attentive wakefulness.

Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments

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Jill R. Crittenden

2011-09-01

Full Text Available The striatum is composed principally of GABAergic, medium spiny projection neurons (MSNs that can be categorized based on their gene expression, electrophysiological profiles and input-output circuits. Major subdivisions of MSN populations include 1 those in ventromedial and dorsolateral striatal regions, 2 those giving rise to the direct and indirect pathways, and 3 those that lie in the striosome and matrix compartments. The first two classificatory schemes have enabled advances in understanding of how basal ganglia circuits contribute to disease. However, despite the large number of molecules that are differentially expressed in the striosomes or the extra-striosomal matrix, and the evidence that these compartments have different input-output connections, our understanding of how this compartmentalization contributes to striatal function is still not clear. A broad view is that the matrix contains the direct and indirect pathway MSNs that form parts of sensorimotor and associative circuits, whereas striosomes contain MSNs that receive input from parts of limbic cortex and project directly or indirectly to the dopamine-containing neurons of the substantia nigra, pars compacta. Striosomes are widely distributed within the striatum and are thought to exert global, as well as local, influences on striatal processing by exchanging information with the surrounding matrix, including through interneurons that send processes into both compartments. It has been suggested that striosomes exert and maintain limbic control over behaviors driven by surrounding sensorimotor and associative parts of the striatal matrix. Consistent with this possibility, imbalances between striosome and matrix functions have been reported in relation to neurological disorders, including Huntington’s disease, L-DOPA-induced dyskinesias, dystonia and drug addiction. Here, we consider how signaling imbalances between the striosomes and matrix might relate to symptomatology in

Effect of in vitro gamma exposure on rat mesencephalic and striatal cellular types and processes length

International Nuclear Information System (INIS)

Coffigny, H.; Court, L.

1994-01-01

The isolated mesencephalic and striatal cells were irradiated in a dose-range of 0.25 to 3 Gy followed by 3 day of culture. The proportion of monopolar, bipolar, tripolar and multipolar cell population was not obviously modified by irradiation. The processes length was similar to controls, except after 3 Gy exposure, for monopolar and bipolar mesencephalic cells and the tripolar striatal cells where it was increased. In these populations, only cells with long processes seemed to survive. (author)

125I-β-CIT imaging study of striatal dopamine transporters in mice model of parkinsonism

International Nuclear Information System (INIS)

Liu Zhenguo; Sun Wenshan; Weng Zhongfang; Chen Shengdi; Shen Minghua; Zhu Chengmo

2001-01-01

Objective: To detect the activity of striatal dopamine transporters (DAT) in lesions of different order of severity of MPTP-induced mice model of parkinsonism by autoradiography with 125 I-β-CIT and to evaluate the clinical use of the β-CIT imaging for DAT detection. Methods: With regard to the different duration (days) of MPTP treatment, the C57BL mice were randomly divided into 5 groups, that is MPTP 1, 3, 5 and 7 day groups and control group treated with normal saline instead of MPTP. Two hours after intravenous administration with 125 I-β-CIT of 148 kBq, the brain tissue sections were imaged by autoradiography. The levels of dopamine (DA) and its metabolites were measured by high performance liquid chromatography and electrochemical detection (HPLC-ECD). The tyrosine hydroxylase (TH)-positive cells and fibres in the substantia nigra and striatum of the mice were observed by means of immunohistochemical technique. Results: As compared with control group, the radioactivity ratios of striatum to cortex (ST/CX) in 4 MPTP-treated groups were significantly reduced, by 20%, 42%, 45% and 52%, respectively. The concentrations of DA in the striatum of 4 MPTP-treated groups were remarkably decreased, by 47%, 75%, 95% and 95%, respectively. The gradual loss of DA neurons and fibres in the substantia nigra and striatum in 4 MPTP-treated groups was observed under microscopy. Conclusions: The functional abnormality of DAT paralleled the changes observed in neurochemistry and neuropathology studies in the lesions of different order of injury of the MPTP-treated mice. The β-CIT scanning for the activity of DAT may be useful for diagnosing PD at earlier phase and for monitoring the progression of the disease

Effect of ghrelin on the motor deficit caused by the ablation of nigrostriatal dopaminergic cells or the inhibition of striatal dopamine receptors.

Science.gov (United States)

Suda, Yukari; Kuzumaki, Naoko; Narita, Michiko; Hamada, Yusuke; Shibasaki, Masahiro; Tanaka, Kenichi; Tamura, Hideki; Kawamura, Takashi; Kondo, Takashige; Yamanaka, Akihiro; Narita, Minoru

2018-02-19

Ghrelin plays roles in a wide range of central functions by activating the growth hormone secretagogue receptor (GHSR). This receptor has recently been found in the substantia nigra (SN) to control dopamine (DA)-related physiological functions. The dysregulation of DA neurons in the SN pars compacta (SNc) and the consequent depletion of striatal DA are known to underlie the motor deficits observed in Parkinson's disease (PD). In the present study, we further investigated the role of the SN-ghrelin system in motor function under the stereotaxic injection of AAV-CMV-FLEX-diphtheria toxin A (DTA) into the SN of dopamine transporter (DAT)-Cre (DAT SN ::DTA) mice to expunge DA neurons of the SNc. First, we confirmed the dominant expression of GHSR1a, which is a functional GHSR, in tyrosine hydroxylase (TH)-positive DA neurons in the SNc of control mice. In DAT SN ::DTA mice, we clearly observed motor dysfunction using several behavioral tests. An immunohistochemical study revealed a dramatic loss of TH-positive DA neurons in the SNc and DAT-labeled axon terminals in the striatum, and an absence of mRNAs for TH and DAT in the SN of DAT SN ::DTA mice. The mRNA level of GHSR1a was drastically decreased in the SN of these mice. In normal mice, we also found the mRNA expression of GHSR1a within GABAergic neurons in the SN pars reticulata (SNr). Under these conditions, a single injection of ghrelin into the SN failed to improve the motor deficits caused by ablation of the nigrostriatal DA network using DAT SN ::DTA mice, whereas intra-SN injection of ghrelin suppressed the motor dysfunction caused by the administration of haloperidol, which is associated with the transient inhibition of DA transmission. These findings suggest that phasic activation of the SNc-ghrelin system could improve the dysregulation of nigrostriatal DA transmission related to the initial stage of PD, but not the motor deficits under the depletion of nigrostriatal DA. Although GHSRs are found in non-DA

Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys

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Alex G. Lee

2016-06-01

Full Text Available Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3 in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [11C]raclopride binding using positron emission tomography (PET. DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys.

Contribution of fronto-striatal regions to emotional valence and repetition under cognitive conflict.

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Chun, Ji-Won; Park, Hae-Jeong; Kim, Dai Jin; Kim, Eosu; Kim, Jae-Jin

2017-07-01

Conflict processing mediated by fronto-striatal regions may be influenced by emotional properties of stimuli. This study aimed to examine the effects of emotion repetition on cognitive control in a conflict-provoking situation. Twenty-one healthy subjects were scanned using functional magnetic resonance imaging while performing a sequential cognitive conflict task composed of emotional stimuli. The regional effects were analyzed according to the repetition or non-repetition of cognitive congruency and emotional valence between the preceding and current trials. Post-incongruence interference in error rate and reaction time was significantly smaller than post-congruence interference, particularly under repeated positive and non-repeated positive, respectively, and post-incongruence interference, compared to post-congruence interference, increased activity in the ACC, DLPFC, and striatum. ACC and DLPFC activities were significantly correlated with error rate or reaction time in some conditions, and fronto-striatal connections were related to the conflict processing heightened by negative emotion. These findings suggest that the repetition of emotional stimuli adaptively regulates cognitive control and the fronto-striatal circuit may engage in the conflict adaptation process induced by emotion repetition. Both repetition enhancement and repetition suppression of prefrontal activity may underlie the relationship between emotion and conflict adaptation. Copyright © 2017 Elsevier B.V. All rights reserved.

Striatal Activity and Reward Relativity: Neural Signals Encoding Dynamic Outcome Valuation.

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Webber, Emily S; Mankin, David E; Cromwell, Howard C

2016-01-01

The striatum is a key brain region involved in reward processing. Striatal activity has been linked to encoding reward magnitude and integrating diverse reward outcome information. Recent work has supported the involvement of striatum in the valuation of outcomes. The present work extends this idea by examining striatal activity during dynamic shifts in value that include different levels and directions of magnitude disparity. A novel task was used to produce diverse relative reward effects on a chain of instrumental action. Rats ( Rattus norvegicus ) were trained to respond to cues associated with specific outcomes varying by food pellet magnitude. Animals were exposed to single-outcome sessions followed by mixed-outcome sessions, and neural activity was compared among identical outcome trials from the different behavioral contexts. Results recording striatal activity show that neural responses to different task elements reflect incentive contrast as well as other relative effects that involve generalization between outcomes or possible influences of outcome variety. The activity that was most prevalent was linked to food consumption and post-food consumption periods. Relative encoding was sensitive to magnitude disparity. A within-session analysis showed strong contrast effects that were dependent upon the outcome received in the immediately preceding trial. Significantly higher numbers of responses were found in ventral striatum linked to relative outcome effects. Our results support the idea that relative value can incorporate diverse relationships, including comparisons from specific individual outcomes to general behavioral contexts. The striatum contains these diverse relative processes, possibly enabling both a higher information yield concerning value shifts and a greater behavioral flexibility.

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

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Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho; Seppaenen, Marko; Noponen, Tommi

2014-01-01

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [ 123 I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

Differences in number and distribution of striatal calbindin medium spiny neurons between a vocal-learner (Melopsittacus undulatus and a non-vocal learner bird (Colinus virginianus

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Elena eGarcia-Calero

2013-12-01

Full Text Available Striatal projecting neurons, known as medium spiny neurons (MSNs, segregate into two compartments called matrix and striosome in the mammalian striatum. The matrix domain is characterized by the presence of calbindin immunopositive (CB+ MSNs, not observed in the striosome subdivision. The existence of a similar CB+ MSN population has recently been described in two striatal structures in male zebra finch (a vocal learner bird: the striatal capsule and the Area X, a nucleus implicated in song learning. Female zebra finches show a similar pattern of CB+ MSNs than males in the developing striatum but loose these cells in juveniles and adult stages. In the present work we analyzed the existence and allocation of CB+MSNs in the striatal domain of the vocal learner bird budgerigar (representative of psittaciformes order and the non-vocal learner bird quail (representative of galliformes order. We studied the co-localization of CB protein with FoxP1, a transcription factor expressed in vertebrate striatal MSNs. We observed CB+ MSNs in the medial striatal domain of adult male and female budgerigars, although this cell type was missing in the potentially homologous nucleus for Area X in budgerigar. In quail, we observed CB+ cells in the striatal domain at developmental and adult stages but they did not co-localize with the MSN marker FoxP1. We also described the existence of the CB+ striatal capsule in budgerigar and quail and compared these results with the CB+ striatal capsule observed in juvenile zebra finches. Together, these results point out important differences in CB+MSN distribution between two representative species of vocal learner and non-vocal learner avian orders (respectively the budgerigar and the quail, but also between close vocal learner bird families.

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

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de Souza Silva, Maria A; Mattern, Claudia; Decheva, Cvetana; Huston, Joseph P; Sadile, Adolfo G; Beu, Markus; Müller, H-W; Nikolaus, Susanne

2016-01-01

Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [(123)I]FP-CIT to the DAT should be decreased due to competition at the receptor. Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [(123)I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand. (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs. (a) demonstrate a direct central action of intranasally

Striatal fast-spiking interneurons: from firing patterns to postsynaptic impact

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Andreas eKlaus

2011-07-01

Full Text Available In the striatal microcircuit, fast-spiking (FS interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization, do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

Neurodevelopmental disruption of cortico-striatal function caused by degeneration of habenula neurons.

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Young-A Lee

2011-04-01

Full Text Available The habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Using a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC and nucleus accumbens (NAcc and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Because of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD, these results

Mechanisms mediating parallel action monitoring in fronto-striatal circuits.

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Beste, Christian; Ness, Vanessa; Lukas, Carsten; Hoffmann, Rainer; Stüwe, Sven; Falkenstein, Michael; Saft, Carsten

2012-08-01

Flexible response adaptation and the control of conflicting information play a pivotal role in daily life. Yet, little is known about the neuronal mechanisms mediating parallel control of these processes. We examined these mechanisms using a multi-methodological approach that integrated data from event-related potentials (ERPs) with structural MRI data and source localisation using sLORETA. Moreover, we calculated evoked wavelet oscillations. We applied this multi-methodological approach in healthy subjects and patients in a prodromal phase of a major basal ganglia disorder (i.e., Huntington's disease), to directly focus on fronto-striatal networks. Behavioural data indicated, especially the parallel execution of conflict monitoring and flexible response adaptation was modulated across the examined cohorts. When both processes do not co-incide a high integrity of fronto-striatal loops seems to be dispensable. The neurophysiological data suggests that conflict monitoring (reflected by the N2 ERP) and working memory processes (reflected by the P3 ERP) differentially contribute to this pattern of results. Flexible response adaptation under the constraint of high conflict processing affected the N2 and P3 ERP, as well as their delta frequency band oscillations. Yet, modulatory effects were strongest for the N2 ERP and evoked wavelet oscillations in this time range. The N2 ERPs were localized in the anterior cingulate cortex (BA32, BA24). Modulations of the P3 ERP were localized in parietal areas (BA7). In addition, MRI-determined caudate head volume predicted modulations in conflict monitoring, but not working memory processes. The results show how parallel conflict monitoring and flexible adaptation of action is mediated via fronto-striatal networks. While both, response monitoring and working memory processes seem to play a role, especially response selection processes and ACC-basal ganglia networks seem to be the driving force in mediating parallel conflict

Intranasal dopamine reduces in vivo [123I]FP-CIT binding to striatal dopamine transporter: correlation with behavioral changes and evidence for Pavlovian conditioned dopamine response

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Maria A de Souza Silva

2016-04-01

Full Text Available Purpose: Dopamine (DA, which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA, nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [123I]FP-CIT to the DAT should be decreased due to competition at the receptor.Methods: Rats were administered intranasal application of 3 mg/kg IN-DA and vehicle (VEH, with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming were assessed for 30 min in an open field prior to administration of [123I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT two hours following administration of the radioligand. Results: 1 After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered dopamine had central action and increased DA levels comparable to that found previously with L-DOPA administration. 2 DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant

Anatomical and electrophysiological changes in striatal TH interneurons after loss of the nigrostriatal dopaminergic pathway.

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Ünal, Bengi; Shah, Fulva; Kothari, Janish; Tepper, James M

2015-01-01

Using transgenic mice that express enhanced green fluorescent protein (EGFP) under the control of the tyrosine hydroxylase (TH) promoter, we have previously shown that there are approximately 3,000 striatal EGFP-TH interneurons per hemisphere in mice. Here, we report that striatal TH-EGFP interneurons exhibit a small, transient but significant increase in number after unilateral destruction of the nigrostriatal dopaminergic pathway. The increase in cell number is accompanied by electrophysiological and morphological changes. The intrinsic electrophysiological properties of EGFP-TH interneurons ipsilateral to 6-OHDA lesion were similar to those originally reported in intact mice except for a significant reduction in the duration of a characteristic depolarization induced plateau potential. There was a significant change in the distribution of the four previously described electrophysiologically distinct subtypes of striatal TH interneurons. There was a concomitant increase in the frequency of both spontaneous excitatory and inhibitory post-synaptic currents, while their amplitudes did not change. Nigrostriatal lesions did not affect somatic size or dendritic length or branching, but resulted in an increase in the density of proximal dendritic spines and spine-like appendages in EGFP-TH interneurons. The changes indicate that electrophysiology properties and morphology of striatal EGFP-TH interneurons depend on endogenous levels of dopamine arising from the nigrostriatal pathway. Furthermore, these changes may serve to help compensate for the changes in activity of spiny projection neurons that occur following loss of the nigrostriatal innervation in experimental or in early idiopathic Parkinson's disease by increasing feedforward GABAergic inhibition exerted by these interneurons.

[18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

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Stark, Adam J; Smith, Christopher T; Petersen, Kalen J; Trujillo, Paula; van Wouwe, Nelleke C; Donahue, Manus J; Kessler, Robert M; Deutch, Ariel Y; Zald, David H; Claassen, Daniel O

2018-01-01

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D 2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D 2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D 2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [ 18 F]fallypride, a high affinity D 2/3 receptor ligand, to measure striatal and extrastriatal D 2/3 nondisplaceable binding potential (BP ND ). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BP ND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D 2/3 receptors, where reduced BP ND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D 2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D 2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Extracting the basal extracellular dopamine concentrations from the evoked responses: re-analysis of the dopamine kinetics.

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Chen, Kevin C; Budygin, Evgeny A

2007-08-15

Fast-scan cyclic voltammetry in conjunction with carbon fiber microelectrode has been used to study dopamine (DA) release and uptake mechanisms in rat brains because of the smaller size of the electrode and the subsecond resolution. Current voltammetry data were analyzed by a DA kinetic model assuming a zero baseline, which is in conflict with existing microdialysis findings and a recent claim of the striatal extracellular DA concentration at micromolar levels. This work applied a new analysis approach based on a modified DA kinetic model to analyze the kinetics of electrically evoked DA overflow in the caudate-putamen of anesthetized rats. The DA uptake parameters were fitted from the electrical stimulation phase, and subsequently used to calculate theoretical DA uptake rates. Comparison of the theoretical uptake rates with experimental clearance rates allows for the study of the tonic DA release process following electrical stimulations. Analyses of DA voltammetry data suggest that the locally averaged basal level of extracellular DA in the rat striatum might be confined between 95 and 220 nM. The disparate time scales in the clearance kinetics of endogenous and exogenous DA were investigated. Long-distance diffusion could only partially explain the slow clearance time course of exogenous DA. Model simulations and parameter analyses on evoked DA responses indicate that suppression of the nonevoked DA release process immediately following electrical stimulation cannot completely account for the rapid clearance of the electrically evoked DA. Inconsistency in the measured uptake strengths in the literature studying endogenous and exogenous DA remains to be investigated in the future.

Reward inference by primate prefrontal and striatal neurons.

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Pan, Xiaochuan; Fan, Hongwei; Sawa, Kosuke; Tsuda, Ichiro; Tsukada, Minoru; Sakagami, Masamichi

2014-01-22

The brain contains multiple yet distinct systems involved in reward prediction. To understand the nature of these processes, we recorded single-unit activity from the lateral prefrontal cortex (LPFC) and the striatum in monkeys performing a reward inference task using an asymmetric reward schedule. We found that neurons both in the LPFC and in the striatum predicted reward values for stimuli that had been previously well experienced with set reward quantities in the asymmetric reward task. Importantly, these LPFC neurons could predict the reward value of a stimulus using transitive inference even when the monkeys had not yet learned the stimulus-reward association directly; whereas these striatal neurons did not show such an ability. Nevertheless, because there were two set amounts of reward (large and small), the selected striatal neurons were able to exclusively infer the reward value (e.g., large) of one novel stimulus from a pair after directly experiencing the alternative stimulus with the other reward value (e.g., small). Our results suggest that although neurons that predict reward value for old stimuli in the LPFC could also do so for new stimuli via transitive inference, those in the striatum could only predict reward for new stimuli via exclusive inference. Moreover, the striatum showed more complex functions than was surmised previously for model-free learning.

Sexual dimorphism in striatal dopaminergic responses promotes monogamy in social songbirds.

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Tokarev, Kirill; Hyland Bruno, Julia; Ljubičić, Iva; Kothari, Paresh J; Helekar, Santosh A; Tchernichovski, Ofer; Voss, Henning U

2017-08-11

In many songbird species, males sing to attract females and repel rivals. How can gregarious, non-territorial songbirds such as zebra finches, where females have access to numerous males, sustain monogamy? We found that the dopaminergic reward circuitry of zebra finches can simultaneously promote social cohesion and breeding boundaries. Surprisingly, in unmated males but not in females, striatal dopamine neurotransmission was elevated after hearing songs. Behaviorally too, unmated males but not females persistently exchanged mild punishments in return for songs. Song reinforcement diminished when dopamine receptors were blocked. In females, we observed song reinforcement exclusively to the mate's song, although their striatal dopamine neurotransmission was only slightly elevated. These findings suggest that song-triggered dopaminergic activation serves a dual function in social songbirds: as low-threshold social reinforcement in males and as ultra-selective sexual reinforcement in females. Co-evolution of sexually dimorphic reinforcement systems can explain the coexistence of gregariousness and monogamy.

ACTHsub(1-24) and lysine vasopressin selectively activate dopamine synthesis in frontal cortex

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Delanoy, R L; Kramarcy, N R; Dunn, A J [Florida Univ., Gainesville (USA). Coll. of Medicine

1982-01-07

The accumulation of (/sup 3/H)catecholamines from (/sup 3/H)tyrosine in frontal cortical, septal, striatal and hippocampal slices was examined following intracerebroventricular (i.c.v.) injections of ACTHsub(1-24), lysine vasopressin (LVP) and saline. Both ACTHsub(1-24) and LVP (1..mu..g) selectively increased the accumulation of (/sup 3/H)dopamine (DA) in frontal cortical slices, but did not affect that of (/sup 3/H)norepinephrine (NE). LVP but not ACTHsub(1-24) also inhibited the accumulation of (/sup 3/H)DA in striatal slices. ACTHsub(1-24) did not alter the accumulation of (/sup 3/H)NE in hippocampal slices, nor did LVP alter the accumulation of either catecholamine (CA) in septal slices. In vitro incubations with ACTH analogs or LVP failed to alter the rate of accumulation of (/sup 3/H)CAs in striatal, substantia nigral and frontal cortical slices, except for an inhibitory effect at high doses. This effect is believed to be an artifact of precursor dilution caused by release of tyrosine following degradation of the peptides. Neither peptide modified the increased (/sup 3/H)CA accumulation stimulated by 26 mM K/sup +/, nor did ACTHsub(1-24) modify the inhibition of (/sup 3/H)CA accumulation caused by 3 X 10/sup -6/ M Haloperidol or 3 X 10/sup -7/ M apomorphine. Selective activation of the mesocortical DA system has also been reported to occur in response to footshock, suggesting the possibility that endogenous ACTH and/or LVP might mediate the stress-induced activation of mesocortical DA synthesis. Alternatively, i.c.v. injections of these peptides may themselves be stressful and thus indirectly elicit the response.

Diagnostic imaging of dementia with Lewy bodies by susceptibility-weighted imaging of nigrosomes versus striatal dopamine transporter single-photon emission computed tomography: a retrospective observational study

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Kamagata, Koji; Sato, Kanako; Suzuki, Michimasa; Hori, Masaaki; Kumamaru, Kanako K.; Aoki, Shigeki [Juntendo University Graduate School of Medicine, Department of Radiology, Bunkyo-ku, Tokyo (Japan); Nakatsuka, Tomoya; Inaoka, Tsutomu; Terada, Hitoshi [Toho University Sakura Medical Center, Department of Radiology, Sakura, Sakura (Japan); Sakakibara, Ryuji; Tsuyusaki, Yohei [Toho University Sakura Medical Center, Department of Neurology, Sakura, Sakura (Japan); Takamura, Tomohiro [University of Yamanashi, Department of Radiology, Chuo-shi, Yamanashi (Japan)

2017-01-15

The characteristics of dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and amnestic mild cognitive impairment (a-MCI) overlap but require different treatments; therefore, it is important to differentiate these pathologies. Assessment of dopamine uptake in the striatum using dopamine transporter (DaT) single-photon emission computed tomography (SPECT) is the gold standard for diagnosing DLB; however, this modality is expensive, time consuming and involves radiation exposure. Degeneration of the substantia nigra nigrosome-1, which occurs in DLB, but not in AD/a-MCI, can be identified by 3T susceptibility-weighted imaging (SWI). Therefore, the aim of this retrospective observational study was to compare SWI with DaT-SPECT for differentiation of DLB from AD/a-MCI. SWI data were acquired for patients with clinically diagnosed DLB (n = 29), AD (n = 18), a-MCI (n = 13) and healthy controls (n = 26). Images were analysed for nigrosome-1 degeneration. Diagnostic accuracy was evaluated for DLB, AD and a-MCI compared with striatal dopamine uptake using DaT-SPECT. SWI achieved 90% diagnostic accuracy (93% sensitivity, 87% specificity) for the detection of nigrosome-1 degeneration in DLB and not in AD/a-MCI as compared with 88.3% accuracy (93% sensitivity, 84% specificity) using DaT-SPECT. SWI nigrosome-1 evaluation was useful in differentiating DLB from AD/a-MCI, with high accuracy. This less invasive and less expensive method is a potential alternative to DaT-SPECT for the diagnosis of DLB. (orig.)

Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice.

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Yukio eYamamura

2013-02-01

Full Text Available Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5, which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5 and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15 is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571, a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum.

Fully Automated Quantification of the Striatal Uptake Ratio of [99mTc]-TRODAT with SPECT Imaging: Evaluation of the Diagnostic Performance in Parkinson's Disease and the Temporal Regression of Striatal Tracer Uptake

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Fang, Yu-Hua Dean; Chiu, Shao-Chieh; Lu, Chin-Song; Weng, Yi-Hsin

2015-01-01

Purpose. We aimed at improving the existing methods for the fully automatic quantification of striatal uptake of [99mTc]-TRODAT with SPECT imaging. Procedures. A normal [99mTc]-TRODAT template was first formed based on 28 healthy controls. Images from PD patients (n = 365) and nPD subjects (28 healthy controls and 33 essential tremor patients) were spatially normalized to the normal template. We performed an inverse transform on the predefined striatal and reference volumes of interest (VOIs) and applied the transformed VOIs to the original image data to calculate the striatal-to-reference ratio (SRR). The diagnostic performance of the SRR was determined through receiver operating characteristic (ROC) analysis. Results. The SRR measured with our new and automatic method demonstrated excellent diagnostic performance with 92% sensitivity, 90% specificity, 92% accuracy, and an area under the curve (AUC) of 0.94. For the evaluation of the mean SRR and the clinical duration, a quadratic function fit the data with R 2 = 0.84. Conclusions. We developed and validated a fully automatic method for the quantification of the SRR in a large study sample. This method has an excellent diagnostic performance and exhibits a strong correlation between the mean SRR and the clinical duration in PD patients. PMID:26366413

Fully Automated Quantification of the Striatal Uptake Ratio of [(99m)Tc]-TRODAT with SPECT Imaging: Evaluation of the Diagnostic Performance in Parkinson's Disease and the Temporal Regression of Striatal Tracer Uptake.

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Fang, Yu-Hua Dean; Chiu, Shao-Chieh; Lu, Chin-Song; Yen, Tzu-Chen; Weng, Yi-Hsin

2015-01-01

We aimed at improving the existing methods for the fully automatic quantification of striatal uptake of [(99m)Tc]-TRODAT with SPECT imaging. A normal [(99m)Tc]-TRODAT template was first formed based on 28 healthy controls. Images from PD patients (n = 365) and nPD subjects (28 healthy controls and 33 essential tremor patients) were spatially normalized to the normal template. We performed an inverse transform on the predefined striatal and reference volumes of interest (VOIs) and applied the transformed VOIs to the original image data to calculate the striatal-to-reference ratio (SRR). The diagnostic performance of the SRR was determined through receiver operating characteristic (ROC) analysis. The SRR measured with our new and automatic method demonstrated excellent diagnostic performance with 92% sensitivity, 90% specificity, 92% accuracy, and an area under the curve (AUC) of 0.94. For the evaluation of the mean SRR and the clinical duration, a quadratic function fit the data with R (2) = 0.84. We developed and validated a fully automatic method for the quantification of the SRR in a large study sample. This method has an excellent diagnostic performance and exhibits a strong correlation between the mean SRR and the clinical duration in PD patients.

