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Sample records for blocking dopamine d1

  1. Supra-normal stimulation of dopamine D1 receptors in the prelimbic cortex blocks behavioral expression of both aversive and rewarding associative memories through a cyclic-AMP-dependent signaling pathway.

    Science.gov (United States)

    Lauzon, Nicole M; Bechard, Melanie; Ahmad, Tasha; Laviolette, Steven R

    2013-04-01

    Dopamine (DA) receptor transmission through either D(1) or D(2)-like subtypes is involved critically in the processing of emotional information within the medial prefrontal cortex (mPFC). However the functional role of specific DA D(1)-like receptor transmission in the expression of emotionally salient associative memories (either aversive or rewarding) is not currently understood. Here we demonstrate that specific activation of DA D(1) receptors in the prelimbic (PLC) division of the mPFC causes a transient block in the behavioral expression of both aversive and rewarding associative memories. We report that intra-PLC microinfusions of a selective D(1) receptor agonist block the spontaneous expression of an associative olfactory fear memory, without altering the stability of the original memory trace. Furthermore, using an unbiased place conditioning procedure (CPP), intra-PLC D(1) receptor activation blocks the spontaneous expression of an associative morphine (5 mg/kg; i.p.) reward memory, while leaving morphine-primed memory expression intact. Interestingly, both intra-PLC D(1)-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cyclic-AMP (cAMP) signaling as both effects were rescued by co-administration of a cAMP signaling inhibitor. The blockade of both rewarding and aversive associative memories is mediated through a D(1)-specific signaling pathway, as neither forms of spontaneous memory expression were blocked by intra-PLC microinfusions of a D(2)-like receptor agonist. Our results demonstrate that the spontaneous expression of either rewarding or aversive emotionally salient memories shares a common, D(1)-receptor mediated substrate within the mPFC.

  2. Dopamine D1 receptor involvement in latent inhibition and overshadowing.

    Science.gov (United States)

    Nelson, Andrew J D; Thur, Karen E; Cassaday, Helen J

    2012-11-01

    Latent inhibition (LI) manifests as poorer conditioning to a stimulus that has previously been experienced without consequence. There is good evidence of dopaminergic modulation of LI, as the effect is reliably disrupted by the indirect dopamine (DA) agonist amphetamine. The disruptive effects of amphetamine on LI are reversed by both typical and atypical antipsychotics, which on their own are able to facilitate LI. However, the contribution of different DA receptors to these effects is poorly understood. Amphetamine effects on another stimulus selection procedure, overshadowing, have been suggested to be D1-mediated. Thus, in the current experiments, we systematically investigated the role of D1 receptors in LI. First, we tested the ability of the full D1 agonist SKF 81297 to abolish LI and compared the effects of this drug on LI and overshadowing. Subsequently, we examined whether the D1 antagonist SCH 23390 can lead to the emergence of LI under conditions that do not produce the effect in normal animals (weak pre-exposure). Finally, we tested the ability of SCH 23390 to block amphetamine-induced disruption of LI. We found little evidence that direct stimulation of D1 receptors abolishes LI (although there was some attenuation of LI at 0.4 mg/kg SKF 81297). Similarly, SCH 23390 failed to enhance LI. However, SCH 23390 did block amphetamine-induced disruption of LI. These data indicate that, while LI may be unaffected by selective manipulation of activity at D1 receptors, the effects of amphetamine on LI are to some extent dependent on actions at D1 receptors.

  3. Medial prefrontal D1 dopamine neurons control food intake.

    Science.gov (United States)

    Land, Benjamin B; Narayanan, Nandakumar S; Liu, Rong-Jian; Gianessi, Carol A; Brayton, Catherine E; Grimaldi, David M; Sarhan, Maysa; Guarnieri, Douglas J; Deisseroth, Karl; Aghajanian, George K; DiLeone, Ralph J

    2014-02-01

    Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor-expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.

  4. Prefrontal D1 dopamine signaling is required for temporal control.

    Science.gov (United States)

    Narayanan, Nandakumar S; Land, Benjamin B; Solder, John E; Deisseroth, Karl; DiLeone, Ralph J

    2012-12-11

    Temporal control, or how organisms guide movements in time to achieve behavioral goals, depends on dopamine signaling. The medial prefrontal cortex controls many goal-directed behaviors and receives dopaminergic input primarily from the midbrain ventral tegmental area. However, this system has never been linked with temporal control. Here, we test the hypothesis that dopaminergic projections from the ventral tegmental area to the prefrontal cortex influence temporal control. Rodents were trained to perform a fixed-interval timing task with an interval of 20 s. We report several results: first, that decreasing dopaminergic neurotransmission using virally mediated RNA interference of tyrosine hydroxylase impaired temporal control, and second that pharmacological disruption of prefrontal D1 dopamine receptors, but not D2 dopamine receptors, impaired temporal control. We then used optogenetics to specifically and selectively manipulate prefrontal neurons expressing D1 dopamine receptors during fixed-interval timing performance. Selective inhibition of D1-expressing prefrontal neurons impaired fixed-interval timing, whereas stimulation made animals more efficient during task performance. These data provide evidence that ventral tegmental dopaminergic projections to the prefrontal cortex influence temporal control via D1 receptors. The results identify a critical circuit for temporal control of behavior that could serve as a target for the treatment of dopaminergic diseases.

  5. Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor

    DEFF Research Database (Denmark)

    Pedersen, U B; Norby, B; Jensen, Anders A.

    1994-01-01

    Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines...... for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl...... cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments...

  6. Dopamine induces neutrophil apoptosis through a dopamine D-1 receptor-independent mechanism.

    LENUS (Irish Health Repository)

    Sookhai, S

    2012-02-03

    BACKGROUND: For the normal resolution of an acute inflammatory response, neutrophil (PMN) apoptosis is essential to maintain immune homeostasis and to limit inappropriate host tissue damage. A delay in PMN apoptosis has been implicated in the pathogenesis of the systemic inflammatory response syndrome (SIRS). Dopamine, a biogenic amine with known cardiovascular and neurotransmitter properties, is used in patients with SIRS to maintain hemodynamic stability. We sought to determine whether dopamine may also have immunoregulatory properties capable of influencing PMN apoptosis, function, and activation state in patients with SIRS. METHODS: PMNs were isolated from healthy volunteers and patients with SIRS and treated with varying doses of dopamine and a dopamine D-1 receptor agonist, fenoldopam. PMN apoptosis was assessed every 6 hours with use of propidium iodide DNA staining and PMN function was assessed with use of respiratory burst activity, phagocytosis ability, and CD11a, CD11b, and CD18 receptor expression as functional markers. RESULTS: There was a significant delay in PMN apotosis in patients with SIRS compared with controls. Treatment of isolated PMNs from both healthy controls and patients with SIRS with 10 and 100 mumol\\/L dopamine induced apoptosis. PMN ingestive and cytocidal capacity were both decreased in patients with SIRS compared with controls. Treatment with dopamine significantly increased phagocytic function. Fenoldopam did not induce PMN apoptosis. CONCLUSION: Our data demonstrate for the first time that dopamine induces PMN apoptosis and modulates PMN function both in healthy controls and in patients with SIRS. These results indicate that dopamine may be beneficial during SIRS through a nonhemodynamic PMN-dependent proapoptotic mechanism.