Colloid characterization and in situ release in shallow groundwater under different hydrogeology conditions.

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Zhou, Jingjing; Liu, Dan; Zhang, Wenjing; Chen, Xuequn; Huan, Ying; Yu, Xipeng

2017-06-01

Changes to groundwater hydrodynamics and chemistry can lead to colloid release that can have a major impact on the groundwater environment. To analyze the effects of colloid release caused by artificial groundwater recharge, field and laboratory tests on colloid characterization and colloid release were conducted. The field tests were carried out at an artificial recharge test site in Shandong Province. In the field investigation, one recharge water sample and five groundwater samples were collected and filtered through three levels of ultrafiltration membranes, with pore sizes of 0.45 μm, 100 kDa, and 50 kDa. The field results indicated that the colloid mass concentrations in groundwater retained between membranes with pore sizes of 100 kDa-0.45 μm and 50 kDa-100 kDa were 19 and 62 mg/L, respectively. In recharge water, the colloid mass concentrations retained by 100-kDa-0.45-μm and 50-kDa-100-kDa membranes were 3 and 99 mg/L, respectively. Colloids detected on the ultrafiltration membranes were mainly inorganic between 100 kDa and 0.45 μm, and mainly organic between 50 and 100 kDa. Based on the field colloid investigation results, the organic colloid was chosen in the laboratory experiments to reveal its release behavior under different conditions. Porous media diameter, flux, ionic strength (IS), and ion valence were changed to determine their influences on organic colloid concentration outflow from undisturbed porous media. The experiment's results indicate that decreasing the diameter, and increasing the flux, ionic strength, and the number of divalent cations, can promote organic colloid release. The organic colloid release rate in the early stage was high and is thus likely to affect the quality of groundwater. The results provide a useful scientific basis for minimizing changes to hydrodynamic and hydrochemical conditions during artificial recharge, thus safeguarding groundwater quality.

Chronic levodopa administration followed by a washout period increased number and induced phenotypic changes in striatal dopaminergic cells in MPTP-monkeys.

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Carla DiCaudo

Full Text Available In addition to the medium spiny neurons the mammalian striatum contains a small population of GABAergic interneurons that are immunoreactive for tyrosine hydroxylase (TH, which dramatically increases after lesions to the nigrostriatal pathway and striatal delivery of neurotrophic factors. The regulatory effect of levodopa (L-Dopa on the number and phenotype of these cells is less well understood. Eleven macaques (Macaca fascicularis were included. Group I (n = 4 received 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP and L-Dopa; Group II (n = 4 was treated with MPTP plus vehicle and Group III (n = 3 consist of intact animals (control group. L-Dopa and vehicle were given for 1 year and animals sacrificed 6 months later. Immunohistochemistry against TH was used to identify striatal and nigral dopaminergic cells. Double and triple labeling immunofluorescence was performed to detect the neurochemical characteristics of the striatal TH-ir cells using antibodies against: TH, anti-glutamate decarboxylase (GAD(67 anti-calretinin (CR anti-dopa decarboxylase (DDC and anti-dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32. The greatest density of TH-ir striatal cells was detected in the striatum of the L-Dopa treated monkeys and particularly in its associative territory. None of the striatal TH-ir cell expressed DARPP-32 indicating they are interneurons. The percentages of TH-ir cells that expressed GAD67 and DDC was approximately 50%. Interestingly, we found that in the L-Dopa group the number of TH/CR expressing cells was significantly reduced. We conclude that chronic L-Dopa administration produced a long-lasting increase in the number of TH-ir cells, even after a washout period of 6 months. L-Dopa also modified the phenotype of these cells with a significant reduction of the TH/CR phenotype in favor of an increased number of TH/GAD cells that do not express CR. We suggest that the increased number of striatal TH-ir cells might be involved

Overeating Behavior and Striatal Dopamine with 6-[18F]-Fluoro-L--Tyrosine PET

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Claire E. Wilcox

2010-01-01

Full Text Available Eating behavior may be affected by dopamine synthesis capacity. In this study, 6-[18F]-fluoro-L--tyrosine (FMT positron emission tomography (PET uptake in striatal subregions was correlated with BMI (kg/m2 and an estimate of the frequency of prior weight loss attempts in 15 healthy subjects. BMI was negatively correlated with FMT uptake in the dorsal caudate. Although the association between BMI and FMT uptake in the dorsal caudate was not significant upon correction for age and sex, the association fell within the range of a statistical trend. Weight loss attempts divided by years trying was also negatively correlated with FMT uptake in the dorsal putamen (=.05. These results suggest an association between low dorsal striatal presynaptic dopamine synthesis capacity and overeating behavior.

Quinolinic acid induces disrupts cytoskeletal homeostasis in striatal neurons. Protective role of astrocyte-neuron interaction.

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Pierozan, Paula; Ferreira, Fernanda; de Lima, Bárbara Ortiz; Pessoa-Pureur, Regina

2015-02-01

Quinolinic acid (QUIN) is an endogenous metabolite of the kynurenine pathway involved in several neurological disorders. Among the several mechanisms involved in QUIN-mediated toxicity, disruption of the cytoskeleton has been demonstrated in striatally injected rats and in striatal slices. The present work searched for the actions of QUIN in primary striatal neurons. Neurons exposed to 10 µM QUIN presented hyperphosphorylated neurofilament (NF) subunits (NFL, NFM, and NFH). Hyperphosphorylation was abrogated in the presence of protein kinase A and protein kinase C inhibitors H89 (20 μM) and staurosporine (10 nM), respectively, as well as by specific antagonists to N-methyl-D-aspartate (50 µM DL-AP5) and metabotropic glutamate receptor 1 (100 µM MPEP). Also, intra- and extracellular Ca(2+) chelators (10 µM BAPTA-AM and 1 mM EGTA, respectively) and Ca(2+) influx through L-type voltage-dependent Ca(2+) channel (10 µM verapamil) are implicated in QUIN-mediated effects. Cells immunostained for the neuronal markers βIII-tubulin and microtubule-associated protein 2 showed altered neurite/neuron ratios and neurite outgrowth. NF hyperphosphorylation and morphological alterations were totally prevented by conditioned medium from QUIN-treated astrocytes. Cocultured astrocytes and neurons interacted with one another reciprocally, protecting them against QUIN injury. Cocultured cells preserved their cytoskeletal organization and cell morphology together with unaltered activity of the phosphorylating system associated with the cytoskeleton. This article describes cytoskeletal disruption as one of the most relevant actions of QUIN toxicity in striatal neurons in culture with soluble factors secreted by astrocytes, with neuron-astrocyte interaction playing a role in neuroprotection. © 2014 Wiley Periodicals, Inc.

Fully Automated Quantification of the Striatal Uptake Ratio of [99mTc]-TRODAT with SPECT Imaging: Evaluation of the Diagnostic Performance in Parkinson’s Disease and the Temporal Regression of Striatal Tracer Uptake

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Yu-Hua Dean Fang

2015-01-01

Full Text Available Purpose. We aimed at improving the existing methods for the fully automatic quantification of striatal uptake of [Tc99m]-TRODAT with SPECT imaging. Procedures. A normal [Tc99m]-TRODAT template was first formed based on 28 healthy controls. Images from PD patients (n=365 and nPD subjects (28 healthy controls and 33 essential tremor patients were spatially normalized to the normal template. We performed an inverse transform on the predefined striatal and reference volumes of interest (VOIs and applied the transformed VOIs to the original image data to calculate the striatal-to-reference ratio (SRR. The diagnostic performance of the SRR was determined through receiver operating characteristic (ROC analysis. Results. The SRR measured with our new and automatic method demonstrated excellent diagnostic performance with 92% sensitivity, 90% specificity, 92% accuracy, and an area under the curve (AUC of 0.94. For the evaluation of the mean SRR and the clinical duration, a quadratic function fit the data with R2=0.84. Conclusions. We developed and validated a fully automatic method for the quantification of the SRR in a large study sample. This method has an excellent diagnostic performance and exhibits a strong correlation between the mean SRR and the clinical duration in PD patients.

Abstinence duration modulates striatal functioning during monetary reward processing in cocaine patients.

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Bustamante, Juan-Carlos; Barrós-Loscertales, Alfonso; Costumero, Víctor; Fuentes-Claramonte, Paola; Rosell-Negre, Patricia; Ventura-Campos, Noelia; Llopis, Juan-José; Ávila, César

2014-09-01

Pre-clinical and clinical studies in cocaine addiction highlight alterations in the striatal dopaminergic reward system that subserve maintenance of cocaine use. Using an instrumental conditioning paradigm with monetary reinforcement, we studied striatal functional alterations in long-term abstinent cocaine-dependent patients and striatal functioning as a function of abstinence and treatment duration. Eighteen patients and 20 controls underwent functional magnetic resonance imaging during a Monetary Incentive Delay task. Region of interest analyses based on masks of the dorsal and ventral striatum were conducted to test between-group differences and the functional effects in the cocaine group of time (in months) with no more than two lapses from the first time patients visited the clinical service to seek treatment at the scanning time (duration of treatment), and the functional effects of the number of months with no lapses or relapses at the scanning session time (length of abstinence). We applied a voxel-wise and a cluster-wise FWE-corrected level (pFWE) at a threshold of P reward anticipation than the control group. The regression analyses in the patients group revealed a positive correlation between duration of treatment and brain activity in the left caudate during reward anticipation. Likewise, length of abstinence negatively correlated with brain activity in the bilateral nucleus accumbens during monetary outcome processing. In conclusion, caudate and nucleus accumbens show a different brain response pattern to non-drug rewards during cocaine addiction, which can be modulated by treatment success. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease.

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Su Jin Chung

Full Text Available The mechanism underlying non-motor symptoms in Parkinson's disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms.We conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS in 151 patients with early-stage Parkinson's disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41 and low non-motor patients (LNM-PD.Patients in the HNM-PD group (n = 71 were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum.This study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson's disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function

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Sarter, Martin; Albin, Roger L.; Kucinski, Aaron; Lustig, Cindy

2015-01-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson’s disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive–behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional–motor integration by striatal circuitry. PMID:24805070

Effects of postnatal anoxia on striatal dopamine metabolism and prepulse inhibition in rats

DEFF Research Database (Denmark)

Sandager-Nielsen, Karin; Andersen, Maibritt B; Sager, Thomas N

2004-01-01

(DOPAC) and homovanillic acid (HVA) concentrations. Furthermore, in the anoxic group only, striatal HVA concentrations were negatively correlated to prefrontal cortical N-acetylaspartate (NAA) levels. Similar findings of distorted prefrontal-subcortical interactions have recently been reported...

Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

NARCIS (Netherlands)

van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

2005-01-01

Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

Altered cingulo-striatal function underlies reward drive deficits in schizophrenia.

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Park, Il Ho; Chun, Ji Won; Park, Hae-Jeong; Koo, Min-Seong; Park, Sunyoung; Kim, Seok-Hyeong; Kim, Jae-Jin

2015-02-01

Amotivation in schizophrenia is assumed to involve dysfunctional dopaminergic signaling of reward prediction or anticipation. It is unclear, however, whether the translation of neural representation of reward value to behavioral drive is affected in schizophrenia. In order to examine how abnormal neural processing of response valuation and initiation affects incentive motivation in schizophrenia, we conducted functional MRI using a deterministic reinforcement learning task with variable intervals of contingency reversals in 20 clinically stable patients with schizophrenia and 20 healthy controls. Behaviorally, the advantage of positive over negative reinforcer in reinforcement-related responsiveness was not observed in patients. Patients showed altered response valuation and initiation-related striatal activity and deficient rostro-ventral anterior cingulate cortex activation during reward approach initiation. Among these neural abnormalities, rostro-ventral anterior cingulate cortex activation was correlated with positive reinforcement-related responsiveness in controls and social anhedonia and social amotivation subdomain scores in patients. Our findings indicate that the central role of the anterior cingulate cortex is in translating action value into driving force of action, and underscore the role of the cingulo-striatal network in amotivation in schizophrenia. Copyright © 2014 Elsevier B.V. All rights reserved.

Dopamine denervation does not alter in vivo 3H-spiperone binding in rat striatum: implications for external imaging of dopamine receptors in Parkinson's disease

International Nuclear Information System (INIS)

Bennett, J.P. Jr.; Wooten, G.F.

1986-01-01

Striatal particulate preparations, both from rats with lesion-induced striatal dopamine (DA) loss and from some striatal dopamine (DA) loss and from some patients with Parkinson's disease, exhibit increased 3 H-neuroleptic binding, which is interpreted to be the mechanism of denervation-induced behavioral supersensitivity to dopaminergic compounds. After intravenous 3 H-spiperone ( 3 H-SP) administration to rats with unilateral nigral lesions, we found no differences in accumulation of total or particulate-bound 3 H-SP in dopamine-denervated compared with intact striata. 3 H-SP in vivo binds to less than 10% of striatal sites labeled by 3 H-SP incubated with striatal particulate preparations in vitro. Quantitative autoradiography of 3 H-SP binding to striatal sections in vitro also failed to reveal any effects of dopamine denervation. 3 H-SP bound to striatal sites in vivo dissociates more slowly than that bound to striatal particulate preparations labeled in vitro. Striatal binding properties of 3 H-SP administered in vivo are quite different from the same kinetic binding parameters estimated in vitro using crude membrane preparations of striatum. In addition, striatal binding of in vivo-administered 3H-SP is not affected by prior lesion of the substantia nigra, which results in profound ipsilateral striatal dopamine depletion. Thus, behavioral supersensitivity to dopaminergic compounds may not be associated with altered striatal binding properties for dopamine receptor ligands in vivo

Mechanism of aminopyridine-induced release of [3H]dopamine from rat brain synaptosomes.

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Scheer, H W; Lavoie, P A

1991-01-01

1. Aminopyridines (APs) induced the release of [3H]dopamine (3H-DA) from rat synaptosomal preparations. 2. 4-AP and 3,4-DAP were of equal efficacy in inducing release of 3H-DA; 3-AP, 2-AP and 2,6-AP were less active; pyridine and pyridine-4-carboxylamide were inactive. 3. Cd2+ was more effective in inhibiting 4-AP-induced release of 3H-DA (IC50 approximately 4 microM) than Co2+ and Ni2+ (IC50s approximately 500 microM). 4. While 4-AP increased the 45Ca2+ content of whole synaptosomal preparations, no effect of 4-AP on 45Ca2+ content was observed in lysed synaptosomal preparations. 5. 4-AP-induced 45Ca2+ uptake was inhibited by Cd2+, Ni2+ and Co2+ in concentration ranges similar to those inhibiting 3H-DA release.

Electrical and chemical transmission between striatal GABAergic output neurones in rat brain slices

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Venance, Laurent; Glowinski, Jacques; Giaume, Christian

2004-01-01

Basal ganglia are interconnected subcortical nuclei, connected to the thalamus and all cortical areas involved in sensory motor control, limbic functions and cognition. The striatal output neurones (SONs), the major striatal population, are believed to act as detectors and integrators of distributed patterns of cerebral cortex inputs. Despite the key role of SONs in cortico-striatal information processing, little is known about their local interactions. Here, we report the existence and characterization of electrical and GABAergic transmission between SONs in rat brain slices. Tracer coupling (biocytin) incidence was high during the first two postnatal weeks and then decreased (postnatal days (P) 5–25, 60%; P25–30, 29%; n = 61). Electrical coupling was observed between 27% of SON pairs (coupling coefficient: 3.1 ± 0.3%, n = 89 at P15) and as shown by single-cell RT-PCR, several connexin (Cx) mRNAs were found to be expressed (Cx31.1, Cx32, Cx36 and Cx47). GABAergic synaptic transmission (abolished by bicuculline, a GABAA receptor antagonist) observed in 19% of SON pairs (n = 62) was reliable (mean failure rate of 6 ± 3%), precise (variation coefficient of latency, 0.06), strong (IPSC amplitudes of 38 ± 12 pA) and unidirectional. Interestingly, electrical and chemical transmission were mutually exclusive. These results suggest that preferential networks of electrically and chemically connected SONs, might be involved in the channelling of cortico-basal ganglia information processing. PMID:15235091

Selective updating of working memory content modulates meso-cortico-striatal activity.

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Murty, Vishnu P; Sambataro, Fabio; Radulescu, Eugenia; Altamura, Mario; Iudicello, Jennifer; Zoltick, Bradley; Weinberger, Daniel R; Goldberg, Terry E; Mattay, Venkata S

2011-08-01

Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modeling. Published by Elsevier Inc.

Specific reactions of different striatal neuron types in morphology induced by quinolinic acid in rats.

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Qiqi Feng

Full Text Available Huntington's disease (HD is a neurological degenerative disease and quinolinic acid (QA has been used to establish HD model in animals through the mechanism of excitotoxicity. Yet the specific pathological changes and the underlying mechanisms are not fully elucidated. We aimed to reveal the specific morphological changes of different striatal neurons in the HD model. Sprague-Dawley (SD rats were subjected to unilaterally intrastriatal injections of QA to mimic the HD model. Behavioral tests, histochemical and immunhistochemical stainings as well as Western blots were applied in the present study. The results showed that QA-treated rats had obvious motor and cognitive impairments when compared with the control group. Immunohistochemical detection showed a great loss of NeuN+ neurons and Darpp32+ projection neurons in the transition zone in the QA group when compared with the control group. The numbers of parvalbumin (Parv+ and neuropeptide Y (NPY+ interneurons were both significantly reduced while those of calretinin (Cr+ and choline acetyltransferase (ChAT+ were not changed notably in the transition zone in the QA group when compared to the controls. Parv+, NPY+ and ChAT+ interneurons were not significantly increased in fiber density while Cr+ neurons displayed an obvious increase in fiber density in the transition zone in QA-treated rats. The varicosity densities of Parv+, Cr+ and NPY+ interneurons were all raised in the transition zone after QA treatment. In conclusion, the present study revealed that QA induced obvious behavioral changes as well as a general loss of striatal projection neurons and specific morphological changes in different striatal interneurons, which may help further explain the underlying mechanisms and the specific functions of various striatal neurons in the pathological process of HD.

A direct ROI quantification method for inherent PVE correction: accuracy assessment in striatal SPECT measurements

Energy Technology Data Exchange (ETDEWEB)

Vanzi, Eleonora; De Cristofaro, Maria T.; Sotgia, Barbara; Mascalchi, Mario; Formiconi, Andreas R. [University of Florence, Clinical Pathophysiology, Florence (Italy); Ramat, Silvia [University of Florence, Neurological and Psychiatric Sciences, Florence (Italy)

2007-09-15

The clinical potential of striatal imaging with dopamine transporter (DAT) SPECT tracers is hampered by the limited capability to recover activity concentration ratios due to partial volume effects (PVE). We evaluated the accuracy of a least squares method that allows retrieval of activity in regions of interest directly from projections (LS-ROI). An Alderson striatal phantom was filled with striatal to background ratios of 6:1, 9:1 and 28:1; the striatal and background ROIs were drawn on a coregistered X-ray CT of the phantom. The activity ratios of these ROIs were derived both with the LS-ROI method and with conventional SPECT EM reconstruction (EM-SPECT). Moreover, the two methods were compared in seven patients with motor symptoms who were examined with N-3-fluoropropyl-2-{beta}-carboxymethoxy-3-{beta}-(4-iodophenyl) (FP-CIT) SPECT, calculating the binding potential (BP). In the phantom study, the activity ratios obtained with EM-SPECT were 3.5, 5.3 and 17.0, respectively, whereas the LS-ROI method resulted in ratios of 6.2, 9.0 and 27.3, respectively. With the LS-ROI method, the BP in the seven patients was approximately 60% higher than with EM-SPECT; a linear correlation between the LS-ROI and the EM estimates was found (r = 0.98, p = 0.03). The LS-ROI PVE correction capability is mainly due to the fact that the ill-conditioning of the LS-ROI approach is lower than that of the EM-SPECT one. The LS-ROI seems to be feasible and accurate in the examination of the dopaminergic system. This approach can be fruitful in monitoring of disease progression and in clinical trials of dopaminergic drugs. (orig.)

Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release

Energy Technology Data Exchange (ETDEWEB)

Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2005-07-01

We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 {+-} 235% (mean {+-} SEM) of basal level vs. 520 {+-} 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 {+-} 83% of basal level vs. 969 {+-} 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine.

Effect of MK-801 on the development of nicotine sensitization of nucleus accumbens dopamine release

International Nuclear Information System (INIS)

Hong, Soo Kyung; Choung, In Soon; Kim, Sang Eun

2005-01-01

We have previously found that MK-801, a noncompetitive NMDA receptor antagonist, prevents behavioral sensitization to nicotine. This study aimed to investigate the effect of MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drug on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with MK-801 (0.3 mg/kg, i.p.) or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for 7 consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens and DA release was monitored using in vivo microdialysis. In rats pretreated with chronic nicotine, local nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response 969 ± 235% (mean ± SEM) of basal level vs. 520 ± 93%, P < 0.05). Co-administration of MK-801 with nicotine attenuated an increase of DA release elicited by local nicotine challenge, compared with nicotine alone (maximal DA response 427 ± 83% of basal level vs. 969 ± 235%, P < 0.01). These results suggest that MK-801 blocks the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of NMDA receptors in the development of behavioral sensitization to nicotine

Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior.

Science.gov (United States)

Burke, Mary V; Small, Dana M

2016-06-01

Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning.

Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

NARCIS (Netherlands)

Naaijen, Jilly; Forde, Natalie J.; Lythgoe, David J.; Akkermans, Sophie E. A.; Openneer, Thaira J. C.; Dietrich, Andrea; Zwiers, Marcel P.; Hoekstra, Pieter J.; Buitelaar, Jan K.

2017-01-01

Objective: Both Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently

Brief exposure to obesogenic diet disrupts brain dopamine networks.

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Robert L Barry

Full Text Available We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT activity, which fine-tunes dopamine (DA signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week obesogenic high-fat (HF diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH.We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3α in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R availability using [18F]fallypride positron emission tomography (PET.We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling

Where attention falls: Increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function.

Science.gov (United States)

Sarter, Martin; Albin, Roger L; Kucinski, Aaron; Lustig, Cindy

2014-07-01

Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry. Copyright © 2014 Elsevier Inc. All rights reserved.

A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging

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Lue Kunhan; Lin Hsinhon; Chuang Kehshih; Kao Chihhao, K.; Hsieh Hungjen; Liu Shuhsin

2014-01-01

In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2

Arc mRNA induction in striatal efferent neurons associated with response learning.

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Daberkow, D P; Riedy, M D; Kesner, R P; Keefe, K A

2007-07-01

The dorsal striatum is involved in motor-response learning, but the extent to which distinct populations of striatal efferent neurons are differentially involved in such learning is unknown. Activity-regulated, cytoskeleton-associated (Arc) protein is an effector immediate-early gene implicated in synaptic plasticity. We examined arc mRNA expression in striatopallidal vs. striatonigral efferent neurons in dorsomedial and dorsolateral striatum of rats engaged in reversal learning on a T-maze motor-response task. Male Sprague-Dawley rats learned to turn right or left for 3 days. Half of the rats then underwent reversal training. The remaining rats were yoked to rats undergoing reversal training, such that they ran the same number of trials but ran them as continued-acquisition trials. Brains were removed and processed using double-label fluorescent in situ hybridization for arc and preproenkephalin (PPE) mRNA. In the reversal, but not the continued-acquisition, group there was a significant relation between the overall arc mRNA signal in dorsomedial striatum and the number of trials run, with rats reaching criterion in fewer trials having higher levels of arc mRNA expression. A similar relation was seen between the numbers of PPE(+) and PPE(-) neurons in dorsomedial striatum with cytoplasmic arc mRNA expression. Interestingly, in behaviourally activated animals significantly more PPE(-) neurons had cytoplasmic arc mRNA expression. These data suggest that Arc in both striatonigral and striatopallidal efferent neurons is involved in striatal synaptic plasticity mediating motor-response learning in the T-maze and that there is differential processing of arc mRNA in distinct subpopulations of striatal efferent neurons.

Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.

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Simonyan, Kristina; Berman, Brian D; Herscovitch, Peter; Hallett, Mark

2013-09-11

Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.

Chronic exposure to dopamine agonists affects the integrity of striatal D2 receptors in Parkinson's patients

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Marios Politis

2017-01-01

Full Text Available We aimed to investigate the integrity and clinical relevance of striatal dopamine receptor type-2 (D2R availability in Parkinson's disease (PD patients. We studied 68 PD patients, spanning from early to advanced disease stages, and 12 healthy controls. All participants received one [11C]raclopride PET scan in an OFF medication condition for quantification of striatal D2R availability in vivo. Parametric images of [11C]raclopride non-displaceable binding potential were generated from the dynamic [11C]raclopride scans using implementation of the simplified reference tissue model with cerebellum as the reference tissue. PET data were interrogated for correlations with clinical data related to disease burden and dopaminergic treatment. PD patients showed a mean 16.7% decrease in caudate D2R and a mean 3.5% increase in putaminal D2R availability compared to healthy controls. Lower caudate [11C]raclopride BPND correlated with longer PD duration. PD patients on dopamine agonist treatment had 9.2% reduced D2R availability in the caudate and 12.8% in the putamen compared to PD patients who never received treatment with dopamine agonists. Higher amounts of lifetime dopamine agonist therapy correlated with reduced D2Rs availability in both caudate and putamen. No associations between striatal D2R availability and levodopa treatment and dyskinesias were found. In advancing PD the caudate and putamen D2R availability are differentially affected. Chronic exposure to treatment with dopamine agonists, but no levodopa, suppresses striatal D2R availability, which may have relevance to output signaling to frontal lobes and the occurrence of executive deficits, but not dyskinesias.

Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

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Ramesh Chandra

2017-06-01

Full Text Available Immediate early genes (IEGs were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations.

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Sharott, Andrew; Vinciati, Federica; Nakamura, Kouichi C; Magill, Peter J

2017-10-11

Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical-basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on "direct pathway" SPNs (dSPNs) and "indirect pathway" SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15-30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits. SIGNIFICANCE STATEMENT Chronic depletion of dopamine

Avaliação da decomposição de plantas aquáticas no solo através da liberação de CO2 Evaluation of aquatic plant decomposition on soil through CO2 release

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M.R. Corrêa

2005-06-01

Full Text Available O objetivo deste trabalho foi avaliar a decomposição de três espécies de plantas aquáticas imersas, incorporadas ao solo, provenientes do controle mecânico, em reservatórios de usinas hidrelétricas. O estudo foi realizado em casa de vegetação, localizada no Núcleo de Pesquisas Avançadas em Matologia (NUPAM da FCA/Unesp-Botucatu. A avaliação foi conduzida em vasos contendo 14 kg de solo, com três incorporações de 50 e 100 t MF de plantas ha-1, sob duas condições de solo: seco e úmido. Com a simulação de descarte da biomassa coletada e incorporada ao solo, pôde-se conhecer, através da liberação de CO2, a degradação de três espécies de macrófitas aquáticas submersas. Para quantificação do CO2 liberado, em cada vaso foi acondicionado um frasco com solução de NaOH, sendo, logo após, lacrados e incubados por 24 horas; em seguida, foram titulados com HCl. Para ajuste e interpolação dos dados, estes foram analisados seguindo modelo de Mitscherlich, com algumas modificações. As liberações acumuladas em solo úmido foram de 1.294 e 1.582 kg CO2 ha-1, sendo 6,2 e 5,6 vezes superiores ao ocorrido em solo seco, para 50 e 100 t MF ha-1, respectivamente, observando-se que cerca de 55% da liberação de CO2 ocorreu nos primeiros 30 dias. Pode-se concluir que o solo seco é a melhor condição para descarte e incorporação da biomassa, porém deverá existir um sistema de irrigação para que o processo de degradação da biomassa incorporada seja acelerado.The purpose of this study was to evaluate decomposition due to mechanical control of three submerged aquatic weed species incorporated into soil at hydroelectric reservoirs. The study was carried out in a greenhouse at the Weed Science Center (NUPAM, FCA/UNESP-Botucatu. Evaluation was performed in vases containing 14 kg of soil, with three 50 and 100 t plant fresh matter ha-1 incorporations, under two soil conditions: dry and wet. By simulating the biomass harvested

Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

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Oran, Yael; Bar-Gad, Izhar

2018-02-14

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders. SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these

Striatal grafts in a rat model of Huntington's disease

DEFF Research Database (Denmark)

Guzman, R; Meyer, M; Lövblad, K O

1999-01-01

Survival and integration into the host brain of grafted tissue are crucial factors in neurotransplantation approaches. The present study explored the feasibility of using a clinical MR scanner to study striatal graft development in a rat model of Huntington's disease. Rat fetal lateral ganglionic...... time-points graft location could not be further verified. Measures for graft size and ventricle size obtained from MR images highly correlated with measures obtained from histologically processed sections (R = 0.8, P fetal rat lateral ganglionic...