  7. Transcriptional regulation of renal dopamine D1 receptor function during oxidative stress.

    Science.gov (United States)

    Banday, Anees A; Lokhandwala, Mustafa F

    2015-05-01

    There exists a strong link between oxidative stress, renal dopaminergic system, and hypertension. It is reported that reactive oxygen species attenuate renal proximal tubular dopamine receptor (D1R) function, which disrupts sodium regulation and leads to hypertension. However, the mechanisms for renal D1R dysfunction are not clear. We investigated the role of redox-sensitive transcription factors AP1 and SP3 in transcriptional suppression of D1R gene and subsequent D1R signaling. Human kidney proximal tubular cells were treated with a pro-oxidant l-buthionine sulfoximine (BSO) with and without an antioxidant tempol. In human kidney cells, BSO caused oxidative stress and reduced D1R mRNA and membrane receptor expression. Incubation of human kidney cells with SKF38393, a D1R agonist, caused a concentration-dependent inhibition of Na/K-ATPase. However, SKF38393 failed to inhibit Na/K-ATPase in BSO-treated cells. BSO increased AP1 and SP3 nuclear expression. Transfection with AP1- or SP3-specific siRNA abolished BSO-induced D1R downregulation. Treatment of rats with BSO for 4 weeks increased oxidative stress and SP3-AP1 expression and reduced D1R numbers in renal proximal tubules. These rats exhibited high blood pressure, and SKF38393 failed to inhibit proximal tubular Na/K-ATPase activity. Control rats were kept on tap water. Tempol per se had no effect on D1R expression or other signaling molecules but prevented BSO-induced oxidative stress, SP3-AP1 upregulation, and D1R dysfunction in both human kidney cells and rats. These data show that oxidative stress via AP1-SP3 activation suppresses D1R transcription and function. Tempol mitigates oxidative stress, blocks AP1-SP3 activation, and prevents D1R dysfunction and hypertension.

  8. Gastrin and D1 dopamine receptor interact to induce natriuresis and diuresis.

    Science.gov (United States)

    Chen, Yue; Asico, Laureano D; Zheng, Shuo; Villar, Van Anthony M; He, Duofen; Zhou, Lin; Zeng, Chunyu; Jose, Pedro A

    2013-11-01

    Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

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

    Science.gov (United States)

    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.

  10. Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

    Directory of Open Access Journals (Sweden)

    Laurent Ladepeche

    Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

  11. Inhibition of GSK3 attenuates dopamine D1 receptor agonist-induced hyperactivity in mice.

    Science.gov (United States)

    Miller, Jonathan S; Tallarida, Ronald J; Unterwald, Ellen M

    2010-05-31

    Recent evidence suggests a critical role for the intracellular signaling protein glycogen synthase kinase-3 (GSK3) in hyperactivity associated with dopaminergic transmission. Here, we investigated whether activation of GSK3 is necessary for the expression of behaviors specifically produced by dopamine D1 receptor activation. To assess the role of GSK3 in dopamine D1 receptor-induced hyperactivity, mice were pretreated with the selective GSK3 inhibitor SB 216763 (0.25-7.5mg/kg, i.p.) or its vehicle prior to administration of the dopamine D1 receptor full-agonist SKF-82958 (1.0mg/kg, i.p.) or saline control. Inhibition of GSK3 via SB 216763 dose-dependently reduced ambulatory and stereotypic activity produced by SKF-82958. These data implicate a role for GSK3 in the behavioral manifestations associated with dopamine D1 receptor activation.

  12. A Role for D1 Dopamine Receptors in Striatal Methamphetamine-Induced Neurotoxicity

    OpenAIRE

    Friend, Danielle M.; Keefe, Kristen A

    2013-01-01

    Methamphetamine (METH) exposure results in long-term damage to the dopamine system in both human METH abusers and animal models. One factor that has been heavily implicated in this METH-induced damage to the dopaminergic system is the activation of D1 Dopamine (DA) receptors. However, a significant caveat to the studies investigating the role of the receptor in such toxicity is that genetic and pharmacological manipulations of the D1 DA receptor also mitigate METH-induced hyperthermia. Import...

  13. Facilitatory effect of dopamine on neuromuscular transmission mediated via dopamine D1-like receptors and prospective interaction with nicotine.

    Science.gov (United States)

    AlQot, H E; Elnozahi, N A; Mohy El-Din, M M; Bistawroos, A E; Abou Zeit-Har, M S

    2015-10-15

    The objective of this study is to probe the effects of dopamine and potential interactions with nicotine at the motor end plate. To accomplish this, we measured the amplitude of nerve-evoked muscle twitches of the isolated rat phrenic hemi-diaphragm preparation. Dopamine potentiated indirect muscle twitches in normal and gallamine-presensitized preparations amounting to a maximum of 31.14±0.71% and 69.23±1.96%, respectively. The dopamine-induced facilitation was well maintained in presence of 10 µM propranolol but greatly reduced in presence of 6 µM SCH 23390 or 3 µM dantrolene. In addition, SKF 81297 attained a plateau at 16 µM as opposed to 64 µM dopamine, with a percentage potentiation of 69.47±1.76. The facilitatory effect of dopamine was potentiated in nicotine treated rats. This study revealed for the first time that the facilitatory effect exerted by dopamine on neuromuscular transmission is mediated via the dopamine D1-like receptors. In addition, it highlighted the possible dependency of dopamine effects on intracellular calcium and signified potential interaction among dopamine and nicotine. Clinically, the findings generated by this study reveal potential targets for approaching motor deficit syndromes.

  14. A new approach for treatment of hypertension: modifying D1 dopamine receptor function.

    Science.gov (United States)

    Zeng, Chunyu; Felder, Robin A; Jose, Pedro A

    2006-10-01

    Essential hypertension is a major factor for myocardial infarction, heart failure and kidney failure. Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and vasodilatation directly or indirectly with other hormones and humoral factors, such as reactive oxygen species and the renin-angiotensin system. Dopamine receptors are classified into five subtypes based on their structure and pharmacology. Among those dopamine receptor subtypes, D(1) receptor is the most important one, during conditions of moderate sodium intake, more than 50% of renal sodium excretion is regulated by D(1)-like receptors. Decreased renal dopamine production and/or impaired D(1) receptor function have been reported in hypertension. Disruption of D(1) receptor results in hypertension. In this paper, we review the mechanisms by which hypertension develops when D(1) receptor function is perturbed. We also discuss possible new approaches developing anti-hypertensive medicine by increasing renal dopamine production, enhancing D(1) receptor function, or modifying its interactions with other blood pressure-regulating systems.

  15. The effect of modafinil on the rat dopamine transporter and dopamine receptors D1-D3 paralleling cognitive enhancement in the radial arm maze

    Directory of Open Access Journals (Sweden)

    Yasemin eKarabacak

    2015-08-01

    Full Text Available A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT and norepinephrine (NET by modafinil was tested. 60 male Sprague Dawley rats were divided into six groups (modafinil-treated 1-5-10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days and tested in a radial arm maze (RAM, a paradigm for testing spatial WM. Hippocampi were taken six hours following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC and complexes containing the D1-3 dopamine receptor subunits (D1-D3-CC were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50=11.11; SERT 1547; NET 182. From day 8 (day 9 for 1 mg/kg body weight modafinil was decreasing WM errors in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1-D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1-3-CC is proposed as a possible mechanism of action.

  16. The effect of modafinil on the rat dopamine transporter and dopamine receptors D1–D3 paralleling cognitive enhancement in the radial arm maze

    Science.gov (United States)

    Karabacak, Yasemin; Sase, Sunetra; Aher, Yogesh D.; Sase, Ajinkya; Saroja, Sivaprakasam R.; Cicvaric, Ana; Höger, Harald; Berger, Michael; Bakulev, Vasiliy; Sitte, Harald H.; Leban, Johann; Monje, Francisco J.; Lubec, Gert

    2015-01-01

    A series of drugs have been reported to increase memory performance modulating the dopaminergic system and herein modafinil was tested for its working memory (WM) enhancing properties. Reuptake inhibition of dopamine, serotonin (SERT) and norepinephrine (NET) by modafinil was tested. Sixty male Sprague–Dawley rats were divided into six groups (modafinil-treated 1–5–10 mg/kg body weight, trained and untrained and vehicle treated trained and untrained rats; daily injected intraperitoneally for a period of 10 days) and tested in a radial arm maze (RAM), a paradigm for testing spatial WM. Hippocampi were taken 6 h following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT-CC and pDAT-CC) and complexes containing the D1–3 dopamine receptor subunits (D1–D3-CC) were determined. Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 = 11.11 μM; SERT 1547 μM; NET 182 μM). From day 8 (day 9 for 1 mg/kg body weight) modafinil was decreasing WM errors (WMEs) in the RAM significantly and remarkably at all doses tested as compared to the vehicle controls. WMEs were linked to the D2R-CC and the pDAT-CC. pDAT and D1–D3-CC levels were modulated significantly and modafinil was shown to enhance spatial WM in the rat in a well-documented paradigm at all the three doses and dopamine reuptake inhibition with subsequent modulation of D1–3-CC is proposed as a possible mechanism of action. PMID:26347626

  17. Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists.