Amphetamine Elicits Opposing Actions on Readily Releasable and Reserve Pools for Dopamine

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Covey, Dan P.; Juliano, Steven A.; Garris, Paul A.

2013-01-01

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID:23671560

Oxidative metabolism and Ca2+ handling in isolated brain mitochondria and striatal neurons from R6/2 mice, a model of Huntington's disease.

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Hamilton, James; Pellman, Jessica J; Brustovetsky, Tatiana; Harris, Robert A; Brustovetsky, Nickolay

2016-07-01

Alterations in oxidative metabolism and defects in mitochondrial Ca 2+ handling have been implicated in the pathology of Huntington's disease (HD), but existing data are contradictory. We investigated the effect of human mHtt fragments on oxidative metabolism and Ca 2+ handling in isolated brain mitochondria and cultured striatal neurons from the R6/2 mouse model of HD. Non-synaptic and synaptic mitochondria isolated from the brains of R6/2 mice had similar respiratory rates and Ca 2+ uptake capacity compared with mitochondria from wild-type (WT) mice. Respiratory activity of cultured striatal neurons measured with Seahorse XF24 flux analyzer revealed unaltered cellular respiration in neurons derived from R6/2 mice compared with neurons from WT animals. Consistent with the lack of respiratory dysfunction, ATP content of cultured striatal neurons from R6/2 and WT mice was similar. Mitochondrial Ca 2+ accumulation was also evaluated in cultured striatal neurons from R6/2 and WT animals. Our data obtained with striatal neurons derived from R6/2 and WT mice show that both glutamate-induced increases in cytosolic Ca 2+ and subsequent carbonilcyanide p-triflouromethoxyphenylhydrazone-induced increases in cytosolic Ca 2+ were similar between WT and R6/2, suggesting that mitochondria in neurons derived from both types of animals accumulated comparable amounts of Ca 2+ Overall, our data argue against respiratory deficiency and impaired Ca 2+ handling induced by human mHtt fragments in both isolated brain mitochondria and cultured striatal neurons from transgenic R6/2 mice. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Striatal D2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

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Wulff, Sanne; Pinborg, Lars Hageman; Svarer, Claus; Jensen, Lars Thorbjørn; Nielsen, Mette Ødegaard; Allerup, Peter; Bak, Nikolaj; Rasmussen, Hans; Frandsen, Erik; Rostrup, Egill; Glenthøj, Birte Yding

2015-01-01

One of best validated findings in schizophrenia research is the association between blockade of dopamine D2 receptors and the effects of antipsychotics on positive psychotic symptoms. The aim of the present study was to examine correlations between baseline striatal D2/3 receptor binding potential (BPp) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D2/3 receptor blockade and alterations of negative symptoms as well as functioning and subjective well-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [123I]iodobenzamide ([123I]-IBZM) was used to examine striatal D2/3 receptor BPp. Patients were examined before and after 6 weeks of treatment with the D2/3 receptor antagonist amisulpride. There was a significant negative correlation between striatal D2/3 receptor BPp at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed significantly lower baseline BPp in the responders. At follow-up, the patients demonstrated a negative correlation between the blockade and functioning, whereas no associations between blockade and negative symptoms or subjective well-being were observed. The results show an association between striatal BPp of dopamine D2/3 receptors in antipsychotic-naïve first-episode patients with schizophrenia and treatment response. Patients with a low BPp have a better treatment response than patients with a high BPp. The results further suggest that functioning may decline at high levels of dopamine receptor blockade. PMID:25698711

Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder

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Jilly Naaijen

2017-01-01

Conclusion: We found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

The influence of "host release factor" on carbon release by zooxanthellae isolated from fed and starved Aiptasia pallida (Verrill).

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Davy, S K; Cook, C B

2001-06-01

Symbiotic dinoflagellates (zooxanthellae) typically respond to extracts of host tissue with enhanced release of short-term photosynthetic products. We examined this "host release factor" (HRF) response using freshly isolated zooxanthellae of differing nutritional status. The nutritional status was manipulated by either feeding or starving the sea anemone Aiptasia pallida (Verrill). The release of fixed carbon from isolated zooxanthellae was measured using 14C in 30 min experiments. Zooxanthellae in filtered seawater alone released approximately 5% of photosynthate irrespective of host feeding history. When we used a 10-kDa ultrafiltrate of A. pallida host tissue as a source of HRF, approximately 14% of photosynthate was released to the medium. This increased to over 25% for zooxanthellae from anemones starved for 29 days or more. The cell-specific photosynthetic rate declined with starvation in these filtrate experiments, but the decline was offset by the increased percentage release. Indeed, the total amount of released photosynthate remained unchanged, or even increased, as zooxanthellae became more nutrient deficient. Similar trends were also observed when zooxanthellae from A. pallida were incubated in a 3-kDa ultrafiltrate of the coral Montastraea annularis, suggesting that HRF in the different filtrates operated in a similar manner. Our results support the suggestion that HRF diverts surplus carbon away from storage compounds to translocated compounds such as glycerol.

Differences in striatal dopamine transporter density between tremor dominant and non-tremor Parkinson's disease

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Kaasinen, Valtteri; Kinos, Maija; Joutsa, Juho [University of Turku and Turku University Hospital, Division of Clinical Neurosciences, Turku (Finland); University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); Seppaenen, Marko [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland); University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland); Noponen, Tommi [University of Turku and Turku University Hospital, Department of Clinical Physiology and Nuclear Medicine, Turku (Finland)

2014-10-15

Parkinson's disease (PD) can manifest with a tremor-dominant or a non-tremor (akinetic-rigid) phenotype. Although the tremor-dominant subtype may show a better prognosis, there is limited information on the phenotypic differences regarding the level of striatal dopamine transmission. The present study investigated striatal dopamine transporter (DAT) binding characteristics in a large sample of patients with and without tremor. [{sup 123}I]FP-CIT SPECT scans of 231 patients with a clinical diagnosis of PD and abnormal FP-CIT binding (157 with tremor, 74 without tremor) and 230 control patients with normal FP-CIT binding (148 with tremor, 82 without tremor) were analysed using an automated region-of-interest analysis of the scans (BRASS). Specific striatal binding ratios were compared between phenotypes and groups using age, sex, and symptom duration, predominant side of symptoms, dopaminergic medications and scanner as covariates. Patients with PD had 28.1 - 65.0 % lower binding in all striatal regions compared to controls (p < 0.001). The mean FP-CIT caudate nucleus uptake and the left caudate nucleus uptake were higher in PD patients with tremor than in PD patients without tremor (mean 9.0 % higher, left 10.5 % higher; p < 0.05), whereas there were no differences between tremor and non-tremor control patients. No significant effects of tremor on DAT binding were observed in the anterior or posterior putamen. The motor phenotype is associated with the extent of caudate dopamine terminal loss in PD, as dopamine function is relatively more preserved in tremor patients. Symptom type is related to caudate dopamine function only in association with Parkinsonian dopaminergic degeneration, not in intact dopamine systems in patients with non-PD tremor. (orig.)

In vivo evaluation of striatal dopamine reuptake sites using 11C-nomifensine and positron emission tomography

International Nuclear Information System (INIS)

Aquilonius, S.-M.; Bergstroem, K.; Eckernaes, S.-Aa.; Leenders, K.L.; Hartvig, P.; Lundquist, H.; Antoni, G.; Gee, A.; Rimland, A.; Uhlin, J.; Langstroem, B.

1987-01-01

In vitro nomifensine demonstrates high affinity and specificity for dopamine reuptake sites in the brain. In the present study 11 C-nomifensine was administered i.v. in trace amounts (10-50 μg) to ketamine anaesthetized Rhesus monkeys (6-10 kg b.w.) and the timecourse of radioactivity within different brain regions was measured by positron emission tomography (PET). Six base-line experiments lasting for 60-80 min were performed. The procedure was repeated after pretreatment with nomifensine (2-6 mg/kg i.v.), another reuptake inhibitor, mazindol (0.3 mg/kg i.v.), desipramine (0.5 mg/kg i.v.) or spiperone (0.3 mg/kg i.v.) before the administration of a second 11 C-nomifensine dose. The highest radioactivity uptake was found in the dopamine innervated striatum and the lowest in a region containing the cerebellum, known to be almost devoid of dopaminergic neurons. The difference between striatal and cerebellar uptake of 11 C-nomifensine derived radioactivity was markedly reduced after nomifensine and mazindol but not after desipramine and spiperone. These results indicate that in vivo the striatal uptake of 11 C-nomifensine, as measured with PET, involves specific binding with the dopamine reuptake sites. In the first human applications of 11 C-nomifensine and PET in a healthy volunteer, the regional uptake of radioactivity was similar to that in base-line experiments with Rhesus monkeys. In the healthy subject the striatal/cerebellar ratio was 1.6, 50 min after the injection of 11 C-nomifensine. In a hemi-parkinsonian patient this ratio was 1.1 contralaterally and 1.3 ipsilaterally to the affected side. 11 C-nomifensine and PET seems to be an auspicious method to measure the striatal dopaminergic nerve terminals of man in vivo. (author)

The functional DRD3 Ser9Gly polymorphism (rs6280) is pleiotropic, affecting reward as well as movement.

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Savitz, Jonathan; Hodgkinson, Colin A; Martin-Soelch, Chantal; Shen, Pei-Hong; Szczepanik, Joanna; Nugent, Allison; Herscovitch, Peter; Grace, Anthony A; Goldman, David; Drevets, Wayne C

2013-01-01

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.

The functional DRD3 Ser9Gly polymorphism (rs6280 is pleiotropic, affecting reward as well as movement.

Directory of Open Access Journals (Sweden)

Jonathan Savitz

Full Text Available Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3 gene (ser9gly, rs6280 on reward-associated dopamine (DA release in the striatum. Twenty-six healthy controls (HCs and 10 unmedicated subjects with major depressive disorder (MDD completed two positron emission tomography (PET scans with [(11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition and on another occasion subjects completed a gambling task (reward condition. A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release in the middle (anterior caudate (p<0.01 and the ventral striatum (p<0.05. The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.

Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum.

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Martin-Soelch, Chantal; Szczepanik, Joanna; Nugent, Allison; Barhaghi, Krystle; Rallis, Denise; Herscovitch, Peter; Carson, Richard E; Drevets, Wayne C

2011-05-01

Electrophysiological studies have shown that mesostriatal dopamine (DA) neurons increase activity in response to unpredicted rewards. With respect to other functions of the mesostriatal dopaminergic system, dopamine's actions show prominent laterality effects. Whether changes in DA transmission elicited by rewards also are lateralized, however, has not been investigated. Using [¹¹C]raclopride-PET to assess the striatal DA response to unpredictable monetary rewards, we hypothesized that such rewards would induce an asymmetric reduction in [¹¹C]raclopride binding in the ventral striatum, reflecting lateralization of endogenous dopamine release. In 24 healthy volunteers, differences in the regional D₂/₃ receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition were measured using the bolus-plus-constant-infusion [¹¹C]raclopride method. During the reward condition subjects randomly received monetary awards while performing a 'slot-machine' task. The ΔBP between conditions was assessed in striatal regions-of-interest and compared between left and right sides. We found a significant condition × lateralization interaction in the ventral striatum. A significant reduction in binding potential (BP(ND) ) in the reward condition vs. the control condition was found only in the right ventral striatum, and the ΔBP was greater in the right than the left ventral striatum. Unexpectedly, these laterality effects appeared to be partly accounted for by gender differences, as our data showed a significant bilateral BP(ND) reduction in women while in men the reduction reached significance only in the right ventral striatum. These data suggest that DA release in response to unpredictable reward is lateralized in the human ventral striatum, particularly in males. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Striatal μ-opioid receptor availability predicts cold pressor pain threshold in healthy human subjects

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Hagelberg, Nora; Aalto, Sargo; Tuominen, Lauri

2012-01-01

the potential associations between μ-opioid receptor BP(ND) and psychophysical measures. The results show that striatal μ-opioid receptor BP(ND) predicts cold pressor pain threshold, but not cold pressor pain tolerance or tactile sensitivity. This finding suggests that striatal μ-opioid receptor density......Previous PET studies in healthy humans have shown that brain μ-opioid receptor activation during experimental pain is associated with reductions in the sensory and affective ratings of the individual pain experience. The aim of this study was to find out whether brain μ-opioid receptor binding...... at the resting state, in absence of painful stimulation, can be a long-term predictor of experimental pain sensitivity. We measured μ-opioid receptor binding potential (BP(ND)) with μ-opioid receptor selective radiotracer [(11)C]carfentanil and positron emission tomography (PET) in 12 healthy male subjects...

Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity

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Mathieu Baudonnat

2017-05-01

Full Text Available Different parallel neural circuits interact and may even compete to process and store information: whereas stimulus–response (S–R learning critically depends on the dorsal striatum (DS, spatial memory relies on the hippocampus (HPC. Strikingly, despite its potential importance for our understanding of addictive behaviors, the impact of drug rewards on memory systems dynamics has not been extensively studied. Here, we assessed long-term effects of drug- vs food reinforcement on the subsequent use of S–R vs spatial learning strategies and their neural substrates. Mice were trained in a Y-maze cue-guided task, during which either food or morphine injections into the ventral tegmental area (VTA were used as rewards. Although drug- and food-reinforced mice learned the Y-maze task equally well, drug-reinforced mice exhibited a preferential use of an S–R learning strategy when tested in a water-maze competition task designed to dissociate cue-based and spatial learning. This cognitive bias was associated with a persistent increase in the phosphorylated form of cAMP response element-binding protein phosphorylation (pCREB within the DS, and a decrease of pCREB expression in the HPC. Pharmacological inhibition of striatal PKA pathway in drug-rewarded mice limited the morphine-induced increase in levels of pCREB in DS and restored a balanced use of spatial vs cue-based learning. Our findings suggest that drug (opiate reward biases the engagement of separate memory systems toward a predominant use of the cue-dependent system via an increase in learning-related striatal pCREB activity. Persistent functional imbalance between striatal and hippocampal activity could contribute to the persistence of addictive behaviors, or counteract the efficiency of pharmacological or psychotherapeutic treatments.

Further studies on the nature of postsynaptic dopamine uptake and metabolism in rat striatum: sodium dependency and investigation of a possible role for carrier-mediated uptake into serotonin neurons

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Schoepp, D.D.; Azzaro, A.J.

1985-06-01

The nature of postsynaptic sites involved in the uptake and metabolism of striatal 3,4-dihydroxyphenylethylamine (dopamine, DA) was investigated. The accumulation of (/sup 3/H)DA (10(-7) M) into slices of rat striatum was found to be greatly dependent on the presence of sodium ion in the incubation medium. However, the formation of the (/sup 3/H)dihydroxyphenylacetic acid (DOPAC) and (/sup 3/H)homovanillic acid (HVA) was only partially reduced in the absence of sodium. Inhibition of carrier-mediated DA neuronal uptake with nomifensine significantly decreased DA accumulation (18% of control) and (/sup 3/H)DOPAC formation (62% of control), but enhanced (/sup 3/H)HVA production (143% of control). Inhibition of the 5-hydroxytryptamine (5-HT, serotonin) neuronal uptake system with fluoxetine (10(-6) M) or selective 5-HT neuronal lesions with 5,7-dihydroxytryptamine (5,7-DHT) had no effect on (/sup 3/H)DOPAC or (/sup 3/H)HVA formed from (/sup 3/H)DA in the presence or absence of nomifensine. These results demonstrate that the uptake and subsequent metabolism of striatal DA to DOPAC and HVA is only partially dependent on carrier-mediated uptake mechanism(s) requiring sodium ion. These data support our previous findings suggesting a significant role for synaptic glial cell deamination and O-methylation of striatal DA. Further, experiments with fluoxetine or 5,7-DHT suggest that 5-HT neurons do not significantly contribute in the synaptic uptake and metabolism of striatal DA.

Higher dopamine release induced by less rather than more preferred reward during a working memory task in the primate prefrontal cortex.

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Kodama, Tohru; Hikosaka, Kazuo; Honda, Yoshiko; Kojima, Takashi; Watanabe, Masataka

2014-06-01

An optimal level of dopamine (DA) in the mammalian prefrontal cortex (PFC) is critical for higher cognitive control of behavior. Too much or too little DA in the PFC induces impairment in working memory (WM) task performance. PFC DA is also concerned with motivation. When reward is anticipated and/or delivered, an increase in PFC DA release is observed. In the primate, more preferred reward induces enhanced WM-related neuronal activity in the dorsolateral PFC (DLPFC). We hypothesized that there would be more DA release in the primate DLPFC when more preferred, as compared with less preferred, reward is delivered during a WM task. Contrary to our hypothesis, we found higher DA release in the DLPFC when less rather than more preferred reward was used during a WM task, while unpredictable free reward delivery induced an increase in DLPFC DA release irrespective of the difference in the incentive value of the reward. Behaviorally, the monkey was more motivated with preferred than with less preferred reward, although it performed the task almost without error irrespective of the difference in the reward. Considering that mild stress induces an increase in DA release in the mammalian PFC, performing a WM task for less preferred reward could have been mildly stressful, and this mild stress may have induced more DLPFC DA release in the present study. The higher DA release in the DLPFC with less preferred reward may be beneficial for monkeys to cope with mildly stressful and unfavorable situations to achieve proficient WM task performance. Copyright © 2014 Elsevier B.V. All rights reserved.

Diversity in Long-Term Synaptic Plasticity at Inhibitory Synapses of Striatal Spiny Neurons

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Rueda-Orozco, Pavel E.; Mendoza, Ernesto; Hernandez, Ricardo; Aceves, Jose J.; Ibanez-Sandoval, Osvaldo; Galarraga, Elvira; Bargas, Jose

2009-01-01

Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term…

Effects of caffeine on striatal neurotransmission: focus on cannabinoid CB1 receptors.

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Rossi, Silvia; De Chiara, Valentina; Musella, Alessandra; Mataluni, Giorgia; Sacchetti, Lucia; Siracusano, Alberto; Bernardi, Giorgio; Usiello, Alessandro; Centonze, Diego

2010-04-01

Caffeine is the most commonly self-administered psychoactive substance worldwide. At usual doses, the effects of caffeine on vigilance, attention, mood and arousal largely depend on the modulation of central adenosine receptors. The present review article describes the action of caffeine within the striatum, to provide a possible molecular mechanism at the basis of the psychomotor and reinforcing properties of this pharmacological agent. The striatum is in fact a subcortical area involved in sensorimotor, cognitive, and emotional processes, and recent experimental findings showed that chronic caffeine consumption enhances the sensitivity of striatal GABAergic synapses to the stimulation of cannabinoid CB1 receptors. The endocannabinoid system is involved in the psychoactive effects of many compounds, and adenosine A2A receptors (the main receptor target of caffeine) elicit a permissive effect towards CB1 receptors, thus suggesting that A2A-CB1 receptor interaction plays a major role in the generation and maintenance of caffeine reinforcing behavior. Aim of this review is to describe the effects of caffeine on striatal neurotransmission with special reference to the modulation of the endocannabinoid system.

Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

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Chung, S J; Lee, Y; Lee, J J; Lee, P H; Sohn, Y H

2017-10-01

Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism. © 2017 EAN.

6-hydroxydopamine-induced degeneration of nigral dopamine neurons: differential effect on nigral and striatal D-1 dopamine receptors

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Porceddu, M.L.; Giorgi, O.; De Montis, G.; Mele, S.; Cocco, L.; Ongini, E.; Biggio, G.

1987-01-01

Dopamine-sensitive adenylate cyclase and 3 H-SCH 23390 binding parameters were measured in the rat substantia nigra and striatum 15 days after the injection of 6-hydroxydopamine into the medial forebrain bundle. The activity of nigral dopamine-sensitive adenylate cyclase and the binding of 3 H-SCH 23390 to rat nigral D-1 dopamine receptors were markedly decreased after the lesion. On the contrary, 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway enhanced both adenylate cyclase activity and the density of 3 H-SCH 23390 binding sites in striatal membrane preparations. The changes in 3 H-SCH 23390 binding found in both nigral and striatal membrane preparations were associated with changes in the total number of binding sites with no modifications in their apparent affinity. The results indicate that: a) within the substantia nigra a fraction (30%) of D-1 dopamine receptors coupled to the adenylate cyclase is located on cell bodies and and/or dendrites of dopaminergic neurons; b) striatal D-1 dopamine receptors are tonically innervated by nigrostriatal afferent fibers. 24 references, 1 figure, 1 table

Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2.

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Taurisano, Paolo; Romano, Raffaella; Mancini, Marina; Giorgio, Annabella Di; Antonucci, Linda A; Fazio, Leonardo; Rampino, Antonio; Quarto, Tiziana; Gelao, Barbara; Porcelli, Annamaria; Papazacharias, Apostolos; Ursini, Gianluca; Caforio, Grazia; Masellis, Rita; Niccoli-Asabella, Artor; Todarello, Orlando; Popolizio, Teresa; Rubini, Giuseppe; Blasi, Giuseppe; Bertolino, Alessandro

2014-01-01

"Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.

Sex differences of gray matter morphology in cortico-limbic-striatal neural system in major depressive disorder.

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Kong, Lingtao; Chen, Kaiyuan; Womer, Fay; Jiang, Wenyan; Luo, Xingguang; Driesen, Naomi; Liu, Jie; Blumberg, Hilary; Tang, Yanqing; Xu, Ke; Wang, Fei

2013-06-01

Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naïve participants with MDD. Participants included 29 medication-naïve individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p sex-related patterns of abnormalities within the cortico-limbic-strial neural system, such as predominant prefrontal-limbic abnormalities in MDD females vs. predominant prefrontal-striatal abnormalities in MDD males, suggest differences in neural circuitry that may mediate sex differences in the clinical presentation of MDD and potential targets for sex-differentiated treatment of the disorder. Copyright © 2013 Elsevier Ltd. All rights reserved.

Increased ventral-striatal activity during monetary decision making is a marker of problem poker gambling severity.

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Brevers, Damien; Noël, Xavier; He, Qinghua; Melrose, James A; Bechara, Antoine

2016-05-01

The aim of this study was to examine the impact of different neural systems on monetary decision making in frequent poker gamblers, who vary in their degree of problem gambling. Fifteen frequent poker players, ranging from non-problem to high-problem gambling, and 15 non-gambler controls were scanned using functional magnetic resonance imaging (fMRI) while performing the Iowa Gambling Task (IGT). During IGT deck selection, between-group fMRI analyses showed that frequent poker gamblers exhibited higher ventral-striatal but lower dorsolateral prefrontal and orbitofrontal activations as compared with controls. Moreover, using functional connectivity analyses, we observed higher ventral-striatal connectivity in poker players, and in regions involved in attentional/motor control (posterior cingulate), visual (occipital gyrus) and auditory (temporal gyrus) processing. In poker gamblers, scores of problem gambling severity were positively associated with ventral-striatal activations and with the connectivity between the ventral-striatum seed and the occipital fusiform gyrus and the middle temporal gyrus. Present results are consistent with findings from recent brain imaging studies showing that gambling disorder is associated with heightened motivational-reward processes during monetary decision making, which may hamper one's ability to moderate his level of monetary risk taking. © 2015 Society for the Study of Addiction.

Reduced amygdala and ventral striatal activity to happy faces in PTSD is associated with emotional numbing.

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Kim L Felmingham

Full Text Available There has been a growing recognition of the importance of reward processing in PTSD, yet little is known of the underlying neural networks. This study tested the predictions that (1 individuals with PTSD would display reduced responses to happy facial expressions in ventral striatal reward networks, and (2 that this reduction would be associated with emotional numbing symptoms. 23 treatment-seeking patients with Posttraumatic Stress Disorder were recruited from the treatment clinic at the Centre for Traumatic Stress Studies, Westmead Hospital, and 20 trauma-exposed controls were recruited from a community sample. We examined functional magnetic resonance imaging responses during the presentation of happy and neutral facial expressions in a passive viewing task. PTSD participants rated happy facial expression as less intense than trauma-exposed controls. Relative to controls, PTSD participants revealed lower activation to happy (-neutral faces in ventral striatum and and a trend for reduced activation in left amygdala. A significant negative correlation was found between emotional numbing symptoms in PTSD and right ventral striatal regions after controlling for depression, anxiety and PTSD severity. This study provides initial evidence that individuals with PTSD have lower reactivity to happy facial expressions, and that lower activation in ventral striatal-limbic reward networks may be associated with symptoms of emotional numbing.

Real-time parallel processing of grammatical structure in the fronto-striatal system: a recurrent network simulation study using reservoir computing.

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Hinaut, Xavier; Dominey, Peter Ford

2013-01-01

Sentence processing takes place in real-time. Previous words in the sentence can influence the processing of the current word in the timescale of hundreds of milliseconds. Recent neurophysiological studies in humans suggest that the fronto-striatal system (frontal cortex, and striatum--the major input locus of the basal ganglia) plays a crucial role in this process. The current research provides a possible explanation of how certain aspects of this real-time processing can occur, based on the dynamics of recurrent cortical networks, and plasticity in the cortico-striatal system. We simulate prefrontal area BA47 as a recurrent network that receives on-line input about word categories during sentence processing, with plastic connections between cortex and striatum. We exploit the homology between the cortico-striatal system and reservoir computing, where recurrent frontal cortical networks are the reservoir, and plastic cortico-striatal synapses are the readout. The system is trained on sentence-meaning pairs, where meaning is coded as activation in the striatum corresponding to the roles that different nouns and verbs play in the sentences. The model learns an extended set of grammatical constructions, and demonstrates the ability to generalize to novel constructions. It demonstrates how early in the sentence, a parallel set of predictions are made concerning the meaning, which are then confirmed or updated as the processing of the input sentence proceeds. It demonstrates how on-line responses to words are influenced by previous words in the sentence, and by previous sentences in the discourse, providing new insight into the neurophysiology of the P600 ERP scalp response to grammatical complexity. This demonstrates that a recurrent neural network can decode grammatical structure from sentences in real-time in order to generate a predictive representation of the meaning of the sentences. This can provide insight into the underlying mechanisms of human cortico-striatal

Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease.

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Ciucci, Michelle R; Schaser, Allison J; Russell, John A

2013-09-01

Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content. Copyright © 2013 Elsevier B.V. All rights reserved.

Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.