    Science.gov (United States)

    Qiang, Li; Sasikumar, T K; Burnett, Duane A; Su, Jing; Tang, Haiqun; Ye, Yuanzan; Mazzola, Robert D; Zhu, Zhaoning; McKittrick, Brian A; Greenlee, William J; Fawzi, Ahmad; Smith, Michelle; Zhang, Hongtao; Lachowicz, Jean E

    2010-02-01

    A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.

  18. Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance

    Directory of Open Access Journals (Sweden)

    Hasbi Ahmed

    2011-06-01

    Full Text Available Abstract Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance.

  19. Histamine H3 receptor activation prevents dopamine D1 receptor-mediated inhibition of dopamine release in the rat striatum: a microdialysis study.

    Science.gov (United States)

    Alfaro-Rodriguez, Alfonso; Alonso-Spilsbury, María; Arch-Tirado, Emilio; Gonzalez-Pina, Rigoberto; Arias-Montaño, José-Antonio; Bueno-Nava, Antonio

    2013-09-27

    Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 μM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 μM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 μM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.

  20. Remote functionalization of SCH 39166: discovery of potent and selective benzazepine dopamine D1 receptor antagonists.

    Science.gov (United States)

    Sasikumar, T K; Burnett, Duane A; Greenlee, William J; Smith, Michelle; Fawzi, Ahmad; Zhang, Hongtao; Lachowicz, Jean E

    2010-02-01

    A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.

  1. The role of the dopamine D1 receptor in social cognition : Studies using a novel genetic rat model

    NARCIS (Netherlands)

    Homberg, Judith R.; Olivier, Jocelien D A; VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K.; Karel, Peter; Shan, Ling; Van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R.; Cuppen, Edwin; Ellenbroek, Bart A.

    2016-01-01

    Social cognitionisan endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 recept

  2. New therapeutic strategies targeting D1-type dopamine receptors for neuropsychiatric disease

    Science.gov (United States)

    Kim, Young-Cho; Alberico, Stephanie L.; Emmons, Eric; Narayanan, Nandakumar S.

    2017-01-01

    The neurotransmitter dopamine acts via two major classes of receptors, D1-type and D2-type. D1 receptors are highly expressed in the striatum and can also be found in the cerebral cortex. Here we review the role of D1 dopamine signaling in two major domains: L-DOPA-induced dyskinesias in Parkinson’s disease and cognition in neuropsychiatric disorders. While there are many drugs targeting D2-type receptors, there are no drugs that specifically target D1 receptors. It has been difficult to use selective D1-receptor agonists for clinical applications due to issues with bioavailability, binding affinity, pharmacological kinetics, and side effects. We propose potential therapies that selectively modulate D1 dopamine signaling by targeting second messengers downstream of D1 receptors, allosteric modulators, or by making targeted modifications to D1-receptor machinery. The development of therapies specific to D1-receptor signaling could be a new frontier in the treatment of neurological and psychiatric disorders.

  3. Characterization of dopamine D1 receptor agonists in vivo- Implications for the treatment of schizophrenia and Parkinson s disease

    OpenAIRE

    Isacson, Ruben

    2008-01-01

    Dopamine is fundamental in human behavior for movement, cognition and reward. A dysfunctional dopamine system is implicated in several neurological and psychiatric disorders such as Parkinson s disease and schizophrenia. Dopamine mediates its effects through five receptors. Dopamine D2 receptors are well studied and successful drug targets in the treatment of Parkinson s disease and schizophrenia. The functional role of dopamine D1 receptors is not fully understood and the c...

  4. Elevated dopamine in the medial prefrontal cortex suppresses cocaine seeking via D1 receptor overstimulation.

    Science.gov (United States)

    Devoto, Paola; Fattore, Liana; Antinori, Silvia; Saba, Pierluigi; Frau, Roberto; Fratta, Walter; Gessa, Gian Luigi

    2016-01-01

    Previous investigations indicate that the dopamine-β-hydroxylase (DBH) inhibitors disulfiram and nepicastat suppress cocaine-primed reinstatement of cocaine self-administration behaviour. Moreover, both inhibitors increase dopamine release in the rat medial prefrontal cortex (mPFC) and markedly potentiate cocaine-induced dopamine release in this region. This study was aimed to clarify if the suppressant effect of DBH inhibitors on cocaine reinstatement was mediated by the high extracellular dopamine in the rat mPFC leading to a supra-maximal stimulation of D1 receptors in the dorsal division of mPFC, an area critical for reinstatement of cocaine-seeking behaviour. In line with previous microdialysis studies in drug-naïve animals, both DBH inhibitors potentiated cocaine-induced dopamine release in the mPFC, in the same animals in which they also suppressed reinstatement of cocaine seeking. Similar to the DBH inhibitors, L-DOPA potentiated cocaine-induced dopamine release in the mPFC and suppressed cocaine-induced reinstatement of cocaine-seeking behaviour. The bilateral microinfusion of the D1 receptor antagonist SCH 23390 into the dorsal mPFC not only prevented cocaine-induced reinstatement of cocaine seeking but also reverted both disulfiram- and L-DOPA-induced suppression of reinstatement. Moreover, the bilateral microinfusion of the D1 receptor agonist chloro-APB (SKF 82958) into the dorsal mPFC markedly attenuated cocaine-induced reinstatement of cocaine seeking. These results suggest that stimulation of D1 receptors in the dorsal mPFC plays a crucial role in cocaine-induced reinstatement of cocaine seeking, whereas the suppressant effect of DBH inhibitors and L-DOPA on drug-induced reinstatement is mediated by a supra-maximal stimulation of D1 receptors leading to their inactivation.

  5. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum.

    Science.gov (United States)

    Goutier, W; Lowry, J P; McCreary, A C; O'Connor, J J

    2016-05-01

    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.

  6. Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus.

    Science.gov (United States)

    Menezes, Jefferson; Alves, Niége; Borges, Sidnei; Roehrs, Rafael; de Carvalho Myskiw, Jociane; Furini, Cristiane Regina Guerino; Izquierdo, Ivan; Mello-Carpes, Pâmela B

    2015-03-31

    Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors.

  7. Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway.

    Science.gov (United States)

    Moreno, Estefanía; Hoffmann, Hanne; Gonzalez-Sepúlveda, Marta; Navarro, Gemma; Casadó, Vicent; Cortés, Antoni; Mallol, Josefa; Vignes, Michel; McCormick, Peter J; Canela, Enric I; Lluís, Carme; Moratalla, Rosario; Ferré, Sergi; Ortiz, Jordi; Franco, Rafael

    2011-02-18

    Previously, using artificial cell systems, we identified receptor heteromers between the dopamine D(1) or D(2) receptors and the histamine H(3) receptor. In addition, we demonstrated two biochemical characteristics of the dopamine D(1) receptor-histamine H(3) receptor heteromer. We have now extended this work to show the dopamine D(1) receptor-histamine H(3) receptor heteromer exists in the brain and serves to provide a novel link between the MAPK pathway and the GABAergic neurons in the direct striatal efferent pathway. Using the biochemical characteristics identified previously, we found that the ability of H(3) receptor activation to stimulate p44 and p42 extracellular signal-regulated MAPK (ERK 1/2) phosphorylation was only observed in striatal slices of mice expressing D(1) receptors but not in D(1) receptor-deficient mice. On the other hand, the ability of both D(1) and H(3) receptor antagonists to block MAPK activation induced by either D(1) or H(3) receptor agonists was also found in striatal slices. Taken together, these data indicate the occurrence of D(1)-H(3) receptor complexes in the striatum and, more importantly, that H(3) receptor agonist-induced ERK 1/2 phosphorylation in striatal slices is mediated by D(1)-H(3) receptor heteromers. Moreover, H(3) receptor-mediated phospho-ERK 1/2 labeling co-distributed with D(1) receptor-containing but not with D(2) receptor-containing striatal neurons. These results indicate that D(1)-H(3) receptor heteromers work as processors integrating dopamine- and histamine-related signals involved in controlling the function of striatal neurons of the direct striatal pathway.