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Yapo, Cedric; Nair, Anu G; Clement, Lorna; Castro, Liliana R; Hellgren Kotaleski, Jeanette; Vincent, Pierre

2017-12-15

Brief dopamine events are critical actors of reward-mediated learning in the striatum; the intracellular cAMP-protein kinase A (PKA) response of striatal medium spiny neurons to such events was studied dynamically using a combination of biosensor imaging in mouse brain slices and in silico simulations. Both D1 and D2 medium spiny neurons can sense brief dopamine transients in the sub-micromolar range. While dopamine transients profoundly change cAMP levels in both types of medium spiny neurons, the PKA-dependent phosphorylation level remains unaffected in D2 neurons. At the level of PKA-dependent phosphorylation, D2 unresponsiveness depends on protein phosphatase-1 (PP1) inhibition by DARPP-32. Simulations suggest that D2 medium spiny neurons could detect transient dips in dopamine level. The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of the dopamine effect on intracellular signalling remains poorly understood. We used genetically encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation levels, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D 1 or D 2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D 2 than on D 1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate to a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of protein phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a 'tone-sensing' mode, allowing them to detect transient dips in basal dopamine

Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3

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Johannes eZimmermann

2015-09-01

Full Text Available The identity of the vesicle neurotransmitter transporter expressed by a neuron largely corresponds with the primary neurotransmitter that cell releases. However, the vesicular glutamate transporter subtype 3 (VGLUT3 is mainly expressed in non-glutamatergic neurons, including cholinergic, serotonergic, or GABAergic neurons. Though a functional role for glutamate release from these non-glutamatergic neurons has been demonstrated, the interplay between VGLUT3 and the neuron’s characteristic neurotransmitter transporter, particularly in the case of GABAergic neurons, at the synaptic and vesicular level is less clear. In this study, we explore how exogenous expression of VGLUT3 in striatal GABAergic neurons affects the packaging and release of glutamate and GABA in synaptic vesicles. We found that VGLUT3 expression in isolated, autaptic GABAergic neurons leads to action potential evoked release of glutamate. Under these conditions, glutamate and GABA could be packaged together in single vesicles release either spontaneously or asynchronously. However, the presence of glutamate in GABAergic vesicles did not affect uptake of GABA itself, suggesting a lack of synergy in vesicle filling for these transmitters. Finally, we found postsynaptic detection of glutamate released from GABAergic terminals difficult when bona fide glutamatergic synapses were present, suggesting that co-released glutamate cannot induce postsynaptic glutamate receptor clustering.

Frontal, Striatal, and Medial Temporal Sensitivity to Value Distinguishes Risk-Taking from Risk-Aversive Older Adults during Decision Making.

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Goh, Joshua O S; Su, Yu-Shiang; Tang, Yong-Jheng; McCarrey, Anna C; Tereshchenko, Alexander; Elkins, Wendy; Resnick, Susan M

2016-12-07

Aging compromises the frontal, striatal, and medial temporal areas of the reward system, impeding accurate value representation and feedback processing critical for decision making. However, substantial variability characterizes age-related effects on the brain so that some older individuals evince clear neurocognitive declines whereas others are spared. Moreover, the functional correlates of normative individual differences in older-adult value-based decision making remain unclear. We performed a functional magnetic resonance imaging study in 173 human older adults during a lottery choice task in which costly to more desirable stakes were depicted using low to high expected values (EVs) of points. Across trials that varied in EVs, participants decided to accept or decline the offered stakes to maximize total accumulated points. We found that greater age was associated with less optimal decisions, accepting stakes when losses were likely and declining stakes when gains were likely, and was associated with increased frontal activity for costlier stakes. Critically, risk preferences varied substantially across older adults and neural sensitivity to EVs in the frontal, striatal, and medial temporal areas dissociated risk-aversive from risk-taking individuals. Specifically, risk-averters increased neural responses to increasing EVs as stakes became more desirable, whereas risk-takers increased neural responses with decreasing EV as stakes became more costly. Risk preference also modulated striatal responses during feedback with risk-takers showing more positive responses to gains compared with risk-averters. Our findings highlight the frontal, striatal, and medial temporal areas as key neural loci in which individual differences differentially affect value-based decision-making ability in older adults. Frontal, striatal, and medial temporal functions implicated in value-based decision processing of rewards and costs undergo substantial age-related changes. However, age

ARPP-16 Is a Striatal-Enriched Inhibitor of Protein Phosphatase 2A Regulated by Microtubule-Associated Serine/Threonine Kinase 3 (Mast 3 Kinase).

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Andrade, Erika C; Musante, Veronica; Horiuchi, Atsuko; Matsuzaki, Hideo; Brody, A Harrison; Wu, Terence; Greengard, Paul; Taylor, Jane R; Nairn, Angus C

2017-03-08

ARPP-16 (cAMP-regulated phospho-protein of molecular weight 16 kDa) is one of several small acid-soluble proteins highly expressed in medium spiny neurons of striatum that are phosphorylated in response to dopamine acting via D1 receptor/protein kinase A (PKA) signaling. We show here that ARPP-16 is also phosphorylated in vitro and in vivo by microtubule-associated serine/threonine kinase 3 (MAST3 kinase), an enzyme of previously unknown function that is enriched in striatum. We find that ARPP-16 interacts directly with the scaffolding A subunit of the serine/threonine protein phosphatase, PP2A, and that phosphorylation of ARPP-16 at Ser46 by MAST3 kinase converts the protein into a selective inhibitor of B55α- and B56δ-containing heterotrimeric forms of PP2A. Ser46 of ARPP-16 is phosphorylated to a high basal stoichiometry in striatum, suggestive of basal inhibition of PP2A in striatal neurons. In support of this hypothesis, conditional knock-out of ARPP-16 in CaMKIIα::cre/floxed ARPP-16/19 mice results in dephosphorylation of a subset of PP2A substrates including phospho-Thr75-DARPP-32, phospho-T308-Akt, and phospho-T202/Y204-ERK. Conditional knock-out of ARPP-16/19 is associated with increased motivation measured on a progressive ratio schedule of food reinforcement, yet an attenuated locomotor response to acute cocaine. Our previous studies have shown that ARPP-16 is phosphorylated at Ser88 by PKA. Activation of PKA in striatal slices leads to phosphorylation of Ser88, and this is accompanied by marked dephosphorylation of Ser46. Together, these studies suggest that phospho-Ser46-ARPP-16 acts to basally control PP2A in striatal medium spiny neurons but that dopamine acting via PKA inactivates ARPP-16 leading to selective potentiation of PP2A signaling. SIGNIFICANCE STATEMENT We describe a novel mechanism of signal transduction enriched in medium spiny neurons of striatum that likely mediates effects of the neurotransmitter dopamine acting on these cells. We

Sex Differences in Medium Spiny Neuron Excitability and Glutamatergic Synaptic Input: Heterogeneity Across Striatal Regions and Evidence for Estradiol-Dependent Sexual Differentiation

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Jinyan Cao

2018-04-01

Full Text Available Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate–putamen, nucleus accumbens core (AcbC, and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17β-estradiol (estradiol in modulating striatal dopamine systems. Indeed, output neurons of the striatum, the medium spiny neurons (MSNs, exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol-mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate–putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function.

Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

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Sergi Ferré

2007-01-01

Full Text Available By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS. Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit, where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

Enhanced striatal dopamine release during food stimulation in binge eating disorder

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Wang, g.j.; Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

2011-01-13

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [{sup 11}C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

Enhanced striatal dopamine release during food stimulation in binge eating disorder

International Nuclear Information System (INIS)

Wang, G.-J.; Geliebter, A.; Volkow, N.D.; Telang, F.W.; Logan, J.; Jaynbe, M.C.; Galanti, K.; Selig, P.A.; Han, H.; Zhu, W.; Wong, C.T.; Fowler, J.S.

2011-01-01

Subjects with binge eating disorder (BED) regularly consume large amounts of food in short time periods. The neurobiology of BED is poorly understood. Brain dopamine, which regulates motivation for food intake, is likely to be involved. We assessed the involvement of brain dopamine in the motivation for food consumption in binge eaters. Positron emission tomography (PET) scans with [ 11 C]raclopride were done in 10 obese BED and 8 obese subjects without BED. Changes in extracellular dopamine in the striatum in response to food stimulation in food-deprived subjects were evaluated after placebo and after oral methylphenidate (MPH), a drug that blocks the dopamine reuptake transporter and thus amplifies dopamine signals. Neither the neutral stimuli (with or without MPH) nor the food stimuli when given with placebo increased extracellular dopamine. The food stimuli when given with MPH significantly increased dopamine in the caudate and putamen in the binge eaters but not in the nonbinge eaters. Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. These results identify dopamine neurotransmission in the caudate as being of relevance to the neurobiology of BED. The lack of correlation between BMI and dopamine changes suggests that dopamine release per se does not predict BMI within a group of obese individuals but that it predicts binge eating.

A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter

DEFF Research Database (Denmark)

Rickhag, Karl Mattias; Hansen, Freja Herborg; Sørensen, Gunnar

2013-01-01

believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different dopamine transporter knock-in mice with disrupted PDZ-binding motifs (dopamine transporter-AAA and dopamine transporter+Ala) are characterized by dramatic loss of dopamine......The dopamine transporter mediates reuptake of dopamine from the synaptic cleft. The cellular mechanisms controlling dopamine transporter levels in striatal nerve terminals remain poorly understood. The dopamine transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence...... transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured dopaminergic neurons and striatal slices from dopamine transporter-AAA mice, we find markedly reduced dopamine transporter surface levels and evidence for enhanced constitutive internalization...

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation.

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Saddoris, Michael P; Cacciapaglia, Fabio; Wightman, R Mark; Carelli, Regina M

2015-08-19

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real

Immunization with DAT fragments is associated with long-term striatal impairment, hyperactivity and reduced cognitive flexibility in mice

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Adriani Walter

2012-11-01

Full Text Available Abstract Background Possible interactions between nervous and immune systems in neuro-psychiatric disorders remain elusive. Levels of brain dopamine transporter (DAT have been implicated in several impulse-control disorders, like attention deficit / hyperactivity disorder (ADHD and obsessive-compulsive disorder (OCD. Here, we assessed the interplay between DAT auto-immunity and behavioural / neurochemical phenotype. Methods Male CD-1 mice were immunized with DAT peptide fragments (DAT-i, or vehicle alone (VEH, to generate elevated circulating levels of DAT auto-antibodies (aAbs. Using an operant delay-of-reward task (20 min daily sessions; timeout 25 sec, mice had a choice between either an immediate small amount of food (SS, or a larger amount of food after a delay (LL, which increased progressively across sessions (from 0 to 150 sec. Results DAT-i mice exhibited spontaneous hyperactivity (2 h-longer wake-up peak; a wake-up attempt during rest. Two sub-populations differing in behavioural flexibility were identified in the VEH control group: they showed either a clear-cut decision to select LL or clear-cut shifting towards SS, as expected. Compared to VEH controls, choice-behaviour profile of DAT-i mice was markedly disturbed, together with long-lasting alterations of the striatal monoamines. Enhanced levels of DA metabolite HVA in DAT-i mice came along with slower acquisition of basal preferences and with impaired shifting; elevation also in DOPAC levels was associated with incapacity to change a rigid selection strategy. This scarce flexibility of performance is indicative of a poor adaptation to task contingencies. Conclusions Hyperactivity and reduced cognitive flexibility are patterns of behaviour consistent with enduring functional impairment of striatal regions. It is yet unclear how anti-DAT antibodies could enter or otherwise affect these brain areas, and which alterations in DAT activity exactly occurred after immunization

Motor Skill Learning Is Associated with Phase-Dependent Modifications in the Striatal cAMP/PKA/DARPP-32 Signaling Pathway in Rodents.

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Yu Qian

Full Text Available Abundant evidence points to a key role of dopamine in motor skill learning, although the underlying cellular and molecular mechanisms are still poorly understood. Here, we used a skilled-reaching paradigm to first examine changes in the expression of the plasticity-related gene Arc to map activity in cortico-striatal circuitry during different phases of motor skill learning in young animals. In the early phase, Arc mRNA was significantly induced in the medial prefrontal cortex (mPFC, cingulate cortex, primary motor cortex, and striatum. In the late phase, expression of Arc did not change in most regions, except in the mPFC and dorsal striatum. In the second series of experiments, we studied the learning-induced changes in the phosphorylation state of dopamine and cAMP-regulated phosphoprotein, 32k Da (DARPP-32. Western blot analysis of the phosphorylation state of DARPP-32 and its downstream target cAMP response element-binding protein (CREB in the striatum revealed that the early, but not late, phase of motor skill learning was associated with increased levels of phospho-Thr34-DARPP-32 and phospho-Ser133-CREB. Finally, we used the DARPP-32 knock-in mice with a point mutation in the Thr34 regulatory site (i.e., protein kinase A site to test the significance of this pathway in motor skill learning. In accordance with our hypothesis, inhibition of DARPP-32 activity at the Thr34 regulatory site strongly attenuated the motor learning rate and skilled reaching performance of mice. These findings suggest that the cAMP/PKA/DARPP-32 signaling pathway is critically involved in the acquisition of novel motor skills, and also demonstrate a dynamic shift in the contribution of cortico-striatal circuitry during different phases of motor skill learning.

A negative relationship between ventral striatal loss anticipation response and impulsivity in borderline personality disorder.

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Herbort, Maike C; Soch, Joram; Wüstenberg, Torsten; Krauel, Kerstin; Pujara, Maia; Koenigs, Michael; Gallinat, Jürgen; Walter, Henrik; Roepke, Stefan; Schott, Björn H

2016-01-01

Patients with borderline personality disorder (BPD) frequently exhibit impulsive behavior, and self-reported impulsivity is typically higher in BPD patients when compared to healthy controls. Previous functional neuroimaging studies have suggested a link between impulsivity, the ventral striatal response to reward anticipation, and prediction errors. Here we investigated the striatal neural response to monetary gain and loss anticipation and their relationship with impulsivity in 21 female BPD patients and 23 age-matched female healthy controls using functional magnetic resonance imaging (fMRI). Participants performed a delayed monetary incentive task in which three categories of objects predicted a potential gain, loss, or neutral outcome. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Compared to healthy controls, BPD patients exhibited significantly reduced fMRI responses of the ventral striatum/nucleus accumbens (VS/NAcc) to both reward-predicting and loss-predicting cues. BIS-11 scores showed a significant positive correlation with the VS/NAcc reward anticipation responses in healthy controls, and this correlation, while also nominally positive, failed to reach significance in BPD patients. BPD patients, on the other hand, exhibited a significantly negative correlation between ventral striatal loss anticipation responses and BIS-11 scores, whereas this correlation was significantly positive in healthy controls. Our results suggest that patients with BPD show attenuated anticipation responses in the VS/NAcc and, furthermore, that higher impulsivity in BPD patients might be related to impaired prediction of aversive outcomes.

Role of DARPP-32 and ARPP-21 in the Emergence of Temporal Constraints on Striatal Calcium and Dopamine Integration

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Bhalla, Upinder S.; Hellgren Kotaleski, Jeanette

2016-01-01

In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling could implement an input-interval dependent gating function, via transient PP1 inhibition, thus enforcing the requirement for temporal proximity. Furthermore, ARPP-21 signaling could impose the additional input-order requirement of calcium and dopamine, due to its Ca2+/calmodulin sequestering property when dopamine arrives first. This highlights the possible role of phosphoproteins in the temporal aspects of striatal signal transduction. PMID:27584878

The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens.

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Jang, Eun Young; Yang, Chae Ha; Hedges, David M; Kim, Soo Phil; Lee, Jun Yeon; Ekins, Tyler G; Garcia, Brandon T; Kim, Hee Young; Nelson, Ashley C; Kim, Nam Jun; Steffensen, Scott C

2017-09-01

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH-induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH-induced locomotor activity, self-administration and enhancement of DA release in the NAc. Systemic administration of a non-specific ROS scavenger, N-tert-butyl-α-phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide-selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH-induced locomotor activity without affecting generalized behavior in METH-naïve rats. PBN and TEMPOL significantly attenuated METH self-administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self-administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH. © 2016 Society for the Study of Addiction.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

NARCIS (Netherlands)

de Koning, Mariken B.; Bloemen, Oswald J. N.; van Duin, Esther D. A.; Booij, Jan; Abel, Kathryn M.; de Haan, Lieuwe; Linszen, Don H.; van Amelsvoort, Thérèse A. M. J.

2014-01-01

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic

Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability

OpenAIRE

Miller, Michael L.; Ren, Yanhua; Szutorisz, Henrietta; Warren, Noël A.; Tessereau, Chloé; Egervári, Gábor; Mlodnicka, Agnieszka; Kapoor, Manav; Chaarani, Bader; Morris, Claudia V.; Schumann, Gunter; Garavan, Hugh; Goate, Alison M.; Bannon, Michael J.; Halperin, Jeffrey M.

2017-01-01

Impulsivity, a multifaceted behavioral hallmark of attention-deficit/hyperactivity disorder (ADHD), strongly influences addiction vulnerability and other psychiatric disorders that incur enormous medical and societal burdens yet the neurobiological underpinnings linking impulsivity to disease remain poorly understood. Here we report the critical role of ventral striatal cAMP-response element modulator (CREM) in mediating impulsivity relevant to drug abuse vulnerability. Using an ADHD rat mode...

Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption.

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London, Tanisha D; Licholai, Julia A; Szczot, Ilona; Ali, Mohamed A; LeBlanc, Kimberly H; Fobbs, Wambura C; Kravitz, Alexxai V

2018-04-04

The striatum controls food-related actions and consumption and is linked to feeding disorders, including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons and indirect pathway medium spiny neurons. The selective contribution of direct pathway medium spiny neurons and indirect pathway medium spiny neurons to food-related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets. While electrophysiology revealed complex task-related dynamics across neurons, population calcium was enhanced during approach and inhibited during consumption in both pathways. We also observed ramping changes in activity that preceded both pellet-directed actions and spontaneous movements. These signals were heterogeneous in the spiking units, with neurons exhibiting either increasing or decreasing ramps. In contrast, the population calcium signals were homogeneous, with both pathways having increasing ramps of activity for several seconds before actions were initiated. An analysis comparing population firing rates to population calcium signals also revealed stronger ramping dynamics in the calcium signals than in the spiking data. In a second experiment, we trained the mice to perform an action sequence to evaluate when the ramping signals terminated. We found that the ramping signals terminated at the beginning of the action sequence, suggesting they may reflect upcoming actions and not preconsumption activity. Plasticity of such mechanisms may underlie disorders that alter action selection, such as drug addiction or obesity. SIGNIFICANCE STATEMENT Alterations in striatal function have been linked to pathological consumption in disorders, such as obesity and drug addiction. We recorded spiking and

Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

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Radl, Daniela; Chiacchiaretta, Martina; Lewis, Robert G; Brami-Cherrier, Karen; Arcuri, Ludovico; Borrelli, Emiliana

2018-01-02

The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R-mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the Drd2 gene, raises the question of whether both isoforms may equally control presynaptic and postsynaptic events. Here, we addressed this question by comparing behavioral and cellular responses of mice with the selective ablation of either D2L or D2S isoform. We establish that the presence of either D2L or D2S can support postsynaptic functions related to the control of motor activity in basal conditions. On the contrary, absence of D2S but not D2L prevents the inhibition of tyrosine hydroxylase phosphorylation and, thereby, of dopamine synthesis, supporting a major presynaptic role for D2S. Interestingly, boosting dopamine signaling in the striatum by acute cocaine administration reveals that absence of D2L, but not of D2S, strongly impairs the motor and cellular response to the drug, in a manner similar to the ablation of both isoforms. These results suggest that when the dopamine system is challenged, D2L signaling is required for the control of striatal circuits regulating motor activity. Thus, our findings show that D2L and D2S share similar functions in basal conditions but not in response to stimulation of the dopamine system.

Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia.

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Cameron, Stella H; Alwakeel, Amr J; Goddard, Liping; Hobbs, Catherine E; Gowing, Emma K; Barnett, Elizabeth R; Kohe, Sarah E; Sizemore, Rachel J; Oorschot, Dorothy E

2015-09-01

Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically

Prenatal ethanol enhances rotational behavior to apomorphine in the 24-month-old rat offspring with small striatal lesion.

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Gomide, Vânia C; Chadi, Gerson

2004-01-01

Pregnant Wistar rats received a hyperproteic liquid diet containing 37.5% ethanol-derived calories during gestation. Isocaloric amount of liquid diet, with maltose-dextrin substituted for ethanol, was given to control pair-fed dams. Offsprings were allowed to survive until 24 months of age. A set of aged female offsprings of both control diet and ethanol diet groups was registered for spontaneous motor activity, by means of an infrared motion sensor activity monitor, or for apomorphine-induced rotational behavior, while another lot of male offsprings was submitted to an unilateral striatal small mechanical lesion by a needle, 6 days before rotational recordings. Prenatal ethanol did not alter spontaneous motor parameters like resting time as well as the events of small and large movements in the aged offsprings. Bilateral circling behavior was already increased 5 min after apomorphine in the unlesioned offsprings of both the control and ethanol diet groups. However, it lasted more elevated for 45- to 75-min time intervals in the gestational ethanol-exposed offsprings, while decreasing faster in the control offsprings. Apomorphine triggered a strong and sustained elevation of contraversive turns in the striatal-lesioned 24-month-old offsprings of the ethanol group, but only a small and transient elevation was seen in the offsprings of the control diet group. Astroglial and microglial reactions were seen surrounding the striatal needle track lesion. Microdensitometric image analysis demonstrated no differences in the levels of tyrosine hydroxylase immunoreactivity in the striatum of 24-month-old unlesioned and lesioned offsprings of control and alcohol diet groups. The results suggest that ethanol exposure during gestation may alter the sensitivity of dopamine receptor in aged offsprings, which is augmented by even a small striatal lesion.

Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

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Pfeifer, Philippe; Tüscher, Oliver; Buchholz, Hans Georg; Gründer, Gerhard; Vernaleken, Ingo; Paulzen, Michael; Zimmermann, Ulrich S; Maus, Stephan; Lieb, Klaus; Eggermann, Thomas; Fehr, Christoph; Schreckenberger, Mathias

2017-09-01

Investigations on the acute effects of alcohol in the human mesolimbic dopamine D 2 /D 3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D 2 /D 3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D 2 /D 3 receptor ligand [ 18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D 2 /D 3 binding potential. Twenty-four healthy male μ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BP ND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BP ND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BP ND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D 2 /D 3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D 2 /D 3 receptors may hint at an addiction relevant trait. © 2016 Society for the Study of Addiction.

Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ΔFosB in mice.

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Sajja, Ravi Kiran; Rahman, Shafiqur

2013-06-01

Chronic administration of ethanol induces persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction. Copyright © 2013 Elsevier Inc. All rights reserved.

Lower levels of uric acid and striatal dopamine in non-tremor dominant Parkinson's disease subtype.

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Ismael Huertas

Full Text Available Parkinson's disease (PD patients who present with tremor and maintain a predominance of tremor have a better prognosis. Similarly, PD patients with high levels of uric acid (UA, a natural neuroprotectant, have also a better disease course. Our aim was to investigate whether PD motor subtypes differ in their levels of UA, and if these differences correlate with the degree of dopamine transporter (DAT availability. We included 75 PD patients from whom we collected information about their motor symptoms, DAT imaging and UA concentration levels. Based on the predominance of their motor symptoms, patients were classified into postural instability and gait disorder (PIGD, n = 36, intermediate (I, n = 22, and tremor-dominant (TD, n = 17 subtypes. The levels of UA and striatal DAT were compared across subtypes and the correlation between these two measures was also explored. We found that PIGD patients had lower levels of UA (3.7 vs 4.5 vs 5.3 mg/dL; P<0.001 and striatal DAT than patients with an intermediate or TD phenotype. Furthermore, UA levels significantly correlated with the levels of striatal DAT. We also observed that some PIGD (25% and I (45% patients had a predominance of tremor at disease onset. We speculate that UA might be involved in the maintenance of the less damaging TD phenotype and thus also in the conversion from TD to PIGD. Low levels of this natural antioxidant could lead to a major neuronal damage and therefore influence the conversion to a more severe motor phenotype.

Diagnostic value of asymmetric striatal D2 receptor upregulation in Parkinson's disease: an [123I]IBZM and [123I]FP-CIT SPECT study

International Nuclear Information System (INIS)

Verstappen, C.C.P.; Bloem, B.R.; Haaxma, C.A.; Horstink, M.W.I.M.; Oyen, W.J.G.

2007-01-01

Striatal postsynaptic D 2 receptors in Parkinson's disease (PD) are thought to be upregulated in the first years of the disease, especially contralateral to the clinically most affected side. The aim of this study was to evaluate whether the highest striatal D 2 binding is found contralateral to the most affected side in PD, and whether this upregulation can be used as a diagnostic tool. Cross-sectional survey was undertaken of 81 patients with clinically asymmetric PD, without antiparkinsonian drugs and with a disease duration of ≤5 years and 26 age-matched controls. Striatal D 2 binding was assessed with [ 123 I]IBZM SPECT, and severity of the presynaptic dopaminergic lesion with [ 123 I]FP-CIT SPECT. The mean striato-occipital ratio of [ 123 I]IBZM binding was significantly higher in PD patients (1.56 ±0.09) than in controls (1.53 ±0.06). In PD patients, higher values were found contralateral to the clinically most affected side (1.57 ±0.09 vs 1.55 ±0.10 ipsilaterally), suggesting D 2 receptor upregulation, and the reverse was seen using [ 123 I]FP-CIT SPECT. However, on an individual basis only 56% of PD patients showed this upregulation. Our study confirms asymmetric D 2 receptor upregulation in PD. However, the sensitivity of contralateral higher striatal [ 123 I]IBZM binding is only 56%. Therefore, the presence of contralateral higher striatal IBZM binding has insufficient diagnostic accuracy for PD, and PD cannot be excluded in patients with parkinsonism and no contralateral upregulation of D 2 receptors, assessed with [ 123 I]IBZM SPECT. (orig.)

De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions

NARCIS (Netherlands)

Mencacci, N.E.; Kamsteeg, E.J.; Nakashima, K.; R'Bibo, L.; Lynch, D.S.; Balint, B.; Willemsen, M.A.A.P.; Adams, M.E.; Wiethoff, S.; Suzuki, K.; Davies, C.H.; Ng, J.; Meyer, E.; Veneziano, L.; Giunti, P.; Hughes, D.; Raymond, F.L.; Carecchio, M.; Zorzi, G.; Nardocci, N.; Barzaghi, C.; Garavaglia, B.; Salpietro, V.; Hardy, J.; Pittman, A.M.; Houlden, H.; Kurian, M.A.; Kimura, H.; Vissers, L.E.L.M.; Wood, N.W.; Bhatia, K.P.

2016-01-01

Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very

Repeated administration of D-amphetamine induces loss of [123I]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

International Nuclear Information System (INIS)

Booij, Jan; Bruin, Kora de; Gunning, W. Boudewijn

2006-01-01

In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in amphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of D-AMPH or methamphetamine (METH) may induce loss of binding to striatal DATs in rats by using an experimental biodistribution study design and a SPECT tracer for the DAT ([ 123 I]FP-CIT). Methods: Groups of male rats (n=10 per group) were treated with D-AMPH (10 mg/kg body weight), METH (10 mg/kg body weight), or saline, twice a day for 5 consecutive days. Five days later, [ 123 I]FP-CIT was injected intravenously, and 2 h later, the rats were sacrificed and radioactivity was assayed. Results: In D-AMPH but not METH-treated rats, striatal [ 123 I]FP-CIT uptake was significantly lower (approximately 17%) than in the control group. Conclusion: These data show that [ 123 I]FP-CIT can be used to detect AMPH-induced changes in DAT binding and may validate the use of DAT radiotracers to study AMPH-induced changes in striatal DAT binding in vivo

Exploring personality traits related to dopamine D2/3 receptor availability in striatal subregions of humans.

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Caravaggio, Fernando; Fervaha, Gagan; Chung, Jun Ku; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Iwata, Yusuke; Wilson, Alan; Graff-Guerrero, Ariel

2016-04-01

While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C]-raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Slow phasic changes in nucleus accumbens dopamine release during fixed ratio acquisition: a microdialysis study.

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Segovia, K N; Correa, M; Salamone, J D

2011-11-24

Nucleus accumbens dopamine (DA) is a critical component of the brain circuitry regulating behavioral output during reinforcement-seeking behavior. Several studies have investigated the characteristics of accumbens DA release during the performance of well-learned operant behaviors, but relatively few have focused on the initial acquisition of particular instrumental behaviors or operant schedules. The present experiments focused on the initial acquisition of operant performance on a reinforcement schedule by studying the transition from a fixed ratio 1 (FR1) schedule to another operant schedule with a higher ratio requirement (i.e. fixed ratio 5 [FR5]). Microdialysis sessions were conducted in different groups of rats that were tested on either the FR1 schedule; the first, second, or third day of FR5 training; or after weeks of FR5 training. Consistent with previous studies, well-trained rats performing on the FR5 schedule after weeks of training showed significant increases in extracellular DA in both core and shell subregions of nucleus accumbens during the behavioral session. On the first day of FR5 training, there was a substantial increase in DA release in nucleus accumbens shell (i.e. approximately 300% of baseline). In contrast, accumbens core DA release was greatest on the second day of FR5 training. In parallel experiments, DA release in core and shell subregions did not significantly increase during free consumption of the same high carbohydrate food pellets that were used in the operant experiments, despite the very high levels of food intake in experienced rats. However, in rats exposed to the high-carbohydrate food for the first time, there was a tendency for extracellular DA to show a small increase. These results demonstrate that transient increases in accumbens DA release occur during the initial acquisition of ratio performance, and suggest that core and shell subregions show different temporal patterns during acquisition of instrumental behavior

Revisiting the 'self-medication' hypothesis in light of the new data linking low striatal dopamine to comorbid addictive behavior.

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Awad, A George; Voruganti, Lakshmi L N P

2015-06-01

Persons with schizophrenia are at a high risk, almost 4.6 times more likely, of having drug abuse problems than persons without psychiatric illness. Among the influential proposals to explain such a high comorbidity rate, the 'self-medication hypothesis' proposed that persons with schizophrenia take to drugs in an effort to cope with the illness and medication side effects. In support of the self-medication hypothesis, data from our earlier clinical study confirmed the strong association between neuroleptic dysphoria and negative subjective responses and comorbid drug abuse. Though dopamine has been consistently suspected as one of the major culprits for the development of neuroleptic dysphoria, it is only recently our neuroimaging studies correlated the emergence of neuroleptic dysphoria to the low level of striatal dopamine functioning. Similarly, more evidence has recently emerged linking low striatal dopamine with the development of vulnerability for drug addictive states in schizophrenia. The convergence of evidence from both the dysphoria and comorbidity research, implicating the role of low striatal dopamine in both conditions, has led us to propose that the person with schizophrenia who develops dysphoria and comorbid addictive disorder is likely to be one and the same.

Striatal D_2/3 Binding Potential Values in Drug-Naïve First-Episode Schizophrenia Patients Correlate With Treatment Outcome

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Wulff, Sanne; Pinborg, Lars Hageman; Svarer, Claus

2015-01-01

potential (BP(p)) values and treatment outcome in a cohort of antipsychotic-naïve first-episode schizophrenia patients. Additionally, we wished to investigate associations between striatal dopamine D(2/3) receptor blockade and alterations of negative symptoms as well as functioning and subjective well......-being. Twenty-eight antipsychotic-naïve schizophrenia patients and 26 controls were included in the study. Single-photon emission computed tomography (SPECT) with [(123)I]iodobenzamide ([(123)I]-IBZM) was used to examine striatal D(2/3) receptor BP(p). Patients were examined before and after 6 weeks...... of treatment with the D(2/3) receptor antagonist amisulpride. There was a significant negative correlation between striatal D(2/3) receptor BP(p) at baseline and improvement of positive symptoms in the total group of patients. Comparing patients responding to treatment to nonresponders further showed...

Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits

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Sebel, Luke E; Graves, Steven M; Chan, C Savio; Surmeier, D James

2017-01-01

Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D2 receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics. PMID:27577602

Striatal Dopamine D2/D3 Receptor Availability Is Associated with Executive Function in Healthy Controls but Not Methamphetamine Users.

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Michael E Ballard

Full Text Available Dopamine D2/D3 receptor availability in the striatum has been linked with executive function in healthy individuals, and is below control levels among drug addicts, possibly contributing to diminished executive function in the latter group. This study tested for an association of striatal D2/D3 receptor availability with a measure of executive function among research participants who met DSM-IV criteria for methamphetamine dependence.Methamphetamine users and non-user controls (n = 18 per group completed the Wisconsin Card Sorting Test and positron emission tomography with [18F]fallypride.The methamphetamine users displayed significantly lower striatal D2/D3 receptor availability on average than controls after controlling for age and education (p = 0.008, but they did not register greater proportions of either perseverative or non-perseverative errors when controlling for education (both ps ≥ 0.622. The proportion of non-perseverative, but not perseverative, errors was negatively correlated with striatal D2/D3 receptor availability among controls (r = -0.588, p = 0.010, but not methamphetamine users (r = 0.281, p = 0.258, and the group-wise interaction was significant (p = 0.030.These results suggest that cognitive flexibility, as measured by perseverative errors on the Wisconsin Card Sorting Test, is not determined by signaling through striatal D2/D3 receptors in healthy controls, and that in stimulant abusers, who have lower D2/D3 receptor availability, compensation can effectively maintain other executive functions, which are associated with D2/D3 receptor signaling in controls.

Populations of striatal medium spiny neurons encode vibrotactile frequency in rats: modulation by slow wave oscillations.

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Hawking, Thomas G; Gerdjikov, Todor V

2013-01-01

Dorsolateral striatum (DLS) is implicated in tactile perception and receives strong projections from somatosensory cortex. However, the sensory representations encoded by striatal projection neurons are not well understood. Here we characterized the contribution of DLS to the encoding of vibrotactile information in rats by assessing striatal responses to precise frequency stimuli delivered to a single vibrissa. We applied stimuli in a frequency range (45-90 Hz) that evokes discriminable percepts and carries most of the power of vibrissa vibration elicited by a range of complex fine textures. Both medium spiny neurons and evoked potentials showed tactile responses that were modulated by slow wave oscillations. Furthermore, medium spiny neuron population responses represented stimulus frequency on par with previously reported behavioral benchmarks. Our results suggest that striatum encodes frequency information of vibrotactile stimuli which is dynamically modulated by ongoing brain state.

Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

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Kucinski, Aaron; Sarter, Martin

2015-04-01

In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Voxel-based analysis of whole-brain effects of age and gender on dopamine transporter SPECT imaging in healthy subjects

International Nuclear Information System (INIS)

Eusebio, Alexandre; Azulay, Jean-Philippe; Ceccaldi, Mathieu; Girard, Nadine; Mundler, Olivier; Guedj, Eric

2012-01-01

Several studies have shown age- and gender-related differences in striatal dopamine transporter (DaT) binding. These studies were based on a striatal region on interest approach that may have underestimated these effects and could not evaluate extrastriatal regions. Our aim was to determine the effects at the voxel level of age and gender on whole-brain DaT distribution using [ 123 I]FP-CIT SPECT in healthy subjects. We performed a whole-brain [ 123 I]FP-CIT SPECT voxel-based analysis using SPM8 and a standardized normalization template (p < 0.05, corrected using the false discovery rate method) in 51 healthy subjects aged from 21 to 79 years. We found an age-related DaT binding decrease in the striatum, anterior cingulate/medial frontal cortices and insulo-opercular cortices. Also DaT binding ratios were higher in women than men in the striatum and opercular cortices. This study showed both striatal and extrastriatal age-related and gender-related differences in DaT binding in healthy subjects using a whole-brain voxel-based non-a priori approach. These differences highlight the need for careful age and gender matching in DaT analyses of neuropsychiatric disorders. (orig.)

Voxel-based analysis of whole-brain effects of age and gender on dopamine transporter SPECT imaging in healthy subjects

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Eusebio, Alexandre; Azulay, Jean-Philippe [APHM, Hopital de la Timone, Service de Neurologie et Pathologie du Mouvement, Marseille (France); CNRS, Aix-Marseille Univ, Institut de Neurosciences de la Timone, Marseille (France); Ceccaldi, Mathieu [APHM, Hopital de la Timone, Service de Neurologie et de Neuropsychologie, Marseille (France); Aix-Marseille Univ, UMR Inserm 1106, Institut de Neurosciences des Systemes, Marseille (France); Girard, Nadine [APHM, Hopital de la Timone, Service de Neuroradiologie diagnostique et interventionnelle, Marseille (France); Mundler, Olivier [APHM, Hopital de la Timone, Service Central de Biophysique et Medecine Nucleaire, Marseille (France); Aix-Marseille Univ, CERIMED, Marseille (France); Guedj, Eric [CNRS, Aix-Marseille Univ, Institut de Neurosciences de la Timone, Marseille (France); APHM, Hopital de la Timone, Service Central de Biophysique et Medecine Nucleaire, Marseille (France); Aix-Marseille Univ, CERIMED, Marseille (France)

2012-11-15

Several studies have shown age- and gender-related differences in striatal dopamine transporter (DaT) binding. These studies were based on a striatal region on interest approach that may have underestimated these effects and could not evaluate extrastriatal regions. Our aim was to determine the effects at the voxel level of age and gender on whole-brain DaT distribution using [{sup 123}I]FP-CIT SPECT in healthy subjects. We performed a whole-brain [{sup 123}I]FP-CIT SPECT voxel-based analysis using SPM8 and a standardized normalization template (p < 0.05, corrected using the false discovery rate method) in 51 healthy subjects aged from 21 to 79 years. We found an age-related DaT binding decrease in the striatum, anterior cingulate/medial frontal cortices and insulo-opercular cortices. Also DaT binding ratios were higher in women than men in the striatum and opercular cortices. This study showed both striatal and extrastriatal age-related and gender-related differences in DaT binding in healthy subjects using a whole-brain voxel-based non-a priori approach. These differences highlight the need for careful age and gender matching in DaT analyses of neuropsychiatric disorders. (orig.)

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

DEFF Research Database (Denmark)

Ziebell, Morten; Andersen, Birgitte B; Pinborg, Lars H

2013-01-01

cognitively evaluated with the Mini Mental State Examination. RESULTS: There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with (123)I-PE2I and SPECT. CONCLUSION: In patients with newly diagnosed DLB...

Optogenetic approaches to evaluate striatal function in animal models of Parkinson disease.

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Parker, Krystal L; Kim, Youngcho; Alberico, Stephanie L; Emmons, Eric B; Narayanan, Nandakumar S

2016-03-01

Optogenetics refers to the ability to control cells that have been genetically modified to express light-sensitive ion channels. The introduction of optogenetic approaches has facilitated the dissection of neural circuits. Optogenetics allows for the precise stimulation and inhibition of specific sets of neurons and their projections with fine temporal specificity. These techniques are ideally suited to investigating neural circuitry underlying motor and cognitive dysfunction in animal models of human disease. Here, we focus on how optogenetics has been used over the last decade to probe striatal circuits that are involved in Parkinson disease, a neurodegenerative condition involving motor and cognitive abnormalities resulting from degeneration of midbrain dopaminergic neurons. The precise mechanisms underlying the striatal contribution to both cognitive and motor dysfunction in Parkinson disease are unknown. Although optogenetic approaches are somewhat removed from clinical use, insight from these studies can help identify novel therapeutic targets and may inspire new treatments for Parkinson disease. Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.

Emotion-induced loss aversion and striatal-amygdala coupling in low-anxious individuals.

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Charpentier, Caroline J; De Martino, Benedetto; Sim, Alena L; Sharot, Tali; Roiser, Jonathan P

2016-04-01

Adapting behavior to changes in the environment is a crucial ability for survival but such adaptation varies widely across individuals. Here, we asked how humans alter their economic decision-making in response to emotional cues, and whether this is related to trait anxiety. Developing an emotional decision-making task for functional magnetic resonance imaging, in which gambling decisions were preceded by emotional and non-emotional primes, we assessed emotional influences on loss aversion, the tendency to overweigh potential monetary losses relative to gains. Our behavioral results revealed that only low-anxious individuals exhibited increased loss aversion under emotional conditions. This emotional modulation of decision-making was accompanied by a corresponding emotion-elicited increase in amygdala-striatal functional connectivity, which correlated with the behavioral effect across participants. Consistent with prior reports of 'neural loss aversion', both amygdala and ventral striatum tracked losses more strongly than gains, and amygdala loss aversion signals were exaggerated by emotion, suggesting a potential role for this structure in integrating value and emotion cues. Increased loss aversion and striatal-amygdala coupling induced by emotional cues may reflect the engagement of adaptive harm-avoidance mechanisms in low-anxious individuals, possibly promoting resilience to psychopathology. © The Author (2015). Published by Oxford University Press.

KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons

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M. Belén Pérez-Ramírez

2015-01-01

Full Text Available Striatal projection neurons (SPNs process motor and cognitive information. Their activity is affected by Parkinson’s disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit.

Reduced striatal volumes in Parkinson’s disease: a magnetic resonance imaging study

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Pitcher Toni L

2012-08-01

Full Text Available Abstract Background The presence and extent of structural changes in the brain as a consequence of Parkinson’s disease (PD is still poorly understood. Methods High-resolution 3-tesla T1-weighted structural magnetic resonance images in sixty-five PD and 27 age-matched healthy control participants were examined. Putamen, caudate, and intracranial volumes were manually traced in the axial plane of 3D reconstructed images. Striatal nuclei volumes were normalized to intracranial volume for statistical comparison. Disease status was assessed using the Unified Parkinson’s Disease Rating Scale and Hoehn and Yahr scale. Cognitive status was assessed using global status tests and detailed neuropsychological testing. Results Both caudate and putamen volumes were smaller in PD brains compared to controls after adjusting for age and gender. Caudate volumes were reduced by 11% (p = 0.001 and putamen volumes by 8.1% (p = 0.025. PD striatal volumes were not found to be significantly correlated with cognitive or motor decline. Conclusion Small, but significant reductions in the volume of both the caudate and putamen occur in PD brains. These reductions are independent of the effects of age and gender, however the relation of these reductions to the functional loss of dopamine, which is characteristic of PD, remains unclear.

Selective increase of auditory cortico-striatal coherence during auditory-cued Go/NoGo discrimination learning.

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Andreas L. Schulz

2016-01-01

Full Text Available Goal directed behavior and associated learning processes are tightly linked to neuronal activity in the ventral striatum. Mechanisms that integrate task relevant sensory information into striatal processing during decision making and learning are implicitly assumed in current reinforcementmodels, yet they are still weakly understood. To identify the functional activation of cortico-striatal subpopulations of connections during auditory discrimination learning, we trained Mongolian gerbils in a two-way active avoidance task in a shuttlebox to discriminate between falling and rising frequency modulated tones with identical spectral properties. We assessed functional coupling by analyzing the field-field coherence between the auditory cortex and the ventral striatum of animals performing the task. During the course of training, we observed a selective increase of functionalcoupling during Go-stimulus presentations. These results suggest that the auditory cortex functionally interacts with the ventral striatum during auditory learning and that the strengthening of these functional connections is selectively goal-directed.

Development and evaluation of sustained release losartan potassium matrix tablet using kollidon SR as release retardant

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Shahid Sarwar

2012-12-01

Full Text Available The present study was undertaken to develop sustained release (SR matrix tablets of losartan potassium, an angiotensin-II antagonist for the treatment of hypertension. The tablets were prepared by direct compression method, along with Kollidon SR as release retardant polymer. The amount of losartan potassium remains fixed (100 mg for all the three formulations whereas the amounts of Kollidon SR were 250 mg, 225 mg, and 200 mg for F-1, F-2, and F-3 respectively. The evaluation involves three stages: the micromeritic properties evaluation of granules, physical property studies of tablets, and in-vitro release kinetics studies. The USP apparatus type II was selected to perform the dissolution test, and the dissolution medium was 900 mL phosphate buffer pH 6.8. The test was carried out at 75 rpm, and the temperature was maintained at 37 ºC ± 0.5 ºC. The release kinetics was analyzed using several kinetics models. Higher polymeric content in the matrix decreased the release rate of drug. At lower polymeric level, the rate and extent of drug release were enhanced. All the formulations followed Higuchi release kinetics where the Regression co-efficient (R² values are 0.958, 0.944, and 0.920 for F-1, F-2, and F-3 respectively, and they exhibited diffusion dominated drug release. Statistically significant (PO presente estudo foi realizado para desenvolver (SR matriz de comprimidos de liberação sustentada de losartana, um antagonista da angiotensina II, para o tratamento da hipertensão arterial. Os comprimidos foram preparados pelo método de compressão direta com Kollidon SR como polímero de liberação lenta. A quantidade de losartana potássica permanece fixa (100 mg para todas as três formulações enquanto que as quantidades de Kollidon SR foram de 250 mg, 225 mg e 200 mg para F-1, F-2 e F-3, respectivamente. A avaliação envolve três etapas- propriedades micromeríticas dos grânulos, estudo das propriedades físicas dos comprimidos e

Prefrontal cortical and striatal activity to happy and fear faces in bipolar disorder is associated with comorbid substance abuse and eating disorder.

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Hassel, Stefanie; Almeida, Jorge R; Frank, Ellen; Versace, Amelia; Nau, Sharon A; Klein, Crystal R; Kupfer, David J; Phillips, Mary L

2009-11-01

The spectrum approach was used to examine contributions of comorbid symptom dimensions of substance abuse and eating disorder to abnormal prefrontal-cortical and subcortical-striatal activity to happy and fear faces previously demonstrated in bipolar disorder (BD). Fourteen remitted BD-type I and sixteen healthy individuals viewed neutral, mild and intense happy and fear faces in two event-related fMRI experiments. All individuals completed Substance-Use and Eating-Disorder Spectrum measures. Region-of-Interest analyses for bilateral prefrontal and subcortical-striatal regions were performed. BD individuals scored significantly higher on these spectrum measures than healthy individuals (pright PFC activity to intense happy faces (pright caudate nucleus activity to neutral faces (pright ventral putamen activity to intense happy (pabuse and eating disorder and prefrontal-cortical and subcortical-striatal activity to facial expressions in BD. Our findings suggest that these comorbid features may contribute to observed patterns of functional abnormalities in neural systems underlying mood regulation in BD.

3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate

DEFF Research Database (Denmark)

Storgaard, J; Kornblit, B T; Zimmer, J

2000-01-01

of lactate dehydrogenase in the medium and glutamic acid decarboxylase in tissue homogenates. 3-NPA toxicity (25-100 microM in 5 mM glucose, 24-48 h) appeared to be highly dependent on culture medium glucose levels. 3-NPA treatment caused also a dose-dependent lactate increase, reaching a maximum......Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay...... of threefold increase above control at 100 microM. Both a high dose of glutamate (5 mM) and glutamate uptake blockade by dl-threo-beta-hydroxyaspartate potentiated 3-NPA neurotoxicity in corticostriatal slice cultures. Furthermore, striatum from corticostriatal cocultures was more sensitive to 3-NPA than...

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

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Becker, Guillaume; Bahri, Mohamed Ali; Michel, Anne; Hustadt, Fabian; Garraux, Gaëtan; Luxen, André; Lemaire, Christian; Plenevaux, Alain

2017-05-01

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [ 18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([ 18 F]FDOPA) and 6-[ 18 F]fluoro-L-m-tyrosine ([ 18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [ 18 F]FMT and [ 18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [ 18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [ 18 F]FMT and [ 18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant K c . However, only [ 18 F]FMT K c succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [ 18 F]FMT could be more sensitive, with respect of [ 18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L

Levodopa-induced dyskinesia is associated with increased thyrotropin releasing hormone in the dorsal striatum of hemi-parkinsonian rats.

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Ippolita Cantuti-Castelvetri

2010-11-01

Full Text Available Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine therapy for Parkinson's disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition.Quantitative real-time polymerase chain reaction (PCR was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson's disease. With this technique, we determined that thyrotropin releasing hormone (TRH was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes.TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson's disease.

Automated striatal uptake analysis of 18F-FDOPA PET images applied to Parkinson's disease patients

International Nuclear Information System (INIS)

Chang Icheng; Lue Kunhan; Hsieh Hungjen; Liu Shuhsin; Kao, Chinhao K.

2011-01-01

6-[ 18 F]Fluoro-L-DOPA (FDOPA) is a radiopharmaceutical valuable for assessing the presynaptic dopaminergic function when used with positron emission tomography (PET). More specifically, the striatal-to-occipital ratio (SOR) of FDOPA uptake images has been extensively used as a quantitative parameter in these PET studies. Our aim was to develop an easy, automated method capable of performing objective analysis of SOR in FDOPA PET images of Parkinson's disease (PD) patients. Brain images from FDOPA PET studies of 21 patients with PD and 6 healthy subjects were included in our automated striatal analyses. Images of each individual were spatially normalized into an FDOPA template. Subsequently, the image slice with the highest level of basal ganglia activity was chosen among the series of normalized images. Also, the immediate preceding and following slices of the chosen image were then selected. Finally, the summation of these three images was used to quantify and calculate the SOR values. The results obtained by automated analysis were compared with manual analysis by a trained and experienced image processing technologist. The SOR values obtained from the automated analysis had a good agreement and high correlation with manual analysis. The differences in caudate, putamen, and striatum were -0.023, -0.029, and -0.025, respectively; correlation coefficients 0.961, 0.957, and 0.972, respectively. We have successfully developed a method for automated striatal uptake analysis of FDOPA PET images. There was no significant difference between the SOR values obtained from this method and using manual analysis. Yet it is an unbiased time-saving and cost-effective program and easy to implement on a personal computer. (author)

Repeated administration of D-amphetamine induces loss of [{sup 123}I]FP-CIT binding to striatal dopamine transporters in rat brain: a validation study

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Booij, Jan [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands)]. E-mail: j.booij@amc.uva.nl; Bruin, Kora de [Department of Nuclear Medicine, Academic Medical Center, 1105 AZ Amsterdam (Netherlands); Gunning, W. Boudewijn [Department of Neurology, Epilepsy Centre Kempenhaeghe, 5590 AB Heeze (Netherlands)

2006-04-15

In recent years, several PET and SPECT studies have shown loss of striatal dopamine transporter (DAT) binding in amphetamine (AMPH) users. However, the use of DAT SPECT tracers to detect AMPH-induced changes in DAT binding has not been validated. We therefore examined if repeated administration of D-AMPH or methamphetamine (METH) may induce loss of binding to striatal DATs in rats by using an experimental biodistribution study design and a SPECT tracer for the DAT ([{sup 123}I]FP-CIT). Methods: Groups of male rats (n=10 per group) were treated with D-AMPH (10 mg/kg body weight), METH (10 mg/kg body weight), or saline, twice a day for 5 consecutive days. Five days later, [{sup 123}I]FP-CIT was injected intravenously, and 2 h later, the rats were sacrificed and radioactivity was assayed. Results: In D-AMPH but not METH-treated rats, striatal [{sup 123}I]FP-CIT uptake was significantly lower (approximately 17%) than in the control group. Conclusion: These data show that [{sup 123}I]FP-CIT can be used to detect AMPH-induced changes in DAT binding and may validate the use of DAT radiotracers to study AMPH-induced changes in striatal DAT binding in vivo.

Effects of an acute therapeutic or rewarding dose of amphetamine on acquisition of Pavlovian autoshaping and ventral striatal dopamine signaling.

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Schuweiler, D R; Athens, J M; Thompson, J M; Vazhayil, S T; Garris, P A

2018-01-15

Rewarding doses of amphetamine increase the amplitude, duration, and frequency of dopamine transients in the ventral striatum. Debate continues at the behavioral level about which component of reward, learning or incentive salience, is signaled by these dopamine transients and thus altered in addiction. The learning hypothesis proposes that rewarding drugs result in pathological overlearning of drug-predictive cues, while the incentive sensitization hypothesis suggests that rewarding drugs result in sensitized attribution of incentive salience to drug-predictive cues. Therapeutic doses of amphetamine, such as those used to treat attention-deficit hyperactivity disorder, are hypothesized to enhance the ventral striatal dopamine transients that are critical for reward-related learning and to enhance Pavlovian learning. However, the effects of therapeutic doses of amphetamine on Pavlovian learning are poorly understood, and the effects on dopamine transients are completely unknown. We determined the effects of an acute pre-training therapeutic or rewarding amphetamine injection on the acquisition of Pavlovian autoshaping in the intact rat. We also determined the effects of these doses on electrically evoked transient-like dopamine signals using fast-scan cyclic voltammetry in the anesthetized rat. The rewarding dose enhanced the amplitude and duration of DA signals, caused acute task disengagement, impaired learning for several days, and triggered incentive sensitization. The therapeutic dose produced smaller enhancements in DA signals but did not have similar behavioral effects. These results underscore the necessity of more studies using therapeutic doses, and suggest a hybrid learning/incentive sensitization model may be required to explain the development of addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

Computed-tomography-guided anatomic standardization for quantitative assessment of dopamine transporter SPECT

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Yokoyama, Kota [National Center of Neurology and Psychiatry, Department of Radiology, Tokyo (Japan); National Center of Neurology and Psychiatry, Integrative Brain Imaging Center, Tokyo (Japan); Imabayashi, Etsuko; Matsuda, Hiroshi [National Center of Neurology and Psychiatry, Integrative Brain Imaging Center, Tokyo (Japan); Sumida, Kaoru; Sone, Daichi; Kimura, Yukio; Sato, Noriko [National Center of Neurology and Psychiatry, Department of Radiology, Tokyo (Japan); Mukai, Youhei; Murata, Miho [National Center of Neurology and Psychiatry, Department of Neurology, Tokyo (Japan)

2017-03-15

For the quantitative assessment of dopamine transporter (DAT) using [{sup 123}I]FP-CIT single-photon emission computed tomography (SPECT) (DaTscan), anatomic standardization is preferable for achieving objective and user-independent quantification of striatal binding using a volume-of-interest (VOI) template. However, low accumulation of DAT in Parkinson's disease (PD) would lead to a deformation error when using a DaTscan-specific template without any structural information. To avoid this deformation error, we applied computed tomography (CT) data obtained using SPECT/CT equipment to anatomic standardization. We retrospectively analyzed DaTscan images of 130 patients with parkinsonian syndromes (PS), including 80 PD and 50 non-PD patients. First we segmented gray matter from CT images using statistical parametric mapping 12 (SPM12). These gray-matter images were then anatomically standardized using the diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL) algorithm. Next, DaTscan images were warped with the same parameters used in the CT anatomic standardization. The target striatal VOIs for decreased DAT in PD were generated from the SPM12 group comparison of 20 DaTscan images from each group. We applied these VOIs to DaTscan images of the remaining patients in both groups and calculated the specific binding ratios (SBRs) using nonspecific counts in a reference area. In terms of the differential diagnosis of PD and non-PD groups using SBR, we compared the present method with two other methods, DaTQUANT and DaTView, which have already been released as software programs for the quantitative assessment of DaTscan images. The SPM12 group comparison showed a significant DAT decrease in PD patients in the bilateral whole striatum. Of the three methods assessed, the present CT-guided method showed the greatest power for discriminating PD and non-PD groups, as it completely separated the two groups. CT-guided anatomic standardization using

Nitric oxide-soluble guanylyl cyclase-cyclic GMP signaling in the striatum: New targets for the treatment of Parkinson's disease?