  8. Expression and therapeutic targeting of dopamine receptor-1 (D1R) in breast cancer.

    Science.gov (United States)

    Borcherding, D C; Tong, W; Hugo, E R; Barnard, D F; Fox, S; LaSance, K; Shaughnessy, E; Ben-Jonathan, N

    2016-06-16

    Patients with advanced breast cancer often fail to respond to treatment, creating a need to develop novel biomarkers and effective therapeutics. Dopamine (DA) is a catecholamine that binds to five G protein-coupled receptors. We discovered expression of DA type-1 receptors (D1Rs) in breast cancer, thereby identifying these receptors as novel therapeutic targets in this disease. Strong to moderate immunoreactive D1R expression was found in 30% of 751 primary breast carcinomas, and was associated with larger tumors, higher tumor grades, node metastasis and shorter patient survival. DA and D1R agonists, signaling through the cGMP/protein kinase G (PKG) pathway, suppressed cell viability, inhibited invasion and induced apoptosis in multiple breast cancer cell lines. Fenoldopam, a peripheral D1R agonist that does not penetrate the brain, dramatically suppressed tumor growth in two mouse models with D1R-expressing xenografts by increasing both necrosis and apoptosis. D1R-expressing primary tumors and metastases in mice were detected by fluorescence imaging. In conclusion, D1R overexpression is associated with advanced breast cancer and poor prognosis. Activation of the D1R/cGMP/PKG pathway induces apoptosis in vitro and causes tumor shrinkage in vivo. Fenoldopam, which is FDA (Food and Drug Administration) approved to treat renal hypertension, could be repurposed as a novel therapeutic agent for patients with D1R-expressing tumors.

  9. D4 and D1 dopamine receptors modulate [3H] GABA release in the substantia nigra pars reticulata of the rat.

    Science.gov (United States)

    Acosta-García, Jacqueline; Hernández-Chan, Nancy; Paz-Bermúdez, Francisco; Sierra, Arturo; Erlij, David; Aceves, Jorge; Florán, Benjamín

    2009-12-01

    Neurons of the globus pallidus express dopamine D4 receptors that can modulate transmitter release by their axon terminals. Indeed, GABA release from pallidal terminals in the subthalamic nucleus and in the reticular nucleus of the thalamus is inhibited by activation of D4 receptors. Here we investigated whether GABA release by pallidal projections to the substantia nigra reticulate (SNr) is also modulated by D4 receptors. Dopamine-stimulated depolarization-induced GABA release in slices of the SNr; however, after selective blockade of D1 receptors, dopamine inhibited release. The selective D4 agonist PD 168,077 (IC(50) = 5.30 nM) mimicked the inhibition of release while the selective D4 antagonist L-745,870 blocked the inhibition. To identify the source of D1 and D4 modulated terminals, we unilaterally injected kainic acid in either the GP or the striatum. After lesions of the pallidum, the D4 induced inhibition of release was blocked while the D1 induced stimulation was still significant. Lesions of the striatum had the converse effects. We conclude that release of dopamine in the SNr enhances GABA release mainly through activation of D1 receptors in striatonigral projections and inhibits release mainly through activation of D4 receptors in pallidonigral projections. Because deficient D4 receptor signaling in globus pallidus terminals will lead to disinhibition of impulse traffic through the thalamus we speculate that the D4 abnormalities observed in ADHD patients may be important in the generation of the syndrome.

  10. Striatal dopamine D1 receptor is essential for contextual fear conditioning.

    Science.gov (United States)

    Ikegami, Masaru; Uemura, Takeshi; Kishioka, Ayumi; Sakimura, Kenji; Mishina, Masayoshi

    2014-02-05

    Fear memory is critical for animals to trigger behavioural adaptive responses to potentially threatening stimuli, while too much or inappropriate fear may cause psychiatric problems. Numerous studies have shown that the amygdala, hippocampus and medial prefrontal cortex play important roles in Pavlovian fear conditioning. Recently, we showed that striatal neurons are required for the formation of the auditory fear memory when the unconditioned stimulus is weak. Here, we found that selective ablation of striatal neurons strongly diminished contextual fear conditioning irrespective of the intensity of footshock. Furthermore, contextual fear conditioning was strongly reduced in striatum-specific dopamine D1 receptor knockout mice. On the other hand, striatum-specific dopamine D2 receptor knockout mice showed freezing responses comparable to those of control mice. These results suggest that striatal D1 receptor is essential for contextual fear conditioning.

  11. Striatal dopamine D1 receptor suppression impairs reward-associative learning.

    Science.gov (United States)

    Higa, Kerin K; Young, Jared W; Ji, Baohu; Nichols, David E; Geyer, Mark A; Zhou, Xianjin

    2017-04-14

    Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R-targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno-associated virus (AAV). We then assessed reward- and punishment-associative learning using a probabilistic learning task and motivation using a progressive-ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)-doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA-treated mice exhibited impaired reward-associative learning, while punishment-associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA-treated mice exhibited normal Barnes maze learning and normal motivation in the progressive-ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward-associative learning whereas punishment-associative learning, aversion-motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward-associative learning deficits, D1R-targeted treatments should be investigated to improve reward learning in these patients.

  12. Aberrant D1 and D3 dopamine receptor transregulation in hypertension.

    Science.gov (United States)

    Zeng, Chunyu; Wang, Dan; Asico, Laureano D; Welch, William J; Wilcox, Christopher S; Hopfer, Ulrich; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2004-03-01

    Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D(1) and D(3) receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D(1)-like agonist, fenoldopam, increased D(3) receptor protein in a time-dependent and concentration-dependent manner (EC(50)=4.5x10(-9) M, t(1/2)=15.8 hours). In SHRs, fenoldopam (10(-5) M) actually decreased the expression of D(3) receptors. D(1) and D(3) receptor co-immunoprecipitation was increased by fenoldopam (10(-7) M/24 h) in WKY rats but not in SHRs. The effects of fenoldopam in CASMCs were similar as those in WKY RPT cells (ie, fenoldopam increased D(1) and D(3) receptor proteins). Both D(3) (PD128907, Emax=80%+/-6%, pED(50)=5+/-0.1) and D(1)-like receptor (fenoldopam, Emax=81%+/-8%, pED(50)=5+/-0.2, n=12) agonists relaxed mesenteric arterial rings. Co-stimulation of D(1) and D(3) receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D(1) and D(3) receptors interact differently in WKY and SHRs. Altered interactions between D(1) and D(3) receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.

  13. Concerted Action of ANP and Dopamine D1-Receptor to Regulate Sodium Homeostasis in Nephrotic Syndrome

    Directory of Open Access Journals (Sweden)

    Cátia Fernandes-Cerqueira

    2013-01-01

    Full Text Available The edema formation in nephrotic syndrome (NS is associated with a blunted response to atrial natriuretic peptide (ANP. The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R. We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS. Urinary sodium, cyclic guanosine monophosphate (cGMP excretion, and D1R protein expression and localization in renal tubules were evaluated in PAN-NS and control rats before and during volume expansion (VE. The effects of zaprinast (phosphodiesterase type 5 inhibitor, alone or in combination with Sch-23390 (D1R antagonist, were examined in both groups. The increased natriuresis and urinary cGMP excretion evoked by acute VE were blunted in PAN-NS despite increased levels of circulating ANP. This was accompanied in PAN-NS by a marked decrease of D1R expression in the renal tubules. Infusion of zaprinast in PAN-NS resulted in increased urinary excretion of cGMP and sodium to similar levels of control rats and increased expression of D1R in the plasma membrane of renal tubular cells. Combined administration of Sch-23390 and zaprinast prevented natriuresis and increased cGMP excretion induced by zaprinast alone. We conclude that D1R may play a major role in the ANP resistance observed in PAN-NS.