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Anthony R West

2011-06-01

Full Text Available Striatal nitric oxide (NO-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons (MSNs which contain high levels of NO receptors called soluble guanylyl cyclases (sGC. NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO-cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO-sGC-cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinson’s disease (PD. Here, we discuss recent developments in the field which have shed light on the role of NO-sGC-cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and L-DOPA-induced dyskinesias.

Corticostriatal and Dopaminergic Response to Beer Flavor with Both fMRI and [(11) C]raclopride Positron Emission Tomography.

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Oberlin, Brandon G; Dzemidzic, Mario; Harezlak, Jaroslaw; Kudela, Maria A; Tran, Stella M; Soeurt, Christina M; Yoder, Karmen K; Kareken, David A

2016-09-01

Cue-evoked drug-seeking behavior likely depends on interactions between frontal activity and ventral striatal (VST) dopamine (DA) transmission. Using [(11) C]raclopride (RAC) positron emission tomography (PET), we previously demonstrated that beer flavor (absent intoxication) elicited VST DA release in beer drinkers, inferred by RAC displacement. Here, a subset of subjects from this previous RAC-PET study underwent a similar paradigm during functional magnetic resonance imaging (fMRI) to test how orbitofrontal cortex (OFC) and VST blood oxygenation level-dependent (BOLD) responses to beer flavor are related to VST DA release and motivation to drink. Male beer drinkers (n = 28, age = 24 ± 2, drinks/wk = 16 ± 10) from our previous PET study participated in a similar fMRI paradigm wherein subjects tasted their most frequently consumed brand of beer and Gatorade(®) (appetitive control). We tested for correlations between BOLD activation in fMRI and VST DA responses in PET, and drinking-related variables. Compared to Gatorade, beer flavor increased wanting and desire to drink, and induced BOLD responses in bilateral OFC and right VST. Wanting and desire to drink correlated with both right VST and medial OFC BOLD activation to beer flavor. Like the BOLD findings, beer flavor (relative to Gatorade) again induced right VST DA release in this fMRI subject subset, but there was no correlation between DA release and the magnitude of BOLD responses in frontal regions of interest. Both imaging modalities showed a right-lateralized VST response (BOLD and DA release) to a drug-paired conditioned stimulus, whereas fMRI BOLD responses in the VST and medial OFC also reflected wanting and desire to drink. The data suggest the possibility that responses to drug-paired cues may be rightward biased in the VST (at least in right-handed males) and that VST and OFC responses in this gustatory paradigm reflect stimulus wanting. Copyright © 2016 by the Research Society on

Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

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Oliveira, Rodrigo F.; Kim, MyungSook; Blackwell, Kim T.

2012-01-01

Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity. PMID:22346744

Synthesis and binding to striatal membranes of non carrier added I-123 labeled 4'-iodococaine

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Metwally, S.A.M.; Gatley, S.J.; Wolf, A.P.; Yu, D.-W.

1992-01-01

An 123 I labeled cocaine analog, 4'-[ 123 I]iodococaine, has been prepared by oxidative destannylation of the tributyltin analog and shown to interact with cocaine binding sites in rat brain striatal membranes. It may thus be a suitable SPECT radiotracer for studies of the dopamine reuptake site in neurodegenerative diseases. (Author)

Sensory Entrainment Mechanisms in Auditory Perception: Neural Synchronization Cortico-Striatal Activation.

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Sameiro-Barbosa, Catia M; Geiser, Eveline

2016-01-01

The auditory system displays modulations in sensitivity that can align with the temporal structure of the acoustic environment. This sensory entrainment can facilitate sensory perception and is particularly relevant for audition. Systems neuroscience is slowly uncovering the neural mechanisms underlying the behaviorally observed sensory entrainment effects in the human sensory system. The present article summarizes the prominent behavioral effects of sensory entrainment and reviews our current understanding of the neural basis of sensory entrainment, such as synchronized neural oscillations, and potentially, neural activation in the cortico-striatal system.

Sensory Entrainment Mechanisms in Auditory Perception: Neural Synchronization Cortico-Striatal Activation

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Sameiro-Barbosa, Catia M.; Geiser, Eveline

2016-01-01

The auditory system displays modulations in sensitivity that can align with the temporal structure of the acoustic environment. This sensory entrainment can facilitate sensory perception and is particularly relevant for audition. Systems neuroscience is slowly uncovering the neural mechanisms underlying the behaviorally observed sensory entrainment effects in the human sensory system. The present article summarizes the prominent behavioral effects of sensory entrainment and reviews our current understanding of the neural basis of sensory entrainment, such as synchronized neural oscillations, and potentially, neural activation in the cortico-striatal system. PMID:27559306

Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.

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Dirleise Colle

Full Text Available Huntington's disease (HD is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP, an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p. once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx, an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage secondary to mitochondrial dysfunction. These data appeared to be of great

Oxytocin and prolactin release after hypertonic saline administration in melatonin-treated male Syrian hamsters

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Juszczak, M.; Steger, R.W.; Fadden, C.; Bartke, A.

1996-01-01

The aim of the present investigations was to examine the effects of melatonin (Mel) on oxytocin (OT) release under conditions of osmotic stimulation, brought about by hypertonic saline administration, as well as to determine whether osmotically stimulated OT release in Mel-treated Syrian hamster is associated with alterations in the release of prolactin (PRL) and in norepinephrine (NE) and dopamine (DA) content in the hypothalamus. In both Mel- and vehicle-treated hamsters, injection of hypertonic saline was followed by a significant decrease in OT content in the pituitary neurointermediate lobe (NIL) and elevation of plasma OT and PRL levels. Melatonin injections had no significant affect on NIL OT content in either isotonic- or hypertonic-saline treated animals. Pretreatment with Mel did not alter plasma OT or PRL levels in isotonic saline-injected animals. However, Mel facilitated the release of OT, but prevented the release of PRL after hypertonic saline administration. Melatonin treatment reduced hypothalamic NE content (but not that of DA) in isotonic-saline treated animals. After osmotic stimulation, hypothalamic content of NE and DA was significantly lower in Mel-treated than in vehicle-treated animals. Data from the present study suggest that the osmotically-stimulated release of OT and PRL seems to be related to the activation of noradrenergic rather than dopaminergic transmission. Both dopaminergic and noradrenergic transmission may be, however, involved in mediating the effects of Mel on the osmotically-activated OT and PRL release. (author). 48 refs, 3 figs

Oxytocin and prolactin release after hypertonic saline administration in melatonin-treated male Syrian hamsters

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Juszczak, M.; Steger, R.W.; Fadden, C.; Bartke, A. [Southern Illinois Univ., Carbondale, IL (United States)

1996-12-31

The aim of the present investigations was to examine the effects of melatonin (Mel) on oxytocin (OT) release under conditions of osmotic stimulation, brought about by hypertonic saline administration, as well as to determine whether osmotically stimulated OT release in Mel-treated Syrian hamster is associated with alterations in the release of prolactin (PRL) and in norepinephrine (NE) and dopamine (DA) content in the hypothalamus. In both Mel- and vehicle-treated hamsters, injection of hypertonic saline was followed by a significant decrease in OT content in the pituitary neurointermediate lobe (NIL) and elevation of plasma OT and PRL levels. Melatonin injections had no significant affect on NIL OT content in either isotonic- or hypertonic-saline treated animals. Pretreatment with Mel did not alter plasma OT or PRL levels in isotonic saline-injected animals. However, Mel facilitated the release of OT, but prevented the release of PRL after hypertonic saline administration. Melatonin treatment reduced hypothalamic NE content (but not that of DA) in isotonic-saline treated animals. After osmotic stimulation, hypothalamic content of NE and DA was significantly lower in Mel-treated than in vehicle-treated animals. Data from the present study suggest that the osmotically-stimulated release of OT and PRL seems to be related to the activation of noradrenergic rather than dopaminergic transmission. Both dopaminergic and noradrenergic transmission may be, however, involved in mediating the effects of Mel on the osmotically-activated OT and PRL release. (author). 48 refs, 3 figs.

Perineuronal nets play a role in regulating striatal function in the mouse.

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Hyunchul Lee

Full Text Available The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs, aggregations of chondroitin-sulfate proteoglycans (CSPGs, form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41% of these structures surrounds parvalbumin positive (PV+ interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

Perineuronal nets play a role in regulating striatal function in the mouse.

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Lee, Hyunchul; Leamey, Catherine A; Sawatari, Atomu

2012-01-01

The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.

Olfactory bulb short axon cell release of GABA and dopamine produces a temporally biphasic inhibition-excitation response in external tufted cells.

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Liu, Shaolin; Plachez, Celine; Shao, Zuoyi; Puche, Adam; Shipley, Michael T

2013-02-13

Evidence for coexpression of two or more classic neurotransmitters in neurons has increased, but less is known about cotransmission. Ventral tegmental area (VTA) neurons corelease dopamine (DA), the excitatory transmitter glutamate, and the inhibitory transmitter GABA onto target cells in the striatum. Olfactory bulb (OB) short axon cells (SACs) form interglomerular connections and coexpress markers for DA and GABA. Using an optogenetic approach, we provide evidence that mouse OB SACs release both GABA and DA onto external tufted cells (ETCs) in other glomeruli. Optical activation of channelrhodopsin specifically expressed in DAergic SACs produced a GABA(A) receptor-mediated monosynaptic inhibitory response, followed by DA-D(1)-like receptor-mediated excitatory response in ETCs. The GABA(A) receptor-mediated hyperpolarization activates I(h) current in ETCs; synaptically released DA increases I(h), which enhances postinhibitory rebound spiking. Thus, the opposing actions of synaptically released GABA and DA are functionally integrated by I(h) to generate an inhibition-to-excitation "switch" in ETCs. Consistent with the established role of I(h) in ETC burst firing, we show that endogenous DA release increases ETC spontaneous bursting frequency. ETCs transmit sensory signals to mitral/tufted output neurons and drive intraglomerular inhibition to shape glomerulus output to downstream olfactory networks. GABA and DA cotransmission from SACs to ETCs may play a key role in regulating output coding across the glomerular array.

DA-6034 Induces [Ca(2+)]i Increase in Epithelial Cells.

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Yang, Yu-Mi; Park, Soonhong; Ji, Hyewon; Kim, Tae-Im; Kim, Eung Kweon; Kang, Kyung Koo; Shin, Dong Min

2014-04-01

DA-6034, a eupatilin derivative of flavonoid, has shown potent effects on the protection of gastric mucosa and induced the increases in fluid and glycoprotein secretion in human and rat corneal and conjunctival cells, suggesting that it might be considered as a drug for the treatment of dry eye. However, whether DA-6034 induces Ca(2+) signaling and its underlying mechanism in epithelial cells are not known. In the present study, we investigated the mechanism for actions of DA-6034 in Ca(2+) signaling pathways of the epithelial cells (conjunctival and corneal cells) from human donor eyes and mouse salivary gland epithelial cells. DA-6034 activated Ca(2+)-activated Cl(-) channels (CaCCs) and increased intracellular calcium concentrations ([Ca(2+)]i) in primary cultured human conjunctival cells. DA-6034 also increased [Ca(2+)]i in mouse salivary gland cells and human corneal epithelial cells. [Ca(2+)]i increase of DA-6034 was dependent on the Ca(2+) entry from extracellular and Ca(2+) release from internal Ca(2+) stores. Interestingly, these effects of DA-6034 were related to ryanodine receptors (RyRs) but not phospholipase C/inositol 1,4,5-triphosphate (IP3) pathway and lysosomal Ca(2+) stores. These results suggest that DA-6034 induces Ca(2+) signaling via extracellular Ca(2+) entry and RyRs-sensitive Ca(2+) release from internal Ca(2+) stores in epithelial cells.

Concomitant Appearance of Pisa Syndrome and Striatal Hand in Parkinson’s Disease

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Sanjay Pandey

2011-10-01

Full Text Available Pisa syndrome is (PS usually seen in patients receiving antipsychotic drugs and characterised by lateral flexion of trunk and axial dystonia. It is believed that antipsychotic drugs lead to dopamine blockage causing PS. We describe a Parkinson’s disease patient who was doing well with levodopa/carbidopa for 3 years and developed lateral flexion of trunk. His abnormal posture used to completely improve upon lying down position. He also had striatal hand deformity suggestive of focal dystonia.

Beneficial effects of vitamin C and vitamin E on reserpine-induced oral dyskinesia in rats: critical role of striatal catalase activity.

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Faria, Rulian Ricardo; Abílio, Vanessa Costhek; Grassl, Christian; Chinen, Cibele Cristina; Negrão, Luciana Takahashi Ribeiro; de Castro, Juliana Pedroso Moraes Vilela; Fukushiro, Daniela Fukue; Rodrigues, Marcelo Scarpari Dutra; Gomes, Patricia Helena Zanier; Registro, Sibele; de Carvalho, Rita de Cassia; D'Almeida, Vania; Silva, Regina Helena; Ribeiro, Rosana de Alencar; Frussa-Filho, Roberto

2005-06-01

Oral dyskinesias are implicated in a series of neuropathologies and have been associated to an increase in oxidative stress. Several antioxidants, including vitamin E, decrease reserpine-induced oral dyskinesia (OD) in rodents and we have described a protective role of striatal catalase against the development of OD. The aim of this study was to verify the effects of vitamin C alone or in combination with vitamin E on reserpine-induced OD as well as to determine a possible role of catalase in the antidyskinetic property of these vitamins. Different doses of vitamin C attenuated reserpine-induced increase in OD. A similar treatment with an effective dose of vitamin C concomitant to an effective dose of vitamin E potentiated the antidyskinetic effect of both vitamins when administered alone. The administration of these vitamins alone produced an increase in striatal catalase activity that likewise was potentiated by their combined administration. In addition, the antidyskinetic property of vitamin E and vitamin C was abolished by a concomitant treatment with the catalase inhibitor aminotriazole. These results indicate a beneficial effect of these vitamins and reinforce the critical role of striatal catalase against the development of oral dyskinesias.

Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study.

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Greenberg, Tsafrir; Chase, Henry W; Almeida, Jorge R; Stiffler, Richelle; Zevallos, Carlos R; Aslam, Haris A; Deckersbach, Thilo; Weyandt, Sarah; Cooper, Crystal; Toups, Marisa; Carmody, Thomas; Kurian, Benji; Peltier, Scott; Adams, Phillip; McInnis, Melvin G; Oquendo, Maria A; McGrath, Patrick J; Fava, Maurizio; Weissman, Myrna; Parsey, Ramin; Trivedi, Madhukar H; Phillips, Mary L

2015-09-01

Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error- (discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures. A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals. Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms. The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward identifying potential biosignatures

Recruitment of prefrontal-striatal circuit in response to skilled motor challenge.

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Guo, Yumei; Wang, Zhuo; Prathap, Sandhya; Holschneider, Daniel P

2017-12-13

A variety of physical fitness regimens have been shown to improve cognition, including executive function, yet our understanding of which parameters of motor training are important in optimizing outcomes remains limited. We used functional brain mapping to compare the ability of two motor challenges to acutely recruit the prefrontal-striatal circuit. The two motor tasks - walking in a complex running wheel with irregularly spaced rungs or walking in a running wheel with a smooth internal surface - differed only in the extent of skill required for their execution. Cerebral perfusion was mapped in rats by intravenous injection of [C]-iodoantipyrine during walking in either a motorized complex wheel or in a simple wheel. Regional cerebral blood flow (rCBF) was quantified by whole-brain autoradiography and analyzed in three-dimensional reconstructed brains by statistical parametric mapping and seed-based functional connectivity. Skilled or simple walking compared with rest, increased rCBF in regions of the motor circuit, somatosensory and visual cortex, as well as the hippocampus. Significantly greater rCBF increases were noted during skilled walking than for simple walking. Skilled walking, unlike simple walking or the resting condition, was associated with a significant positive functional connectivity in the prefrontal-striatal circuit (prelimbic cortex-dorsomedial striatum) and greater negative functional connectivity in the prefrontal-hippocampal circuit. Our findings suggest that the level of skill of a motor training task determines the extent of functional recruitment of the prefrontal-corticostriatal circuit, with implications for a new approach in neurorehabilitation that uses circuit-specific neuroplasticity to improve motor and cognitive functions.

Dopamine-induced programmed cell death is associated with cytochrome c release and caspase-3 activation in snail salivary gland cells.

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Pirger, Zsolt; Rácz, Boglárka; Kiss, Tibor

2009-02-01

PCD (programmed cell death) is a common mechanism to remove unwanted and excessive cells from organisms. In several exocrine cell types, PCD mode of release of secretory products has been reported. The molecular mechanism of the release, however, is largely unknown. Our aim was to study the molecular mechanism of saliva release from cystic cells, the specific cell type of snail SGs (salivary glands). SG cells in active feeding animals revealed multiple morphological changes characteristic of PCD. Nerve stimulation and DA (dopamine) increased the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling)-positive cells both in inactive and feeding animals. The DA-induced PCD was prevented by TEA (tetraethylammonium chloride) and eticlopride, emphasizing the role of K channels and D2 receptors in the PCD of cystic cells. DA enhanced cyto-c (cytochrome c) translocation into the cytosol and methyl-beta-cyclodextrin prevented it, suggesting apoptosome formation and ceramide involvement in the PCD linking of the surface DA receptor to mitochondria. Western blot analysis revealed that the release of cyto-c was under the control of Bcl-2 and Bad. DA also increased the active caspase-3 in gland cells while D2 receptor antagonists and TEA attenuated it. Our results provide evidence for a type of transmitter-mediated pathway that regulates the PCD of secretory cells in a mitochondrial-caspase-dependent manner. The activation of specific molecules, such as K channels, DA receptors, cyto-c, ceramide, Bcl-2 proteins and caspase-3, but not caspase-8, was demonstrated in cells involved in the DA-induced PCD, suggesting that PCD is a physiological method for the release of saliva from SG cells.

The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

International Nuclear Information System (INIS)

Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina; Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya; Pessoa-Pureur, Regina

2014-01-01

Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to 32 P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca 2+ /calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca 2+ quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca 2+ influx through voltage-dependent Ca 2+ channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative disorders. - Highlights: �

History of childhood adversity is positively associated with ventral striatal dopamine responses to amphetamine.

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Oswald, Lynn M; Wand, Gary S; Kuwabara, Hiroto; Wong, Dean F; Zhu, Shijun; Brasic, James R

2014-06-01

Childhood exposure to severe or chronic trauma is an important risk factor for the later development of adult mental health problems, such as substance abuse. Even in nonclinical samples of healthy adults, persons with a history of significant childhood adversity seem to experience greater psychological distress than those without this history. Evidence from rodent studies suggests that early life stress may impair dopamine function in ways that increase risks for drug abuse. However, the degree to which these findings translate to other species remains unclear. This study was conducted to examine associations between childhood adversity and dopamine and subjective responses to amphetamine in humans. Following intake assessment, 28 healthy male and female adults, aged 18-29 years, underwent two consecutive 90-min positron emission tomography studies with high specific activity [(11)C]raclopride. The first scan was preceded by intravenous saline; the second by amphetamine (AMPH 0.3 mg/kg). Consistent with prior literature, findings showed positive associations between childhood trauma and current levels of perceived stress. Moreover, greater number of traumatic events and higher levels of perceived stress were each associated with higher ventral striatal dopamine responses to AMPH. Findings of mediation analyses further showed that a portion of the relationship between childhood trauma and dopamine release may be mediated by perceived stress. Overall, results are consistent with preclinical findings suggesting that early trauma may lead to enhanced sensitivity to psychostimulants and that this mechanism may underlie increased vulnerability for drug abuse.

POLYURETHANE COMPOSITES AS DRUG CARRIERS:: RELEASE PATTERNS

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M. V. Grigoreva

2013-10-01

Full Text Available Biodegradable polyurethanes attract interest of those developing composite materials for biomedical applications. One of their features is their ability to serve as carriers, or matrixes, for medicines and other bioactive compounds to produce a therapeutic effect in body through targeted and/or prolonged delivery of these compounds in the process of their controlled release from matrix. The review presents polyurethane composites as matrices for a number of drugs. The relation between structure of the composites and their degradability both in vitro and in vivo and the dependence of drug release kinetics on physicochemical properties of polyurethane matrix are highlighted. The release of drugs (cefazolin, naltrexone and piroxicam from the composites based on cross-linked polyurethanes (synthesized from laprols, Mw between 1,500 and 2,000 Da and toluylene diisocyanate demonstrated more or less the same pattern (about 10 days in vitro and three to five days in vivo. In contrast, the composites with dioxydine based on a linear polyurethanes (synthesized from oligotetramethilene glycol, Mw 1,000 Da, diphenylmethane-4,4’-diisocyanate and 1,4-butanediol retained their antimicrobial activity at least 30 days. They also showed a significantly higher breaking strength as compared to that of the composites based on cross-linked polyurethanes.

HIV Infection Is Associated with Impaired Striatal Function during Inhibition with Normal Cortical Functioning on Functional MRI

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du Plessis, Stéfan; Vink, Matthijs; Joska, John A; Koutsilieri, Eleni; Bagadia, Asif; Stein, Dan J; Emsley, Robin

2015-01-01

The aim of the present study was to investigate the effect of HIV infection on cortical and subcortical regions of the frontal-striatal system involved in the inhibition of voluntary movement. Functional MRI (fMRI) studies suggest that human immunodeficiency virus (HIV) infection is associated with

Episodic Memory Encoding Interferes with Reward Learning and Decreases Striatal Prediction Errors

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Braun, Erin Kendall; Daw, Nathaniel D.

2014-01-01

Learning is essential for adaptive decision making. The striatum and its dopaminergic inputs are known to support incremental reward-based learning, while the hippocampus is known to support encoding of single events (episodic memory). Although traditionally studied separately, in even simple experiences, these two types of learning are likely to co-occur and may interact. Here we sought to understand the nature of this interaction by examining how incremental reward learning is related to concurrent episodic memory encoding. During the experiment, human participants made choices between two options (colored squares), each associated with a drifting probability of reward, with the goal of earning as much money as possible. Incidental, trial-unique object pictures, unrelated to the choice, were overlaid on each option. The next day, participants were given a surprise memory test for these pictures. We found that better episodic memory was related to a decreased influence of recent reward experience on choice, both within and across participants. fMRI analyses further revealed that during learning the canonical striatal reward prediction error signal was significantly weaker when episodic memory was stronger. This decrease in reward prediction error signals in the striatum was associated with enhanced functional connectivity between the hippocampus and striatum at the time of choice. Our results suggest a mechanism by which memory encoding may compete for striatal processing and provide insight into how interactions between different forms of learning guide reward-based decision making. PMID:25378157

ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation

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Tina Zimmermann

2016-10-01

Full Text Available Huntington's disease (HD is characterized by fatal motoric failures induced by loss of striatal medium spiny neurons. Neuronal cell death has been linked to impaired expression and axonal transport of the neurotrophin BDNF (brain-derived neurotrophic factor. By transplanting embryonic stem cell-derived neural progenitors overexpressing BDNF, we combined cell replacement and BDNF supply as a potential HD therapy approach. Transplantation of purified neural progenitors was analyzed in a quinolinic acid (QA chemical and two genetic HD mouse models (R6/2 and N171-82Q on the basis of distinct behavioral parameters, including CatWalk gait analysis. Explicit rescue of motor function by BDNF neural progenitors was found in QA-lesioned mice, whereas genetic mouse models displayed only minor improvements. Tumor formation was absent, and regeneration was attributed to enhanced neuronal and striatal differentiation. In addition, adult neurogenesis was preserved in a BDNF-dependent manner. Our findings provide significant insight for establishing therapeutic strategies for HD to ameliorate neurodegenerative symptoms.

The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra.

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Margaret I Davis

Full Text Available Presynaptic cannabinoid-1 receptors (CB1-R bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs. CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR, which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets. Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals

Ventral striatal activity links adversity and reward processing in children

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Niki H. Kamkar

2017-08-01

Full Text Available Adversity impacts many aspects of psychological and physical development including reward-based learning and decision-making. Mechanisms relating adversity and reward processing in children, however, remain unclear. Here, we show that adversity is associated with potentiated learning from positive outcomes and impulsive decision-making, but unrelated to learning from negative outcomes. We then show via functional magnetic resonance imaging that the link between adversity and reward processing is partially mediated by differences in ventral striatal response to rewards. The findings suggest that early-life adversity is associated with alterations in the brain’s sensitivity to rewards accounting, in part, for the link between adversity and altered reward processing in children.

Synaptosomal uptake and release of dopamine and 5-hydroxy-tryptamine in the nucleus accumbens in vitro following in vivo administration of lysergic acid diethylamide in rats

International Nuclear Information System (INIS)

Hetey, L.; Quiring, K.

1980-01-01

The uptake and the depolarisation-induced release of dopamine (DA) and serotonin (5-HT) were investigated after systemic application of LSD on synaptosomes of the nucleus accumbens of rats. For the release experiments synaptosomes were prelabelled with [ 14 C]-DA and [ 3 H]-5-HT, respectively, and superfused with physiological and potassium-enriched (50 mM) solutions. Low doses of LSD (0.1 and 0.5 mg/kg i.p.) induced a dose-dependent inhibition of the DA release and an increase of the DA uptake, respectively. LSD inhibited both the release and the uptake of 5-HT significantly. The results are discussed with respect to a reliable characterization of the in vivo induced effects of LSD on the isolated synaptosomes. (author)

Altered cortico-striatal-thalamic connectivity in relation to spatial working memory capacity in children with ADHD

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Kathryn L. Mills

2012-01-01

Full Text Available Introduction: Attention deficit hyperactivity disorder (ADHD captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting state functional connectivity (rs-fcMRI studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical-striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD.Methods: We correlated the rs-fcMRI of five thalamic regions of interest with spatial span working memory scores in a sample of 67 children aged 7-11 years (ADHD and typically developing children; TDC. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7-11 years from the ADHD-200 dataset. Thalamic regions of interest were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus.Results/Conclusions: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype.

Tyrosine 402 Phosphorylation of Pyk2 Is Involved in Ionomycin-Induced Neurotransmitter Release

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Zhang, Zhao; Zhang, Yun; Mou, Zheng; Chu, Shifeng; Chen, Xiaoyu; He, Wenbin; Guo, Xiaofeng; Yuan, Yuhe; Takahashi, Masami; Chen, Naihong

2014-01-01

Protein tyrosine kinases, which are highly expressed in the central nervous system, are implicated in many neural processes. However, the relationship between protein tyrosine kinases and neurotransmitter release remains unknown. In this study, we found that ionomycin, a Ca2+ ionophore, concurrently induced asynchronous neurotransmitter release and phosphorylation of a non-receptor protein tyrosine kinase, proline-rich tyrosine kinase 2 (Pyk2), in clonal rat pheochromocytoma PC12 cells and cerebellar granule cells, whereas introduction of Pyk2 siRNA dramatically suppressed ionomycin-induced neurotransmitter release. Further study indicated that Tyr-402 (Y402) in Pyk2, instead of other tyrosine sites, underwent rapid phosphorylation after ionomycin induction in 1 min to 2 min. We demonstrated that the mutant of Pyk2 Y402 could abolish ionomycin-induced dopamine (DA) release by transfecting cells with recombinant Pyk2 and its mutants (Y402F, Y579F, Y580F, and Y881F). In addition, Src inhibition could prolong phosphorylation of Pyk2 Y402 and increase DA release. These findings suggested that Pyk2 was involved in ionomycin-induced neurotransmitter release through phosphorylation of Y402. PMID:24718602

A case of Cotard syndrome: (123)I-IBZM SPECT imaging of striatal D(2) receptor binding.

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De Risio, Sergio; De Rossi, Giuseppe; Sarchiapone, Marco; Camardese, Giovanni; Carli, Vladimir; Cuomo, Chiara; Satta, Maria Antonietta; Di Giuda, Daniela

2004-01-15

A case of 'dèlire de nègation' that suddenly appeared in a 43-year-old male is presented. No alteration in regional cerebral blood, as measured by (99m)Tc-HMPAO-SPECT, was found, but (123)I-IBZM-SPECT analysis showed reduced striatal D(2) receptor binding that further decreased after treatment.

Synthesis and binding to striatal membranes of non carrier added I-123 labeled 4'-iodococaine

Energy Technology Data Exchange (ETDEWEB)

Metwally, S.A.M.; Gatley, S.J.; Wolf, A.P.; Yu, D.-W. (Brookhaven National Lab., Upton, NY (United States))

1992-03-01

An {sup 123}I labeled cocaine analog, 4'-({sup 123}I)iodococaine, has been prepared by oxidative destannylation of the tributyltin analog and shown to interact with cocaine binding sites in rat brain striatal membranes. It may thus be a suitable SPECT radiotracer for studies of the dopamine reuptake site in neurodegenerative diseases. (Author).

Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex.

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Devoto, Paola; Flore, Giovanna; Saba, Pierluigi; Frau, Roberto; Gessa, Gian L

2015-10-01

Disulfiram has been claimed to be useful in cocaine addiction therapy, its efficacy being attributed to dopamine-beta-hydroxylase (DBH) inhibition. Our previous results indicate that disulfiram and the selective DBH inhibitor nepicastat increase extracellular dopamine (DA) in the rat medial prefrontal cortex (mPFC), and markedly potentiated cocaine-induced increase. Concomitantly, in rats with cocaine self-administration history, cocaine-seeking behavior induced by drug priming was prevented, probably through overstimulation of D1 receptors due to the DA increase. The present research was aimed at studying the neurochemical mechanisms originating the enhanced DA release. Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors. Fifteen days after neurotoxin or its vehicle administration, tissue and extracellular NA were reduced to less than 2% the control value, while extracellular DA was increased by approximately 100%. In control rats, nepicastat given alone and in combination with cocaine increased extracellular DA by about 250% and 1100%, respectively. In denervated rats, nepicastat slightly affected extracellular DA, while in combination with cocaine increased extracellular DA by 250%. No differences were found in the caudate nucleus. Clonidine almost totally reversed the extracellular DA elevation produced by nepicastat-cocaine combination, while it was ineffective in denervated rats. This research shows that the increase of extracellular DA produced by nepicastat alone or in combination with cocaine was prevented by noradrenergic denervation. The

Co-release of noradrenaline and dopamine in the cerebral cortex elicited by single train and repeated train stimulation of the locus coeruleus

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Saba Pierluigi

2005-05-01

Full Text Available Abstract Background Previous studies by our group suggest that extracellular dopamine (DA and noradrenaline (NA may be co-released from noradrenergic nerve terminals in the cerebral cortex. We recently demonstrated that the concomitant release of DA and NA could be elicited in the cerebral cortex by electrical stimulation of the locus coeruleus (LC. This study analyses the effect of both single train and repeated electrical stimulation of LC on NA and DA release in the medial prefrontal cortex (mPFC, occipital cortex (Occ, and caudate nucleus. To rule out possible stressful effects of electrical stimulation, experiments were performed on chloral hydrate anaesthetised rats. Results Twenty min electrical stimulation of the LC, with burst type pattern of pulses, increased NA and DA both in the mPFC and in the Occ. NA in both cortices and DA in the mPFC returned to baseline within 20 min after the end of the stimulation period, while DA in the Occ reached a maximum increase during 20 min post-stimulation and remained higher than baseline values at 220 min post-stimulation. Local perfusion with tetrodotoxin (TTX, 10 μM markedly reduced baseline NA and DA in the mPFC and Occ and totally suppressed the effect of electrical stimulation in both areas. A sequence of five 20 min stimulations at 20 min intervals were delivered to the LC. Each stimulus increased NA to the same extent and duration as the first stimulus, whereas DA remained elevated at the time next stimulus was delivered, so that baseline DA progressively increased in the mPFC and Occ to reach about 130 and 200% the initial level, respectively. In the presence of the NA transport (NAT blocker desipramine (DMI, 100 μM, multiple LC stimulation still increased extracellular NA and DA levels. Electrical stimulation of the LC increased NA levels in the homolateral caudate nucleus, but failed to modify DA level. Conclusion The results confirm and extend that LC stimulation induces a concomitant

Moderation of the Relationship Between Reward Expectancy and Prediction Error-Related Ventral Striatal Reactivity by Anhedonia in Unmedicated Major Depressive Disorder: Findings From the EMBARC Study

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Greenberg, Tsafrir; Chase, Henry W.; Almeida, Jorge R.; Stiffler, Richelle; Zevallos, Carlos R.; Aslam, Haris A.; Deckersbach, Thilo; Weyandt, Sarah; Cooper, Crystal; Toups, Marisa; Carmody, Thomas; Kurian, Benji; Peltier, Scott; Adams, Phillip; McInnis, Melvin G.; Oquendo, Maria A.; McGrath, Patrick J.; Fava, Maurizio; Weissman, Myrna; Parsey, Ramin; Trivedi, Madhukar H.; Phillips, Mary L.

2016-01-01

Objective Anhedonia, disrupted reward processing, is a core symptom of major depressive disorder. Recent findings demonstrate altered reward-related ventral striatal reactivity in depressed individuals, but the extent to which this is specific to anhedonia remains poorly understood. The authors examined the effect of anhedonia on reward expectancy (expected outcome value) and prediction error-(discrepancy between expected and actual outcome) related ventral striatal reactivity, as well as the relationship between these measures. Method A total of 148 unmedicated individuals with major depressive disorder and 31 healthy comparison individuals recruited for the multisite EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study underwent functional MRI during a well-validated reward task. Region of interest and whole-brain data were examined in the first- (N=78) and second- (N=70) recruited cohorts, as well as the total sample, of depressed individuals, and in healthy individuals. Results Healthy, but not depressed, individuals showed a significant inverse relationship between reward expectancy and prediction error-related right ventral striatal reactivity. Across all participants, and in depressed individuals only, greater anhedonia severity was associated with a reduced reward expectancy-prediction error inverse relationship, even after controlling for other symptoms. Conclusions The normal reward expectancy and prediction error-related ventral striatal reactivity inverse relationship concords with conditioning models, predicting a shift in ventral striatal responding from reward outcomes to reward cues. This study shows, for the first time, an absence of this relationship in two cohorts of unmedicated depressed individuals and a moderation of this relationship by anhedonia, suggesting reduced reward-contingency learning with greater anhedonia. These findings help elucidate neural mechanisms of anhedonia, as a step toward

Fast oscillations in cortical-striatal networks switch frequency following rewarding events and stimulant drugs.

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Berke, J D

2009-09-01

Oscillations may organize communication between components of large-scale brain networks. Although gamma-band oscillations have been repeatedly observed in cortical-basal ganglia circuits, their functional roles are not yet clear. Here I show that, in behaving rats, distinct frequencies of ventral striatal local field potential oscillations show coherence with different cortical inputs. The approximately 50 Hz gamma oscillations that normally predominate in awake ventral striatum are coherent with piriform cortex, whereas approximately 80-100 Hz high-gamma oscillations are coherent with frontal cortex. Within striatum, entrainment to gamma rhythms is selective to fast-spiking interneurons, with distinct fast-spiking interneuron populations entrained to different gamma frequencies. Administration of the psychomotor stimulant amphetamine or the dopamine agonist apomorphine causes a prolonged decrease in approximately 50 Hz power and increase in approximately 80-100 Hz power. The same frequency switch is observed for shorter epochs spontaneously in awake, undrugged animals and is consistently provoked for reward receipt. Individual striatal neurons can participate in these brief high-gamma bursts with, or without, substantial changes in firing rate. Switching between discrete oscillatory states may allow different modes of information processing during decision-making and reinforcement-based learning, and may also be an important systems-level process by which stimulant drugs affect cognition and behavior.

Regulation of GABA and benzodiazepine receptors following neurotoxin-induced striatal and medial forebrain bundle lesions

International Nuclear Information System (INIS)

Pan, H.S.I.

1985-01-01

GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic saturation, and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies

Ability of 18F-DOPA PET/CT and fused 18F-DOPA PET/MRI to assess striatal involvement in paediatric glioma

International Nuclear Information System (INIS)

Morana, Giovanni; Severino, Mariasavina; Tortora, Domenico; Rossi, Andrea; Puntoni, Matteo; Garre, Maria Luisa; Massollo, Michela; Naseri, Merhdad; Piccardo, Arnoldo; Lopci, Egesta

2016-01-01

To assess the diagnostic performance of 18 F-DOPA PET/CT and fused 18 F-DOPA PET/MRI in detecting striatal involvement in children with gliomas. This retrospective study included 28 paediatric patients referred to our institution for the presence of primary, residual or recurrent glioma (12 boys, 16 girls; mean age 10.7 years) and investigated with 18 F-DOPA PET/CT and brain MRI. Fused 18 F-DOPA PET/MR images were obtained and compared with PET/CT and MRI images. Accuracy, sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for striatal involvement were calculated for each diagnostic tool. Univariate and multivariate logistic analyses were applied to evaluate the associations between 18 F-DOPA PET/CT and fused 18 F-DOPA PET/MRI diagnostic results and tumour uptake outside the striatum, grade, dimension and site of striatal involvement (ventral and/or dorsal). Accuracy, sensitivity, specificity, PPV, and NPV were 100 % for MRI, 93 %, 89 %, 100 %, 100 % and 82 % for 18 F-DOPA PET/MRI, and 75 %, 74 %, 78 %, 88 % and 58 % for 18 F-DOPA PET/CT, respectively. 18 F-DOPA PET/MRI showed a trend towards higher accuracy compared with 18 F-DOPA PET/CT (p = 0.06). MRI showed significantly higher accuracy compared with 18 F-DOPA PET/CT (p = 0.01), but there was no significant difference between MRI and 18 F-DOPA PET/MRI. Both univariate and multivariate logistic analyses showed a significant association (OR 8.0 and 7.7, respectively) between the tumour-to-normal striatal uptake (T/S) ratio and the diagnostic ability of 18 F-DOPA PET/CT (p = 0.03). A strong significant association was also found between involvement of the dorsal striatum and the 18 F-DOPA PET/CT results (p = 0.001), with a perfect prediction of involvement of the dorsal striatum by 18 F-DOPA PET/MRI. Physiological striatal 18 F-DOPA uptake does not appear to be a main limitation in the evaluation of basal ganglia involvement. 18 F-DOPA PET/CT correctly detected

Direct monitoring of dopamine and 5-HT release in substantia nigra and ventral tegmental area in vitro

DEFF Research Database (Denmark)

Rice, M E; Richards, C D; Nedergaard, S

1994-01-01

Fast-scan cyclic voltammetry with carbon fibre microelectrodes was used to detect endogenous dopamine (DA) and 5-hydroxytryptamine (5-HT) release from three distinct regions of guinea-pig mid-brain in vitro: rostral and caudal substantia nigra (SN) and the ventral tegmental area (VTA). Previous...... these regions with in situ electrodes and demonstrates the utility of fast-scan cyclic voltammetry to investigate the mechanisms and possible non-classical functions of somato-dendritic DA release....

Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson's disease

NARCIS (Netherlands)

Antonini, A; Leenders, KL; Vontobel, P; Maguire, RP; Missimer, J; Psylla, M; Gunther, [No Value

1997-01-01

We used PET with the tracers [F-18]fluorodeoxyglucose (FDG), [F-18]fluorodopa (FDOPA) and [C-11]raclopride (RACLO) to study striatal glucose and dopa metabolism, and dopamine D-2 receptor binding, respectively, in nine patients with multiple system atrophy. Ten patients with classical Parkinson's

Evaluation of blood loss after early or late release of ischemia in patients undergoing total knee replacement Avaliação da perda sanguínea após a liberação precoce ou tardia da isquemia em pacientes submetidos à artroplastia total do joelho

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Marcos George de Souza Leão

2013-04-01

Full Text Available OBJECTIVE: compare blood loss in 40 patients underwent to unilateral total knee replacement with the release of ischemia before and after skin closure and compressive dressing. METHODS: in a prospective randomized study, in 40 patients underwent to total knee replacement, dividing then into two groups: group A in which the ischemia was released before skin closure, allowing bleeding control and group B where the ischemia was released after skin suture and pressure dressing. We compared the results of laboratory tests of serum hemoglobin before surgery and 48 hours postoperatively, the blood volume contained in vacuum suction drain and the transfusions that was necessary. RESULTS: As a result, the post operative serum hemoglobin levels had a mean decrease of 3.57 g/dL in group A and 4.24 g/dL in group B with an average of 0.67g/dL difference between them, statistically insignificant.The observed mean drainage, in the vacuum drain, were 705 mL in group A and 700 mL in group B. The 5ml difference between medians was considered statistically insignificant. The number of patients who received transfusions was four patients in both groups and all received two units of red blood cells. CONCLUSION: the post operative serum hemoglobin levels, as well as the need of blood transfusion, in the patient underwent to total knee replacement, where the ischemia was released before wound closure, has no statistical effect in comparison with patients where the sutures and bandages were done after the ischemia release. Level of Evidence IB - Individual randomized controlled trial with narrow confidence interval. OBJETIVO: Avaliar comparativamente a perda sanguínea em pacientes submetidos à artroplastia total do joelho, com liberação da isquemia antes e após suturas e curativo compressivo. MÉTODOS: Fez-se um estudo prospectivo randomizado em 40 pacientes submetidos à artroplastia total do joelho divididos em dois grupos. No primeiro grupo a isquemia foi

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models.

Science.gov (United States)

Thiele, Sherri L; Chen, Betty; Lo, Charlotte; Gertler, Tracey S; Warre, Ruth; Surmeier, James D; Brotchie, Jonathan M; Nash, Joanne E

2014-11-01

Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5±14.6%; LTD protocol 177.7±22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3±4.0% and LTD protocol: 63.3±8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4±22.0% and LTD protocol: 52.1±18.5% of baseline. Direct pathway: LTP protocol: 140.7±7.3% and LTD protocol: 58.4±6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9±21.3% and LTD protocol 52.0±14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6±13.2% and LTD protocol 166.7±15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs

Striatal activation reflects urgency in perceptual decision making.

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van Maanen, Leendert; Fontanesi, Laura; Hawkins, Guy E; Forstmann, Birte U

2016-10-01

Deciding between multiple courses of action often entails an increasing need to do something as time passes - a sense of urgency. This notion of urgency is not incorporated in standard theories of speeded decision making that assume information is accumulated until a critical fixed threshold is reached. Yet, it is hypothesized in novel theoretical models of decision making. In two experiments, we investigated the behavioral and neural evidence for an "urgency signal" in human perceptual decision making. Experiment 1 found that as the duration of the decision making process increased, participants made a choice based on less evidence for the selected option. Experiment 2 replicated this finding, and additionally found that variability in this effect across participants covaried with activation in the striatum. We conclude that individual differences in susceptibility to urgency are reflected by striatal activation. By dynamically updating a response threshold, the striatum is involved in signaling urgency in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

Episodic memory encoding interferes with reward learning and decreases striatal prediction errors.

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Wimmer, G Elliott; Braun, Erin Kendall; Daw, Nathaniel D; Shohamy, Daphna

2014-11-05

Learning is essential for adaptive decision making. The striatum and its dopaminergic inputs are known to support incremental reward-based learning, while the hippocampus is known to support encoding of single events (episodic memory). Although traditionally studied separately, in even simple experiences, these two types of learning are likely to co-occur and may interact. Here we sought to understand the nature of this interaction by examining how incremental reward learning is related to concurrent episodic memory encoding. During the experiment, human participants made choices between two options (colored squares), each associated with a drifting probability of reward, with the goal of earning as much money as possible. Incidental, trial-unique object pictures, unrelated to the choice, were overlaid on each option. The next day, participants were given a surprise memory test for these pictures. We found that better episodic memory was related to a decreased influence of recent reward experience on choice, both within and across participants. fMRI analyses further revealed that during learning the canonical striatal reward prediction error signal was significantly weaker when episodic memory was stronger. This decrease in reward prediction error signals in the striatum was associated with enhanced functional connectivity between the hippocampus and striatum at the time of choice. Our results suggest a mechanism by which memory encoding may compete for striatal processing and provide insight into how interactions between different forms of learning guide reward-based decision making. Copyright © 2014 the authors 0270-6474/14/3414901-12$15.00/0.

From real-world events to psychosis: the emerging neuropharmacology of delusions.

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Morrison, Paul D; Murray, R M

2009-07-01

The earliest stages of delusion are characterized by an overabundance of meaningful coincidences impinging on the sufferer's existing worldview. Successive events are seen by him as pointing to, and then confirming, a fundamentally new reality that takes him over and engulfs his everyday life. Research over the last 4 decades has revealed the importance of dopamine (DA), D2 receptors, and the basal ganglia in psychotic thinking. Recent work has implicated the aberrant reward learning initiated by the excess release of striatal DA in the attribution of excessive importance or "salience" to insignificant stimuli and events. But our knowledge of what is happening beyond D2 receptors has remained scant. The gap is especially apparent at the cellular and microcircuit levels, encompassing the plastic changes, which are believed to be essential for new learning, and whose processes may go awry in major mental illness. Now new pharmacological findings are advancing our understanding of information processing and learning within the striatum. DA has an important role in setting the strength of individual striatal connections, but it does not act in isolation. Two other modulator systems are critical, the endocannabinoids and adenosine. Thus, at medium spiny neurons belonging to the indirect pathway, D2 stimulation evokes endocannabinoid-mediated depression of cortical inputs. Adenosine acting at A2A receptors elicits the opposite effect. Remarkably, drugs that target the endocannabinoid and purinergic systems also have pro- or antipsychotic properties. Here, we discuss how the 3 modulators regulate learning within the striatum and how their dysfunction may lead to delusional thinking.

Ventral striatal activity links adversity and reward processing in children.

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Kamkar, Niki H; Lewis, Daniel J; van den Bos, Wouter; Morton, J Bruce

2017-08-01

Adversity impacts many aspects of psychological and physical development including reward-based learning and decision-making. Mechanisms relating adversity and reward processing in children, however, remain unclear. Here, we show that adversity is associated with potentiated learning from positive outcomes and impulsive decision-making, but unrelated to learning from negative outcomes. We then show via functional magnetic resonance imaging that the link between adversity and reward processing is partially mediated by differences in ventral striatal response to rewards. The findings suggest that early-life adversity is associated with alterations in the brain's sensitivity to rewards accounting, in part, for the link between adversity and altered reward processing in children. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

An allosteric enhancer of M4muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

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Dencker, Ditte; Weikop, Pia; Sørensen, Gunnar

2012-01-01

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M4 acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M4 receptors could...

The phosphorylation status and cytoskeletal remodeling of striatal astrocytes treated with quinolinic acid

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Pierozan, Paula; Ferreira, Fernanda; Ortiz de Lima, Bárbara; Gonçalves Fernandes, Carolina [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil); Totarelli Monteforte, Priscila; Castro Medaglia, Natalia de; Bincoletto, Claudia; Soubhi Smaili, Soraya [Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP (Brazil); Pessoa-Pureur, Regina, E-mail: rpureur@ufrgs.br [Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS 90035-003 (Brazil)

2014-04-01

Quinolinic acid (QUIN) is a glutamate agonist which markedly enhances the vulnerability of neural cells to excitotoxicity. QUIN is produced from the amino acid tryptophan through the kynurenine pathway (KP). Dysregulation of this pathway is associated with neurodegenerative conditions. In this study we treated striatal astrocytes in culture with QUIN and assayed the endogenous phosphorylating system associated with glial fibrillary acidic protein (GFAP) and vimentin as well as cytoskeletal remodeling. After 24 h incubation with 100 µM QUIN, cells were exposed to {sup 32}P-orthophosphate and/or protein kinase A (PKA), protein kinase dependent of Ca{sup 2+}/calmodulin II (PKCaMII) or protein kinase C (PKC) inhibitors, H89 (20 μM), KN93 (10 μM) and staurosporin (10 nM), respectively. Results showed that hyperphosphorylation was abrogated by PKA and PKC inhibitors but not by the PKCaMII inhibitor. The specific antagonists to ionotropic NMDA and non-NMDA (50 µM DL-AP5 and CNQX, respectively) glutamate receptors as well as to metabotropic glutamate receptor (mGLUR; 50 µM MCPG), mGLUR1 (100 µM MPEP) and mGLUR5 (10 µM 4C3HPG) prevented the hyperphosphorylation provoked by QUIN. Also, intra and extracellular Ca{sup 2+} quelators (1 mM EGTA; 10 µM BAPTA-AM, respectively) prevented QUIN-mediated effect, while Ca{sup 2+} influx through voltage-dependent Ca{sup 2+} channel type L (L-VDCC) (blocker: 10 µM verapamil) is not implicated in this effect. Morphological analysis showed dramatically altered actin cytoskeleton with concomitant change of morphology to fusiform and/or flattened cells with retracted cytoplasm and disruption of the GFAP meshwork, supporting misregulation of actin cytoskeleton. Both hyperphosphorylation and cytoskeletal remodeling were reversed 24 h after QUIN removal. Astrocytes are highly plastic cells and the vulnerability of astrocyte cytoskeleton may have important implications for understanding the neurotoxicity of QUIN in neurodegenerative

Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome

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Byron Chen

2017-08-01

Full Text Available Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4, a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs, which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS.

The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease

International Nuclear Information System (INIS)

Wang Qiujun; Liang Ge; Yang Hui; Wang Shouping; Eckenhoff, Maryellen F.; Wei Huafeng

2011-01-01

Isoflurane is known to increase β-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh Q111/Q111 ) and wild type (STHdh Q7/Q7 ) striatal neurons. The primary cultured neurons were exposed for 24 h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP 3 ) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh Q111/Q111 cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh Q111/Q111 huntingtin cells than in the wild type STHdh Q7/Q7 striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh Q111/Q111 cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP 3 receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh Q111/Q111 striatal cells.

Effects of exercise on depressive behavior and striatal levels of norepinephrine, serotonin and their metabolites in sleep-deprived mice.

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Daniele, Thiago Medeiros da Costa; de Bruin, Pedro Felipe Carvalhedo; Rios, Emiliano Ricardo Vasconcelos; de Bruin, Veralice Meireles Sales

2017-08-14

Exercise is a promising adjunctive therapy for depressive behavior, sleep/wake abnormalities, cognition and motor dysfunction. Conversely, sleep deprivation impairs mood, cognition and functional performance. The objective of this study is to evaluate the effects of exercise on anxiety and depressive behavior and striatal levels of norepinephrine (NE), serotonin and its metabolites in mice submitted to 6h of total sleep deprivation (6h-TSD) and 72h of Rapid Eye Movement (REM) sleep deprivation (72h-REMSD). Experimental groups were: (1) mice submitted to 6h-TSD by gentle handling; (2) mice submitted to 72h-REMSD by the flower pot method; (3) exercise (treadmill for 8 weeks); (4) exercise followed by 6h-TSD; (5) exercise followed by 72h-REMSD; (6) control (home cage). Behavioral tests included the Elevated Plus Maze and tail-suspension. NE, serotonin and its metabolites were determined in the striatum using high-performance liquid chromatography (HPLC). Sleep deprivation increased depressive behavior (time of immobilization in the tail-suspension test) and previous exercise hindered it. Sleep deprivation increased striatal NE and previous exercise reduced it. Exercise only was associated with higher levels of serotonin. Furthermore, exercise reduced serotonin turnover associated with sleep deprivation. In brief, previous exercise prevented depressive behavior and reduced striatal high NE levels and serotonin turnover. The present findings confirm the effects of exercise on behavior and neurochemical alterations associated with sleep deprivation. These findings provide new avenues for understanding the mechanisms of exercise. Copyright © 2017 Elsevier B.V. All rights reserved.

An association between RBMX, a heterogeneous nuclear ribonucleoprotein, and ARTS-1 regulates extracellular TNFR1 release

International Nuclear Information System (INIS)

Adamik, Barbara; Islam, Aminul; Rouhani, Farshid N.; Hawari, Feras I.; Zhang Jing; Levine, Stewart J.

2008-01-01

The type I, 55-kDa tumor necrosis factor receptor (TNFR1) is released to the extracellular space by two mechanisms, the constitutive release of TNFR1 exosome-like vesicles and the inducible proteolytic cleavage of TNFR1 ectodomains. Both pathways appear to be regulated by an interaction between TNFR1 and ARTS-1 (aminopeptidase regulator of TNFR1 shedding). Here, we sought to identify ARTS-1-interacting proteins that modulate TNFR1 release. Co-immunoprecipitation identified an association between ARTS-1 and RBMX (RNA-binding motif gene, X chromosome), a 43-kDa heterogeneous nuclear ribonucleoprotein. RNA interference attenuated RBMX expression, which reduced both the constitutive release of TNFR1 exosome-like vesicles and the IL-1β-mediated inducible proteolytic cleavage of soluble TNFR1 ectodomains. Reciprocally, over-expression of RBMX increased TNFR1 exosome-like vesicle release and the IL-1β-mediated inducible shedding of TNFR1 ectodomains. This identifies RBMX as an ARTS-1-associated protein that regulates both the constitutive release of TNFR1 exosome-like vesicles and the inducible proteolytic cleavage of TNFR1 ectodomains

Interaction between striatal volume and DAT1 polymorphism predicts working memory development during adolescence

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F. Nemmi

2018-04-01

Full Text Available There is considerable inter-individual variability in the rate at which working memory (WM develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development.We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19.We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19.The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity. Keywords: Working memory, Development, Dopamine, Striatum, DAT-1, rs40184

Decreased striatal D2 receptor density associated with severe behavioral abnormality in Alzheimer's disease

International Nuclear Information System (INIS)

Tanaka, Yasuhiro; Meguro, Kenichi; Yamaguchi, Satoshi

2003-01-01

Since patients manifesting behavioral and psychological symptoms of dementia (BPSD) are a burden for their families and caregivers, the underlying neurobiological mechanism of this condition should be clarified. Using positron emission tomography (PET), we previously reported that wandering behavior in dementia was associated with a disturbed dopaminergic neuron system. We herein investigated the relationship between the severity of BPSD and the striatal D 2 receptor density in Alzheimer's disease (AD). Ten patients with probable AD as per the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) criteria and five normal subjects were examined with PET. The tracer used was [ 11 C]raclopride (D 2 antagonist). The uptake of [ 11 C]raclopride was calculated as the estimation of binding potential (BP) of the striatum to the cerebellum. The AD patients were institutionalized in multiple nursing homes, and their BPSD were evaluated by the Behavioral Pathology in AD Frequency Weighted Severity Scale (BEHAVE-AD-FW) scale (Reisberg). There was a significant inverse Spearman's correlation between BEHAVE-AD-FW score and the BP, especially between the score of the behavioral domain and the BP values. The BP was found to be lower in severer BPSD patients. Patients with AD who manifest severe BPSD may have some dysfunction of striatal dopamine metabolism compared with those without BPSD. (author)

Relationship between striatal [123I]β-CIT binding and four major clinical signs in Parkinson's disease

International Nuclear Information System (INIS)

Shinotoh, Hitoshi; Uchida, Yoshitaka; Ito, Hisao; Hattori, Takamichi

2000-01-01

We investigated the correlation between clinical severity and striatal [ 123 I]β-CIT binding in 12 patients with Parkinson's Disease (PD: 6 men and 6 women, age: 65±7 years, Hoehn-Yahr stage: 1 to 3). The clinical severity of PD patients was measured with the Unified Parkinson's Disease Rating Scale (UPDRS) after withdrawal of antiparkinsonian medication at least 12 hours before assessment. [ 123 I]β-CIT binding in the caudate and putamen was measured at 3 hours [V'' 3 (day 1)], and at 24 hours [V'' 3 (day 2)] after tracer injection with small square ROIs. The specific striatal uptake index (day 2) was calculated with large square ROIs that encompassed the whole striatum. The best correlation (r=-0.82, p 3 (day 2) and the motor UPDRS scores. When the motor UPDRS scores were divided into four subscales, bradykinesia was the only sign that correlated significantly with putamenal V'' 3 (day 2) (r=-0.81, p 123 I]β-CIT SPECT is a useful marker of disease severity in PD with potential utility in the serial monitoring of disease progression. (author)

Essential fatty acid-rich diets protect against striatal oxidative damage induced by quinolinic acid in rats.