  14. Dopamine facilitates dendritic spine formation by cultured striatal medium spiny neurons through both D1 and D2 dopamine receptors.

    Science.gov (United States)

    Fasano, Caroline; Bourque, Marie-Josée; Lapointe, Gabriel; Leo, Damiana; Thibault, Dominic; Haber, Michael; Kortleven, Christian; Desgroseillers, Luc; Murai, Keith K; Trudeau, Louis-Éric

    2013-04-01

    Variations of dopamine (DA) levels induced by drugs of abuse or in the context of Parkinson's disease modulate the number of dendritic spines in medium spiny neurons (MSNs) of the striatum, showing that DA plays a major role in the structural plasticity of MSNs. However, little is presently known regarding early spine development in MSNs occurring before the arrival of cortical inputs and in particular about the role of DA and D1 (D1R) and D2 (D2R) DA receptors. A cell culture model reconstituting early cellular interactions between MSNs, intrinsic cholinergic interneurons and DA neurons was used to study the role of DA in spine formation. After 5 or 10 days in vitro, the presence of DA neurons increased the number of immature spine-like protrusions. In MSN monocultures, chronic activation of D1R or D2R also increased the number of spines and spinophilin expression in MSNs, suggesting a direct role for these receptors. In DA-MSN cocultures, chronic blockade of D1R or D2R reduced the number of dendritic spines. Interestingly, the combined activation or blockade of both D1R and D2R failed to elicit more extensive spine formation, suggesting that both receptors act through a mechanism that is not additive. Finally, we found increased ionotropic glutamate receptor responsiveness and miniature excitatory postsynaptic current (EPSC) frequency in DA-MSN co-cultures, in parallel with a higher number of spines containing PSD-95, suggesting that the newly formed spines present functional post-synaptic machinery preparing the MSNs to receive additional glutamatergic contacts. These results represent a first step in the understanding of how dopamine neurons promote the structural plasticity of MSNs during the development of basal ganglia circuits.

  15. Defective renal dopamine D1 receptor function contributes to hyperinsulinemia-mediated hypertension.

    Science.gov (United States)

    Ahmad Banday, Anees; Lokhandwala, Mustafa F

    2006-11-01

    Hyperinsulinemia is reported to play a role in hypertension, as abnormalities in blood pressure regulation and sodium handling exist in diabetes mellitus. Kidney dopamine promotes sodium excretion via the activation of renal D1 receptors. Because there is a close relationship between renal D1 receptor function and sodium excretion, it is hypothesized that a defect in this mechanism may contribute to decreased sodium excretion and hypertension during hyperinsulinemia. Renal D1 receptor function was studied in insulin-induced hypertension in male Sprague Dawley rats. Insulin pellets were implanted subcutaneously for controlled insulin release for three weeks; sham rats served as a control. Compared to control rats, insulin pellets increased plasma insulin levels by eight fold and decreased blood glucose by 40%. Insulin also caused a 22 mmHg increase in mean arterial blood pressure compared to control animals. The intravenous infusion of SKF-38393, a D1 receptor agonist, increased sodium excretion in control rats, but SKF-38393 failed to produce natriuresis in hyperinsulinemic animals. Renal proximal tubules from hyperinsulinemic rats had a reduced D1 receptor number, defective receptor-G protein coupling, and blunted SKF-38393 induced Na, K-ATPase inhibition. Insulin seems to reduce D1 receptor expression and coupling to the G-protein, leading to a reduced D1 receptor-mediated Na, K-ATPase inhibition, and a diminished natriuretic response to SKF-38393. These phenomena could account for sodium retention and hypertension associated with hyperinsulinemia.

  16. Requirement for the endocannabinoid system in social interaction impairment induced by coactivation of dopamine D1 and D2 receptors in the piriform cortex.

    Science.gov (United States)

    Zenko, Michelle; Zhu, Yongyong; Dremencov, Eliyahu; Ren, Wei; Xu, Lin; Zhang, Xia

    2011-08-01

    The dopamine receptor family consists of D1-D5 receptors (D1R-D5R), and we explored the contributions of each dopamine receptor subtype in the piriform cortex (PirC) to social interaction impairment (SII). Rats received behavioral tests or electrophysiological recording of PirC neuronal activity after injection of the D1R/D5R agonist SKF38393, the D2R/D3R/D4R agonist quinpirole, or both, with or without pretreatment with dopamine receptor antagonists, D1R or D5R antisense oligonucleotides, the cannabinoid CB1 receptor antagonist AM281, or the endocannabinoid transporter inhibitor VDM11. Systemic injection of SKF38393 and quinpirole together, but not each one alone, induced SII and increased PirC firing rate, which were blocked by D1R or D2R antagonist. Intra-PirC microinfusion of SKF38393 and quinpirole together, but not each one alone, also induced SII, which was blocked by D1R antisense oligonucleotides or D2R antagonist but not by D3R or D4R antagonist or D5R antisense oligonucleotides. SII induced by intra-PirC SKF38393/quinpirole was blocked by AM281 and enhanced by VDM11, whereas neither AM281 nor VDM11 alone affected social interaction behavior. Coadministration of SKF38393 and quinpirole produced anxiolytic effects without significant effects on locomotor activity, olfaction, and acquisition of olfactory short-term memory. These findings suggest that SII induced by coactivation of PirC D1R and D2R requires the endocannabinoid system.

  17. Prenatal lipopolysaccharide exposure results in dysfunction of the renal dopamine D1 receptor in offspring.

    Science.gov (United States)

    Wang, Xinquan; Luo, Hao; Chen, Caiyu; Chen, Ken; Wang, Jialiang; Cai, Yue; Zheng, Shuo; Yang, Xiaoli; Zhou, Lin; Jose, Pedro A; Zeng, Chunyu

    2014-11-01

    Adverse environment in early life can modulate the adult phenotype, including blood pressure. Lipopolysaccharide (LPS) exposure in utero results in increased blood pressure in the offspring, but the exact mechanisms are not clear. Studies have shown that the renal dopamine D1 receptor (D1R) plays an important role in maintaining sodium homeostasis and normal blood pressure; dysfunction of D1R is associated with oxidative stress and hypertension. In this study, we determined if dysfunction of the renal D1R is involved in fetal-programmed hypertension, and if oxidative stress contributes to this process. Pregnant Sprague-Dawley (SD) rats were intraperitoneally injected with LPS (0.79 mg/kg) or saline at gestation days 8, 10, and 12. As compared with saline-injected (control) dams, offspring of LPS-treated dams had increased blood pressure, decreased renal sodium excretion, and increased markers of oxidative stress. In addition, offspring of LPS-treated dams had decreased renal D1R expression, increased D1R phosphorylation, and G protein-coupled receptor kinase type 2 (GRK2) and type 4 (GRK4) protein expression, and impaired D1R-mediated natriuresis and diuresis. All of the findings in the offspring of LPS-treated dams were normalized after treatment with TEMPOL, an oxygen free radical scavenger. In conclusion, prenatal LPS exposure, via an increase in oxidative stress, impairs renal D1R function and leads to hypertension in the offspring. Normalization of renal D1R function by amelioration of oxidative stress may be a therapeutic target of fetal programming of hypertension.