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Morales-Martínez, Adriana; Sánchez-Mendoza, Alicia; Martínez-Lazcano, Juan Carlos; Pineda-Farías, Jorge Baruch; Montes, Sergio; El-Hafidi, Mohammed; Martínez-Gopar, Pablo Eliasib; Tristán-López, Luis; Pérez-Neri, Iván; Zamorano-Carrillo, Absalom; Castro, Nelly; Ríos, Camilo; Pérez-Severiano, Francisca

2017-09-01

Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive- or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive- or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/µl) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARγ expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive- and fish-oil-rich diets exert neuroprotective effects.

Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling

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Yeunkum Lee

2017-06-01

Full Text Available Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3-overexpressing transgenic (TG mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1 signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1, TSC2 and Ras homolog enriched in striatum (Rhes, via 94 common interactors that we denominated “Shank3-mTORC1 interactome”. We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1 proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD. Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream

Impulsivity in Parkinson’s Disease Is Associated With Alterations in Affective and Sensorimotor Striatal Networks

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Marit F. L. Ruitenberg

2018-04-01

Full Text Available A subset of patients with Parkinson’s disease (PD experiences problems with impulse control, characterized by a loss of voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of such impulse control disorders (ICDs in PD. We collected resting-state functional connectivity and structural MRI data from 21 PD patients with ICDs and 30 patients without such disorders. To assess impulsivity, all patients completed the Barratt Impulsiveness Scale and performed an information-gathering task. MRI results demonstrated substantial differences in neural characteristics between PD patients with and without ICDs. Results showed that impulsivity was linked to alterations in affective basal ganglia circuitries. Specifically, reduced frontal–striatal connectivity and GPe volume were associated with more impulsivity. We suggest that these changes affect decision making and result in a preference for risky or inappropriate actions. Results further showed that impulsivity was linked to alterations in sensorimotor striatal networks. Enhanced connectivity within this network and larger putamen volume were associated with more impulsivity. We propose that these changes affect sensorimotor processing such that patients have a greater propensity to act. Our findings suggest that the two mechanisms jointly contribute to impulsive behaviors in PD.

Effect of release of dopamine on iron transformations and reactive oxygen species (ROS) generation under conditions typical of coastal waters.

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Sun, Yingying; Pham, A Ninh; Waite, T David

2018-01-24

Seasonally persistent blooms of Ulvaria obscura var. blyttii, the prominent species present in green tides in the northern Pacific and Atlantic, have been well documented in recent decades. The synthesis and release of dopamine (DA) by Ulvaria obscura var. blyttii has been proposed to be associated with the suppression and inhibition of the growth of other organisms competing for limited resources. To better understand the potential benefits obtained from the release of DA, the transformation of DA as well its concomitant impact on the local seawater environment are investigated in this study. The results show that, despite several toxic quinones being produced during the oxidation of DA, aminochrome (DAC) is likely to be the only quinone playing an allelopathic role in view of its expected accumulation in the surrounding environment. As a consequence of the direct oxidation of DA and DA induced generation of 5,6-dihydroxyindole (DHI), high concentrations of H 2 O 2 accumulate over time, especially in the presence of elements including iron, calcium and magnesium. The oxidative stress to other organisms induced by the release of DA may be particularly detrimental as a result of H 2 O 2 induced reduction in photosynthesis, inactivation of antioxidant systems or even the generation of ˙OH. DA induced iron mobilization may benefit the continuously persistent blooms of Ulvaria obscura var. blyttii or even the whole community via alleviation in iron deficiency within the bloom region.

Time Processing in Children with Tourette's Syndrome

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Vicario, Carmelo Mario; Martino, Davide; Spata, Felice; Defazio, Giovanni; Giacche, Roberta; Martino, Vito; Rappo, Gaetano; Pepi, Anna Maria; Silvestri, Paola Rosaria; Cardona, Francesco

2010-01-01

Background: Tourette syndrome (TS) is characterized by dysfunctional connectivity between prefrontal cortex and sub-cortical structures, and altered meso-cortical and/or meso-striatal dopamine release. Since time processing is also regulated by fronto-striatal circuits and modulated by dopaminergic transmission, we hypothesized that time…

Dopamine Release and Uptake Impairments and Behavioral Alterations Observed in Mice that Model Fragile X Mental Retardation Syndrome.

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Fulks, Jenny L; O'Bryhim, Bliss E; Wenzel, Sara K; Fowler, Stephen C; Vorontsova, Elena; Pinkston, Jonathan W; Ortiz, Andrea N; Johnson, Michael A

2010-10-20

In this study we evaluated the relationship between amphetamine-induced behavioral alterations and dopamine release and uptake characteristics in Fmr1 knockout (Fmr1 KO) mice, which model fragile X syndrome. The behavioral analyses, obtained at millisecond temporal resolution and 2 mm spatial resolution using a force-plate actometer, revealed that Fmr1 KO mice express a lower degree of focused stereotypy compared to wild type (WT) control mice after injection with 10 mg/kg (ip) amphetamine. To identify potentially related neurochemical mechanisms underlying this phenomenon, we measured electrically-evoked dopamine release and uptake using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in striatal brain slices. At 10 weeks of age, dopamine release per pulse, which is dopamine release corrected for differences in uptake, was unchanged. However, at 15 (the age of behavioral testing) and 20 weeks of age, dopamine per pulse and the maximum rate of dopamine uptake was diminished in Fmr1 KO mice compared to WT mice. Dopamine uptake measurements, obtained at different amphetamine concentrations, indicated that dopamine transporters in both genotypes have equal affinities for amphetamine. Moreover, dopamine release measurements from slices treated with quinpirole, a D2-family receptor agonist, rule out enhanced D2 autoreceptor sensitivity as a mechanism of release inhibition. However, dopamine release, uncorrected for uptake and normalized against the corresponding pre-drug release peaks, increased in Fmr1 KO mice, but not in WT mice. Collectively, these data are consistent with a scenario in which a decrease in extracellular dopamine levels in the striatum result in diminished expression of focused stereotypy in Fmr1 KO mice.

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis.

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Vingerhoets, Claudia; Bloemen, Oswald J N; Boot, Erik; Bakker, Geor; de Koning, Mariken B; da Silva Alves, Fabiana; Booij, Jan; van Amelsvoort, Thérèse A M J

2018-02-28

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123 I-labelled iodobenzamide ([ 123 I]IBZM) was used to measure striatal DA D 2/3 receptor binding potential (D 2 R BP ND ). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D 2 R BP ND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings. Copyright © 2017 Elsevier B.V. All rights reserved.

Avaliação da perda sanguínea na artroplastia total do joelho com e sem soltura do torniquete Blood loss in total knee arthroplasty with and without tourniquet release

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José Wanderley Vasconcelos

2011-01-01

Full Text Available OBJETIVO: Avaliar a perda sanguínea em pacientes submetidos à artroplastia total cimentada do joelho com e sem soltura trans-operatória do torniquete pneumático para a hemostasia. MÉTODOS: Foram estudados 72 pacientes submetidos à artroplastia total, num total de 80 joelhos, divididos em dois grupos: Grupo 1 onde se manteve o torniquete pneumático até a sutura e curativo da ferida operatória, e Grupo 2 onde foi realizada a soltura do torniquete pneumático após a cimentação da prótese, com realização de hemostasia direta, antes da sutura e curativo. Os pacientes foram avaliados quanto ao sangramento pelo dreno de sucção e à contagem de hemoglobina e hematócrito, considerando os intervalos de duas, 24 e 48 horas de pós-operatório. RESULTADOS: Não houve diferença significante entre os dois grupos quanto ao sangramento pós-operatório e decréscimo dos parâmetros hematimétricos. Somente um paciente do Grupo 2 necessitou transfusão de concentrado de hemáceas no pós-operatório. CONCLUSÃO: O sangramento pós-operatório na ATJ mostrou-se igual com e sem a soltura do torniquete pneumático para a realização da hemostasia.OBJECTIVE: To evaluate blood loss in patients submitted to cemented total knee arthroplasty with and without perioperative tourniquet release for hemostasis. METHODS: Seventy-two patients (eighty knees were submitted to total knee arthroplasty, allocated into two groups: in Group 1, in which the pneumatic tourniquet was maintained until suture and dressing of the operated wound, and Group 2, in which the pneumatic tourniquet was released intraoperatively after cementing the prosthesis, with direct hemostasis, before the suture and dressing. The patients were evaluated for blood loss by the suction drain, and hemoglobin and hematocrit counts, at intervals of 2, 24 and 48 hours in the postoperative period tube. RESULTS: There was no significant difference between the groups in terms of postoperative blood

Regulation of drugs affecting striatal cholinergic activity by corticostriatal projections

International Nuclear Information System (INIS)

Ladinsky, H.

1986-01-01

Research demonstrates that the chronic degeneration of the corticostriatal excitatory pathway makes the cholinergic neurons of the striatum insensitive to the neuropharmacological action of a number of different drugs. Female rats were used; they were killed and after the i.v. infusion of tritium-choline precursor, choline acetyltransferase activity was measured. Striatal noradrenaline, dopamine and serotonin content was measured by electrochemical detection coupled with high pressure liquid chromatography. Uptake of tritium-glutamic acid was estimated. The data were analyzed statistically. It is shown that there is evidence that the effects of a number of drugs capable of depressing cholinergic activity through receptor-mediated responses are operative only if the corticostriatal pathway is integral. Neuropharmacological responses in the brain appear to be the result of an interaction between several major neurotransmitter systems

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum.

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Bergstrom, B P; Garris, P A

1999-03-01

The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.

Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model.

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Wu, Jun; Ryskamp, Daniel A; Liang, Xia; Egorova, Polina; Zakharova, Olga; Hung, Gene; Bezprozvanny, Ilya

2016-01-06

In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca(2+) levels. Depletion of ER Ca(2+) leads to overactivation of the neuronal store-operated Ca(2+) entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development. In Huntington's disease (HD) mutant Huntingtin (mHtt) causes early corticostriatal synaptic dysfunction and eventual neurodegeneration of medium spine neurons (MSNs) through poorly understood mechanisms. We report here that corticostriatal cocultures prepared from

Long-term protective effects of methamphetamine preconditioning against single-day methamphetamine toxic challenges.

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Hodges, A B; Ladenheim, B; McCoy, M T; Beauvais, G; Cai, N; Krasnova, I N; Cadet, J L

2011-03-01

Methamphetamine (METH) use is associated with neurotoxic effects which include decreased levels of dopamine (DA), serotonin (5-HT) and their metabolites in the brain. We have shown that escalating METH dosing can protect against METH induced neurotoxicity in rats sacrificed within 24 hours after a toxic METH challenge. The purpose of the current study was to investigate if the protective effects of METH persisted for a long period of time. We also tested if a second challenge with a toxic dose of METH would cause further damage to monoaminergic terminals. Saline-pretreated rats showed significant METH-induced decreases in striatal DA and 5-HT levels in rats sacrificed 2 weeks after the challenge. Rats that received two METH challenges showed no further decreases in striatal DA or 5-HT levels in comparison to the single METH challenge. In contrast, METH-pretreated rats showed significant protection against METH-induced striatal DA and 5-HT depletion. In addition, the METH challenge causes substantial decreases in cortical 5-HT levels which were not further potentiated by a second drug challenge. METH preconditioning provided almost complete protection against METH -induced 5-HT depletion. These results are consistent with the idea that METH pretreatment renders the brain refractory to METH-induced degeneration of brain monoaminergic systems.

Strawberry or blueberry supplementation may protect against increased oxidative stress vulnerability from both irradiation and aging

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Joseph, J. A.; Shukitt-Hale, B.; Carey, A.; Rabin, B. M.

In several studies we have now shown that there are some interesting parallels between aging and the effects of heavy particle irradiation (56Fe) in a rat model. Interestingly this research also has shown that, much as has been seen in aged animals, dietary supplementation with high antioxidant-strawberry (SB) or blueberry (BB) extracts (2% of the diet) reversed many of the age-related changes. Similarly, supplementing the diets of young rats with SBs or BBs (2% of diet as in the aged animals) for 8 weeks prior to being exposed to 56Fe (1 GeV/n), using the AGS or NSRL at Brookhaven National Laboratory, prevented the deleterious effects of the radiation exposure on the motor, cognitive and neuronal parameters described above. In the present experiment we examined whether striatal tissue obtained from BB- or SB-supplemented or control-fed, irradiated or non-radiated, young rats would show differential sensitivity (as assessed via decrements in mAChR stimulation of dopamine release) to hydrogen peroxide, a reactive oxygen species (ROS) generating agent. The results indicated that, just as we had seen previously with respect to radiation protection in the parameters described above, the tissue from the SB or BB-supplemented irradiated or non-radiated animals showed increased mAChR-stimulated DA release from the striatal tissue following hydrogen peroxide exposure compared to that seen in non-supplemented irradiated or non-radiated animals (e.g., DA rels. p moles/mg protein, rad + H202 non-supplemented = 90, SB = 260, BB = 360). These results show that aging and irradiation may produce similar decrements in dopamine release and that, much as we have seen previously with age, radiation enhances the vulnerability to oxidative stressors, but these are reduced with SB or BB supplementation. They are discussed in-terms of protection against the effects of exposure to heavy particles and aging via nutritional supplementation with foods that are high in antioxidant activity

Dopamine release in the medial preoptic area is related to hormonal action and sexual motivation.

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Kleitz-Nelson, Hayley K; Dominguez, Juan M; Ball, Gregory F

2010-12-01

To help elucidate how general the role of dopamine (DA) release in the medial preoptic area (mPOA) is for the activation of male sexual behavior in vertebrates, we recently developed an in vivo microdialysis procedure in the mPOA of Japanese quail. Using these techniques in the present experiment, the temporal pattern of DA release in relation to the precopulatory exposure to a female and to the expression of both appetitive and consummatory aspects of male sexual behavior was investigated. Extracellular samples from the mPOA of adult sexually experienced male quail were collected every 6 min before, while viewing, while in physical contact with, and after exposure to a female. In the absence of a precopulatory rise in DA, males failed to copulate when the barrier separating them from the female was removed. In contrast, males that showed a substantial increase in mPOA DA during precopulatory interactions behind the barrier, copulated with females after its removal. However, there was no difference in DA during periods when the quail were copulating as compared to when the female was present but the males were not copulating. In addition, we show that precopulatory DA predicts future DA levels and copulatory behavior frequency. Furthermore, the size of the cloacal gland, an accurate indicator of testosterone action, is positively correlated with precopulatory DA. Taken together, these results provide further support for the hypothesis that DA action in the mPOA is specifically linked to sexual motivation as compared to copulatory behavior per se. © 2010 APA, all rights reserved.

The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11 C]-raclopride and [11 C]-(+)-PHNO PET.

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Caravaggio, Fernando; Ku Chung, Jun; Plitman, Eric; Boileau, Isabelle; Gerretsen, Philip; Kim, Julia; Iwata, Yusuke; Patel, Raihaan; Chakravarty, M Mallar; Remington, Gary; Graff-Guerrero, Ariel

2017-11-01

Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D 2/3 receptors (D 2/3 R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D 2/3 R availability measured with an antagonist radiotracer ([ 11 C]-raclopride) versus an agonist radiotracer ([ 11 C]-(+)-PHNO) were examined. Data from 62 subjects scanned with [ 11 C]-raclopride (mean age = 38.98 ± 14.45; 23 female) and 68 subjects scanned with [ 11 C]-(+)-PHNO (mean age = 38.54 ± 14.59; 25 female) were used. Subcortical volumes were extracted from T1-weighted images using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Partial correlations were used controlling for age, gender, and total brain volume. For [ 11 C]-(+)-PHNO, ventral caudate volumes were positively correlated with BP ND in the dorsal caudate and globus pallidus (GP). Ventral striatum (VS) volumes were positively correlated with BP ND in the VS. With [ 11 C]-raclopride, BP ND in the VS was negatively correlated with subiculum volume of the hippocampus. Moreover, BP ND in the GP was negatively correlated with the volume of the lateral posterior nucleus of the thalamus. Findings are purely exploratory and presented corrected and uncorrected for multiple comparisons. We hope they will help inform the interpretation of future PET studies where concurrent changes in D 2/3 R and brain morphology are observed. Hum Brain Mapp 38:5519-5534, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Striatal dopamine D2 receptor binding and dopamine release during cue-elicited craving in recently abstinent opiate-dependent males

NARCIS (Netherlands)

Zijlstra, Fleur; Booij, Jan; van den Brink, Wim; Franken, Ingmar H. A.

2008-01-01

Opiate addiction is a chronic disorder characterized by relapse behaviour, often preceded by craving and anhedonia. Chronic craving and anhedonia have been associated with low availability of dopamine D2 receptors (D2Rs) and cue-elicited craving has been linked with endogenous dopamine release. We

Neuroprotective effects of curcumin and highly bioavailable curcumin on oxidative stress induced by sodium nitroprusside in rat striatal cell culture.

Science.gov (United States)

Nazari, Qand Agha; Kume, Toshiaki; Izuo, Naotaka; Takada-Takatori, Yuki; Imaizumi, Atsushi; Hashimoto, Tadashi; Izumi, Yasuhiko; Akaike, Akinori

2013-01-01

Curcumin, a polyphenolic compound extracted from Curcuma longa, has several pharmacological activities such as anticancer, anti-inflammatory, and antioxidant effects. The purpose of this study was to investigate the protective effects of curcumin and THERACURMIN, a highly bioavailable curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in primary striatal cell culture. THERACURMIN as well as curcumin significantly prevented SNP-induced cytotoxicity. To elucidate the cytoprotective effects of curcumin and THERACURMIN, we measured the intracellular glutathione level in striatal cells. Curcumin and THERACURMIN significantly elevated the glutathione level, which was decreased by treatment with SNP. Moreover, curcumin showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging ability. Finally, a ferrozine assay showed that curcumin (10-100 µg/mL) has potent Fe(2+)-chelating ability. These results suggest that curcumin and THERACURMIN exert potent protective effects against SNP-induced cytotoxicity by free radical-scavenging and iron-chelating activities.

Kainate-enhanced release of D-(3H)aspartate from cerebral cortex and striatum: reversal by baclofen and pentobarbital

Energy Technology Data Exchange (ETDEWEB)

Potashner, S.J.; Gerard, D.

1983-06-01

A study was made of the actions of the excitant neurotoxin, kainic acid, on the uptake and the release of D-(2,3-3H)aspartate (D-ASP) in slices of guinea pig cerebral neocortex and striatum. The slices took up D-ASP, reaching concentrations of the amino acid in the tissue which were 14-23 times that in the medium. Subsequently, electrical stimulation of the slices evoked a Ca2+-dependent release of a portion of the D-ASP. Kainic acid (10(-5)-10(-3) M) produced a dose-dependent inhibition of D-ASP uptake. The electrically evoked release of D-ASP was increased 1.6-2.0 fold by 10(-5) and 10(-4)M kainic acid. The kainate-enlarged release was Ca2+-dependent. Dihydrokainic acid, an analogue of kainic acid with little excitatory or toxic action, did not increase D-ASP release but depressed D-ASP uptake. Attempts were made to block the action of kainic acid with baclofen and pentobarbital, compounds which depress the electrically evoked release of L-glutamate (L-GLU) and L-aspartate (L-ASP). Baclofen (4 X 10(-6)M), an antispastic drug, and pentobarbital (10(-4)M), an anesthetic agent, each inhibited the electrically evoked release of D-ASP and prevented the enhancement of the release above control levels usually produced by 10(-4)M kainic acid. It is proposed that 10(-5) and 10(-4)M kainic acid may enhance the synaptic release of L-GLU and L-ASP from neurons which use these amino acids as transmitters. This action is prevented by baclofen and pentobarbital. In view of the possibility that cell death in Huntington's disease could involve excessive depolarization of striatal and other cells by glutamate, baclofen might be effective in delaying the loss of neurons associated with this condition.

Resveratrol Produces Neurotrophic Effects on Cultured Dopaminergic Neurons through Prompting Astroglial BDNF and GDNF Release

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Feng Zhang

2012-01-01

Full Text Available Increasing evidence indicated astroglia-derived neurotrophic factors generation might hold a promising therapy for Parkinson’s disease (PD. Resveratrol, naturally present in red wine and grapes with potential benefit for health, is well known to possess a number of pharmacological activities. Besides the antineuroinflammatory properties, we hypothesized the neuroprotective potency of resveratrol is partially due to its additional neurotrophic effects. Here, primary rat midbrain neuron-glia cultures were applied to investigate the neurotrophic effects mediated by resveratrol on dopamine (DA neurons and further explore the role of neurotrophic factors in its actions. Results showed resveratrol produced neurotrophic effects on cultured DA neurons. Additionally, astroglia-derived neurotrophic factors release was responsible for resveratrol-mediated neurotrophic properties as evidenced by the following observations: (1 resveratrol failed to exert neurotrophic effects on DA neurons in the cultures without astroglia; (2 the astroglia-conditioned medium prepared from astroglia-enriched cultures treated with resveratrol produced neurotrophic effects in neuron-enriched cultures; (3 resveratrol increased neurotrophic factors release in the concentration- and time-dependent manners; (4 resveratrol-mediated neurotrophic effects were suppressed by blocking the action of the neurotrophic factors. Together, resveratrol could produce neurotrophic effects on DA neurons through prompting neurotrophic factors release, and these effects might open new alternative avenues for neurotrophic factor-based therapy targeting PD.

In vivo pharmacological characterization of (+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol hydrochloride (SIB-1553A), a novel cholinergic ligand: microdialysis studies.

Science.gov (United States)

Rao, Tadimeti S; Reid, Richard T; Correa, Lucia D; Santori, Emily M; Gardner, Michael F; Sacaan, Aida I; Lorrain, Daniel; Vernier, Jean-Michel

2003-10-03

SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.

Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats.

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Urakawa, S; Hida, H; Masuda, T; Misumi, S; Kim, T-S; Nishino, H

2007-02-09

Rats raised in an enriched environment (enriched rats) have been reported to show less motor dysfunction following brain lesions, but the neuronal correlates of this improvement have not been well clarified. The present study aimed to elucidate the effect of chemical brain lesions and environmental enrichment on motor function and lesion-induced neurogenesis. Three week-old, recently weaned rats were divided into two groups: one group was raised in an enriched environment and the other group was raised in a standard cage for 5 weeks. Striatal damage was induced at an age of 8 weeks by injection of the neuro-toxins 6-hydroxydopamine (6-OHDA) or quinolinic acid (QA) into the striatum, or by injection of 6-OHDA into the substantia nigra (SN), which depleted nigrostriatal dopaminergic innervation. Enriched rats showed better performance on beam walking compared with those raised in standard conditions, but both groups showed similar forelimb use asymmetry in a cylinder test. The number of bromodeoxyuridine-labeled proliferating cells in the subventricular zone was increased by a severe striatal lesion induced by QA injection 1 week after the lesion, but decreased by injection of 6-OHDA into the SN. Following induction of lesions by striatal injection of 6-OHDA or QA, the number of cells positive for doublecortin (DCX) was strongly increased in the striatum; however, there was no change in the number of DCX-positive cells following 6-OHDA injection into the SN. Environmental enrichment enhanced the increase of DCX-positive cells with migrating morphology in the dorsal striatum. In enriched rats, DCX-positive cells traversed the striatal parenchyma far from the corpus callosum and lateral ventricle. DCX-positive cells co-expressed an immature neuronal marker, polysialylated neural cell adhesion molecule, but were negative for a glial marker. These data suggest that environmental enrichment improves motor performance on beam walking and enhances neuronal migration toward

Connectivity-based parcellation reveals distinct cortico-striatal connectivity fingerprints in Autism Spectrum Disorder.

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Balsters, Joshua H; Mantini, Dante; Wenderoth, Nicole

2018-04-15

Autism Spectrum Disorder (ASD) has been associated with abnormal synaptic development causing a breakdown in functional connectivity. However, when measured at the macro scale using resting state fMRI, these alterations are subtle and often difficult to detect due to the large heterogeneity of the pathology. Recently, we outlined a novel approach for generating robust biomarkers of resting state functional magnetic resonance imaging (RS-fMRI) using connectivity based parcellation of gross morphological structures to improve single-subject reproducibility and generate more robust connectivity fingerprints. Here we apply this novel approach to investigating the organization and connectivity strength of the cortico-striatal system in a large sample of ASD individuals and typically developed (TD) controls (N=130 per group). Our results showed differences in the parcellation of the striatum in ASD. Specifically, the putamen was found to be one single structure in ASD, whereas this was split into anterior and posterior segments in an age, IQ, and head movement matched TD group. An analysis of the connectivity fingerprints revealed that the group differences in clustering were driven by differential connectivity between striatum and the supplementary motor area, posterior cingulate cortex, and posterior insula. Our approach for analysing RS-fMRI in clinical populations has provided clear evidence that cortico-striatal circuits are organized differently in ASD. Based on previous task-based segmentations of the striatum, we believe that the anterior putamen cluster present in TD, but not in ASD, likely contributes to social and language processes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Association of Novelty Seeking Scores and Striatal Dopamine D2/D3 Receptor Availability of Healthy Volunteers: Single Photon Emission Computed Tomography With 123I-iodobenzamide

Directory of Open Access Journals (Sweden)

Hsiang Yu Huang

2010-10-01

Full Text Available It has been speculated that novelty seeking (NS behavior is related to the dopaminergic system. Fifty-two subjects completed the Tridimensional Personality Questionnaire and underwent single photon emission computed tomography with 123I-iodobenzamide. A marginally positive correlation was noted between NS and striatal dopamine D2/D3 receptor availability (r = 0.25, p =0.07. A positive association was noted between the NS scores and left striatal D2/D3 receptor availability (r= 0.29, p =0.04. The results suggest that a relationship might exist between NS score and dopaminergic activity.

Dopamine in high-risk populations: A comparison of subjects with 22q11.2 deletion syndrome and subjects at ultra high-risk for psychosis

NARCIS (Netherlands)

Vingerhoets, Claudia; Bloemen, Oswald J. N.; Boot, Erik; Bakker, Geor; de Koning, Mariken B.; da Silva Alves, Fabiana; Booij, Jan; van Amelsvoort, Thérèse A. M. J.

2018-01-01

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in