  18. Dimerization of the D1 dopamine receptors is related with agonist and inverse agonist-induced receptor internalization

    Institute of Scientific and Technical Information of China (English)

    Yi-minTAO; Xue-junXU; Min-huaHONG; JieCHEN; Zhi-qiangCHI; Jing-genLIU

    2004-01-01

    AIM: To examine the relationship between D1 dopamine receptor dimer formation and ligand-induced receptor internalization. METHODS: FLAG-tagged D 1 dopamine receptor was transiently expressed in Sf9 cells. The cells were treated with SKF38393 or (+)butaclamol 1 μmol/L for different periods timeor at different doses for 30 min respectively. Western blot assaywas performed to assess dimer formation and flow evtomv.tv.r

  19. The cooperative roles of the dopamine receptors, D1R and D5R, on the regulation of renal sodium transport.

    Science.gov (United States)

    Gildea, John J; Shah, Ishan T; Van Sciver, Robert E; Israel, Jonathan A; Enzensperger, Christoph; McGrath, Helen E; Jose, Pedro A; Felder, Robin A

    2014-07-01

    Determining the individual roles of the two dopamine D1-like receptors (D1R and D5R) on sodium transport in the human renal proximal tubule has been complicated by their structural and functional similarity. Here we used a novel D5R-selective antagonist (LE-PM436) and D1R- or D5R-specific gene silencing to determine second messenger coupling pathways and heterologous receptor interaction between the two receptors. D1R and D5R colocalize in renal proximal tubule cells and physically interact, as determined by co-immunoprecipitation and fluorescent resonance energy transfer microscopy. Stimulation of renal proximal tubule cells with fenoldopam (D1R/D5R agonist) led to both adenylyl cyclase and phospholipase C (PLC) activation using real-time fluorescent resonance energy transfer biosensors ICUE3 and CYPHR, respectively. Fenoldopam increased cAMP accumulation and PLC activity and inhibited both NHE3 and NaKATPase activities. LE-PM436 and D5R siRNA blocked the fenoldopam-stimulated PLC pathway but not cAMP accumulation, whereas D1R siRNA blocked both fenoldopam-stimulated cAMP accumulation and PLC signaling. Either D1R or D5R siRNA, or LE-PM436 blocked the fenoldopam-dependent inhibition of sodium transport. Further studies using the cAMP-selective D1R/D5R agonist SKF83822 and PLC-selective D1R/D5R agonist SKF83959 confirmed the cooperative influence of the two pathways on sodium transport. Thus, D1R and D5R interact in the inhibition of NHE3 and NaKATPase activity, the D1R primarily by cAMP, whereas the D1R/D5R heteromer modulates the D1R effect through a PLC pathway.

  20. Identification of human dopamine D1-like receptor agonist using a cell-based functional assay

    Institute of Scientific and Technical Information of China (English)

    Nan JIANG; Ke-qing OU-YANG; Shao-xi CAI; Ying-he HU; Zhi-liang XU

    2005-01-01

    Aim: To establish a cell-based assay to screen human dopamine D1 and D5 receptor agonists against compounds from a natural product compound library.Methods: Synthetic responsive elements 6×cAMP response elements (CRE) and a mini promoter containing a TATA box were inserted into the pGL3 basic vector to generate the reporter gene construct pCRE/TA/Luci. CHO cells were co-transfected with the reporter gene construct and human D1 or D5 receptor cDNA in mammalian expression vectors. Stable cell lines were established for agonist screening. A natural product compound library from over 300 herbs has been established. The extracts from these herbs were used for human D1 and D5 receptor agonist screenings. Results: A number of extracts were identified that activated both D1 and D5 receptors. One of the herb extracts, SBG492, demonstrated distinct pharmacological characteristics with human D1 and D5 receptors.The EC50 values of SBG492 were 342.7 μg/mL for the D1 receptor and 31.7 μg/mL for the D5 receptor. Conclusion: We have established a cell-based assay for high-throughput drug screening to identify D 1-like receptor agonists from natural products. Several extracts that can active D1-like receptors were discovered.These compounds could be useful tools for studies on the functions of these receptors in the brain and could potentially be developed into therapeutic drugs for the treatment of central nervous system diseases.

  1. Dopamine D1 receptor-agonist interactions: A mutagenesis and homology modeling study.

    Science.gov (United States)

    Mente, Scot; Guilmette, Edward; Salafia, Michelle; Gray, David

    2015-01-01

    The dopamine D1 receptor is a G protein-coupled receptor that regulates intracellular signaling via agonist activation. Although the number of solved GPCR X-ray structures has been steadily increasing, still no structure of the D1 receptor exists. We have used site-directed mutagenesis of 12 orthosteric vicinity residues of possible importance to G protein-coupled activation to examine the function of prototypical orthosteric D1 agonists and partial agonists. We find that residues from four different regions of the D1 receptor make significant contributions to agonist function. All compounds studied, which are catechol-amines, are found to interact with the previously identified residues: the conserved D103(3.32), as well as the trans-membrane V serine residues. Additional key interactions are found for trans-membrane VI residues F288(6.51), F289(6.52) and N292(6.55), as well as the extra-cellular loop residue L190(ECL2). Molecular dynamics simulations of a D1 homology model have been used to help put the ligand-residue interactions into context. Finally, we considered the rescaling of fold-shift data as a method to account for the change in the size of the mutated side-chain and found that this rescaling helps to relate the calculated ligand-residue energies with observed experimental fold-shifts.

  2. Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents

    Science.gov (United States)

    Dwyer, Jennifer B.; Leslie, Frances M.

    2016-01-01

    Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional

  3. Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.

    Science.gov (United States)

    Roberts, Michael D; Gilpin, Leigh; Parker, Kyle E; Childs, Thomas E; Will, Matthew J; Booth, Frank W

    2012-02-01

    Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals.

  4. Dopamine-induced hypophagia is mediated by D1 and 5HT-2c receptors in chicken.

    Science.gov (United States)

    Zendehdel, Morteza; Hasani, Keyvan; Babapour, Vahab; Mortezaei, Sepideh Seyedali; Khoshbakht, Yalda; Hassanpour, Shahin

    2014-03-01

    The present study was designed to examine the effects of intracerebroventricular (ICV) injection of Dopamine (10, 20 and 40 nmol), L-DOPA (dopamine precursor; 62.5, 125 and 250 nmol), 6-OHDA (dopamine inhibitor; 75, 150 and 300 nmol), SCH 23390 (D1 antagonist; 2.5, 5 and 10 nmol), AMI-193 (D2 antagonist; 2.5, 5 and 10 nmol), NGB2904 (D3 antagonist; 3.2, 6.4 and 12.8 nmol), L-741 T742 (D4 antagonist;1.5, 3 and 6 nmol) on food intake in FD3 chickens. At following, birds were ICV injected using 8-OH-DPAT (5-HT1A agonist; 15.25 nmol) and SB242084 (5-HT2C antagonist;1.5 μg) prior dopamine (40 nmol) injection. Cumulative food intake was determined until 3 h post-injection. According to the results, dopamine significantly decreased food intake in chickens (p dopamine on food intake was decreased by SCH 23390 pretreatment (P dopamine. In addition, hypophagic effect of dopamine was attenuated by SB242084 (P dopamine decrease food intake via D1 receptor and there is an interaction between dopaminergic and serotonergic systems via 5-HT2C receptor in chickens.

  5. Cloning, expression, and functional analysis of human dopamine D1 receptors

    Institute of Scientific and Technical Information of China (English)

    Wan-chun SUN; Lei JIN; Yan CAO; Li-zhen WANG; Fan MENG; Xing-zu ZHU

    2005-01-01

    Aim: To construct an HEK293 cell line stably expressing human dopamine D1 receptor (D1R). Methods: cDNA was amplified by RT-PCR using total RNA from human embryo brain tissue as the template. The PCR products were subcloned into the plasmid pcDNA3 and cloned into the plasmid pcDNA3.1. The cloned D1R cDNA was sequenced and stably expressed in HEK293 cells. Expression of D1R in HEK293 cells was monitored by the [3H]SCH23390 binding assay. The function of D1R was studied by the cAMP accumulation assay, CRE-SEAP reporter gene activity assay, and intracellular calcium assay. Results: An HEK293 cell line stably expressing human D1R was obtained. A saturation radioligand binding experiment with [3H]SCH23390 demonstrated that the Kd and Bmax values were 1.5±0.2 nmol/L and 2.94±0.15 nmol/g of protein, respectively. In the[3H]SCH23390 competition assay, D1R agonist SKF38393 displaced[3H]SCH23390 with an IC50 value of 2.0 (1.5-2.8) μmol/L. SKF38393 increased the intracellular cAMP level and CRE-SEAP activity through D1R expressed in HEK293 cells in a concentration-dependent manner with an EC50 value of 0.25(0.12-0.53) μmol/L and 0.39 (0.27-0.57) μmol/L at 6 h/0.59 (0.22-1.58) μmol/L at 12 h, respectively. SKF38393 also increased the intracellular calcium level in a concentration-dependent manner with EC50 value of 27 (8.6-70) nmol/L.Conclusion: An HEK293 cell line stably expressing human D1R was obtained successfuly. The study also demonstrated that the CRE-SEAP activity assay could be substituted for the cAMP accumulation assay for measuring increase in cAMP levels. Thus, both intracellular calcium measurements and the CRE-SEAP activity assay are suitable for high-throughput screening in drug research.

  6. Oxidative stress causes renal dopamine D1 receptor dysfunction and salt-sensitive hypertension in Sprague-Dawley rats.

    Science.gov (United States)

    Banday, Anees A; Lau, Yuen-Sum; Lokhandwala, Mustafa F

    2008-02-01

    Renal dopamine plays an important role in maintaining sodium homeostasis and blood pressure (BP) during increased sodium intake. The present study was carried out to determine whether renal dopamine D1 receptor (D1R) dysfunction contributes to increase in salt sensitivity during oxidative stress. Male Sprague-Dawley rats, divided into various groups, received tap water (vehicle); 1% NaCl (high salt [HS]); L-buthionine sulfoximine (BSO), an oxidant; and HS plus BSO with or without Tempol, an antioxidant, for 12 days. Compared with vehicle, HS intake increased urinary dopamine production and decreased basal renal Na/K-ATPase activity but did not affect BP. BSO-treated rats exhibited oxidative stress and a mild increase in BP. In these rats, D1R expression and G protein coupling were reduced, and SKF38393, a D1R agonist, failed to inhibit Na/K-ATPase activity and promote sodium excretion. Concomitant administration of BSO and HS caused oxidative stress, D1R dysfunction, and a marked increase in BP. Although renal dopamine production was increased, it failed to reduce the basal Na/K-ATPase activity in these animals. Treatment of BSO plus HS rats with Tempol decreased oxidative stress and restored endogenous, as well as exogenous, D1R agonist-mediated Na/K-ATPase inhibition and normalized BP. In conclusion, during HS intake, the increased dopamine production via Na/K-ATPase inhibition prevents an increase in BP. During oxidative stress, D1R function is defective, and there is mild hypertension. However, in the presence of oxidative stress, HS intake causes marked elevation in BP, which results from a defective renal D1R function leading to the failure of dopamine to inhibit Na/K-ATPase and promote sodium excretion.

  7. Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice.

    Science.gov (United States)

    Thomsen, Morgane; Caine, Simon Barak

    2016-04-05

    Muscarinic and dopamine brain systems interact intimately, and muscarinic receptor ligands, like dopamine ligands, can modulate the reinforcing and discriminative stimulus (S(D)) effects of cocaine. To enlighten the dopamine/muscarinic interactions as they pertain to the S(D) effects of cocaine, we evaluated whether muscarinic M1, M2 or M4 receptors are necessary for dopamine D1 and/or D2 antagonist mediated modulation of the S(D) effects of cocaine. Knockout mice lacking M1, M2, or M4 receptors, as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. Effects of pretreatments with the dopamine D1 antagonist SCH 23390 and the dopamine D2 antagonist eticlopride were evaluated. In intact mice, both SCH 23390 and eticlopride attenuated the cocaine discriminative stimulus effect, as expected. SCH 23390 similarly attenuated the cocaine discriminative stimulus effect in M1 knockout mice, but not in mice lacking M2 or M4 receptors. The effects of eticlopride were comparable in each knockout strain. These findings demonstrate differences in the way that D1 and D2 antagonists modulate the S(D) effects of cocaine, D1 modulation being at least partially dependent upon activity at the inhibitory M2/M4 muscarinic subtypes, while D2 modulation appeared independent of these systems.

  8. Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.

    Science.gov (United States)

    Moreno, Estefanía; Moreno-Delgado, David; Navarro, Gemma; Hoffmann, Hanne M; Fuentes, Silvia; Rosell-Vilar, Santi; Gasperini, Paola; Rodríguez-Ruiz, Mar; Medrano, Mireia; Mallol, Josefa; Cortés, Antoni; Casadó, Vicent; Lluís, Carme; Ferré, Sergi; Ortiz, Jordi; Canela, Enric; McCormick, Peter J

    2014-03-05

    The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.

  9. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    Science.gov (United States)

    Steinberg, Elizabeth E; Boivin, Josiah R; Saunders, Benjamin T; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2014-01-01

    The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS), a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA) dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc), a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  10. Positive reinforcement mediated by midbrain dopamine neurons requires D1 and D2 receptor activation in the nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Elizabeth E Steinberg

    Full Text Available The neural basis of positive reinforcement is often studied in the laboratory using intracranial self-stimulation (ICSS, a simple behavioral model in which subjects perform an action in order to obtain exogenous stimulation of a specific brain area. Recently we showed that activation of ventral tegmental area (VTA dopamine neurons supports ICSS behavior, consistent with proposed roles of this neural population in reinforcement learning. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. Here, we examine in transgenic rats whether dopamine neuron-specific ICSS relies on the connection between the VTA and the nucleus accumbens (NAc, a brain region also implicated in positive reinforcement. We find that optogenetic activation of dopaminergic terminals innervating the NAc is sufficient to drive ICSS, and that ICSS driven by optical activation of dopamine neuron somata in the VTA is significantly attenuated by intra-NAc injections of D1 or D2 receptor antagonists. These data demonstrate that the NAc is a critical efferent target sustaining dopamine neuron-specific ICSS, identify receptor subtypes through which dopamine acts to promote this behavior, and ultimately help to refine our understanding of the neural circuitry mediating positive reinforcement.

  11. Effects of dopamine D1 and D2 receptor antagonists on laryngeal neurophysiology in the rat.

    Science.gov (United States)

    Feng, Xin; Henriquez, Victor M; Walters, Judith R; Ludlow, Christy L

    2009-08-01

    Hypophonia is an early symptom in Parkinson's disease (PD) that involves an increase in laryngeal muscle activity, interfering with voice production. Our aim was to use an animal model to better understand the role of different dopamine receptor subtypes in the control of laryngeal neurophysiology. First, we evaluated the combined effects of SCH23390-a D(1) receptor antagonist with a D(2) receptor antagonist (eticlopride) on laryngeal neurophysiology, and then tested the separate effects of selective receptor antagonists. Thyroarytenoid (TA) and gastrocnemius (GN) muscle activity was measured at rest and while stimulating the internal branch of superior laryngeal nerve to elicit the laryngeal adductor response (LAR) in alpha-chloralose-anesthetized rats. Paired stimuli at different interstimulus intervals between 250 and 5,000 ms measured central conditioning of the LAR. Changes in resting muscle activity, response latency, amplitude, and LAR conditioning after each drug were compared with the saline control. SCH23390 alone increased the resting TA muscle activity (P < 0.05). With the combined SCH23390 + eticlopride or SCH23390 alone, response latency decreased (P < 0.01), amplitude increased (P < 0.01), and the test LAR was reduced at 2,000-ms ISI (P < 0.01). No LAR changes occurred when eticlopride was administered alone at a low dose and only a tendency to suppress responses was found at a high dose. No changes in GN muscle activity occurred in any of the groups. The results suggest that a loss of stimulation of D(1) receptors plays a significant role in laryngeal pathophysiology in PD.

  12. Dopamine D1 receptor stimulation modulates the formation and retrieval of novel object recognition memory: Role of the prelimbic cortex.

    Science.gov (United States)

    Pezze, Marie A; Marshall, Hayley J; Fone, Kevin C F; Cassaday, Helen J

    2015-11-01

    Previous studies have shown that dopamine D1 receptor antagonists impair novel object recognition memory but the effects of dopamine D1 receptor stimulation remain to be determined. This study investigated the effects of the selective dopamine D1 receptor agonist SKF81297 on acquisition and retrieval in the novel object recognition task in male Wistar rats. SKF81297 (0.4 and 0.8 mg/kg s.c.) given 15 min before the sampling phase impaired novel object recognition evaluated 10 min or 24 h later. The same treatments also reduced novel object recognition memory tested 24 h after the sampling phase and when given 15 min before the choice session. These data indicate that D1 receptor stimulation modulates both the encoding and retrieval of object recognition memory. Microinfusion of SKF81297 (0.025 or 0.05 μg/side) into the prelimbic sub-region of the medial prefrontal cortex (mPFC) in this case 10 min before the sampling phase also impaired novel object recognition memory, suggesting that the mPFC is one important site mediating the effects of D1 receptor stimulation on visual recognition memory.

  13. Methamphetamine induces dopamine D1 receptor-dependent endoplasmic reticulum stress-related molecular events in the rat striatum.

    Directory of Open Access Journals (Sweden)

    Subramaniam Jayanthi

    Full Text Available Methamphetamine (METH is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide

  14. The dopamine and cannabinoid interaction in the modulation of emotions and cognition: Assessing the role of cannabinoid CB1 receptor in neurons expressing dopamine D1 receptors

    Directory of Open Access Journals (Sweden)

    Ana Luisa eTerzian

    2011-08-01

    Full Text Available Although cannabinoid CB1 receptors (CB1Rs are densely expressed in neurons expressing dopamine D1 receptors (D1Rs, it is not fully understood to what extent they modulate emotional behaviors. We used conditional CB1R knock-out animals lacking CB1Rs in neurons expressing D1R (D1-CB1-/- in order to answer this question. To elucidate the behavioral effects of CB1R deficiency in this specific neuronal subpopulation, we subjected D1-CB1-/- mice to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, social behavior and fear-related memory paradigms. D1-CB1-/- did not show any difference in the exploration-based paradigms such as open field, elevated plus maze or novel object investigation test, except for an increase in novelty-induced grooming. By contrast, they showed a mild anhedonia-like state as described by the slightly decreased preference for sweet solution, as compared to wild-type control (WT group. This decrease, however, could be observed only during the first day of exposure, thus suggesting increased neophobia as an alternative explanation. Accordingly, mutant mice performed normally in the forced swim test, a procedure widely used for evaluating behavioral despair in rodents. However, weak- to moderate anxiety-like phenotypes were evident when D1-CB1-/- mice were tested for social behavior. Most strikingly, D1-CB1-/- mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within session extinction, suggesting that a specific reduction of endocannabinoid signaling in neurons expressing dopamine D1Rs is able to affect acute fear adaptation. These results provided first direct evidence for a cross-talk between dopaminergic D1Rs and endocannabinoid system in terms of controlling negative affect.

  15. Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

    Science.gov (United States)

    Cueva, J.P.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.

    2012-01-01

    Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

  16. Novel role of sorting nexin 5 in renal D(1) dopamine receptor trafficking and function: implications for hypertension.

    Science.gov (United States)

    Villar, Van Anthony M; Armando, Ines; Sanada, Hironobu; Frazer, Lauren C; Russo, Christen M; Notario, Patricia M; Lee, Hewang; Comisky, Lauren; Russell, Holly Ann; Yang, Yu; Jurgens, Julie A; Jose, Pedro A; Jones, John E

    2013-05-01

    The D1 dopamine receptor (D1R) is widely expressed in the kidney and plays a crucial role in blood pressure regulation. Although much is known about D1R desensitization, especially through G-protein-coupled receptor kinase 4 (GRK4), comparatively little is known about other aspects of D1R trafficking and the proteins involved in the process. We now report the discovery of a dynamic interaction between sorting nexin 5 (SNX5), a component of the mammalian retromer, and D1R in human renal epithelial cells. We show that internalization of agonist-activated D1R is regulated by both SNX5 and GRK4, and that SNX5 is critical to the recycling of the receptor to the plasma membrane. SNX5 depletion increases agonist-activated D1R phosphorylation (>50% at basal condition), prevents D1R internalization and cAMP response, and delays receptor recycling compared to mock siRNA-transfected controls. Moreover, renal restricted subcapsular infusion of Snx5-specific siRNA (vs. mock siRNA) decreases sodium excretion (Δ=-0.2±0.005 mEq/mg creatinine) and further elevates the systolic blood pressure (Δ=48±5 mm Hg) in spontaneously hypertensive rats, indicating that SNX5 depletion impairs renal D1R function. These studies demonstrate an essential role for SNX5 in regulating D1R function, which may have important diagnostic, prognostic, and therapeutic implications in the management of essential hypertension.

  17. Design, synthesis and preliminary evaluation of dopamine-amino acid conjugates as potential D1 dopaminergic modulators.

    Science.gov (United States)

    Tutone, Marco; Chinnici, Aurora; Almerico, Anna Maria; Perricone, Ugo; Sutera, Flavia Maria; De Caro, Viviana

    2016-11-29

    The dopamine-amino acid conjugate DA-Phen was firstly designed to obtain a useful prodrug for the therapy of Parkinson's disease, but experimental evidence shows that it effectively interacts with D1 dopamine receptors (D1DRs), leading to an enhancement in cognitive flexibility and to the development of adaptive strategies in aversive mazes, together with a decrease in despair-like behavior. In this paper, homology modelling, molecular dynamics, and site mapping of D1 receptor were carried out with the aim of further performing docking studies on other dopamine conjugates compared with D1 agonists, in the attempt to identify new compounds with potential dopaminergic activity. Two new conjugates (DA-Trp 2C, and DA-Leu 3C) have been identified as the most promising candidates, and consequently synthesized. Preliminary evaluation in terms of distribution coefficient (D(pH7.4)), stability in rat brain homogenate, and in human plasma confirmed that DA-Trp (2C), and DA-Leu (3C) could be considered as very valuable candidates for further in vivo studies as new dopaminergic drugs.

  18. A pair of dopamine neurons target the D1-like dopamine receptor DopR in the central complex to promote ethanol-stimulated locomotion in Drosophila.

    Directory of Open Access Journals (Sweden)

    Eric C Kong

    Full Text Available Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol.

  19. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

    Science.gov (United States)

    Tobón, Krishna E; Catuzzi, Jennifer E; Cote, Samantha R; Sonaike, Adenike; Kuzhikandathil, Eldo V

    2015-07-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals.

  20. Effect of dopamine, dopamine D-1 and D-2 receptor modulation on ACTH and cortisol levels in normal men and women

    DEFF Research Database (Denmark)

    Boesgaard, S; Hagen, C; Andersen, A N;

    1990-01-01

    The regulation of the hypothalamic-pituitary-adrenal axis by dopamine is not fully understood. Therefore, we have studied the effect of dopamine, metoclopramide, a D-2 receptor antagonist, and fenoldopam, a specific D-1 receptor agonist, on ACTH and cortisol levels in normal subjects. Normal women...... received 5-h infusions of either glucose (N = 6) or dopamine at rates of 0.04 (N = 6), 0.4 (N = 6) and 4.0 micrograms.kg-1.min-1 (N = 8). After 3 h, 10 mg metoclopramide was given iv. No intergroup differences regarding ACTH and cortisol levels were observed (p greater than 0.05). In a second study six...... women received dopamine (4.0 micrograms.kg-1.min-1) or glucose for 18 h. During the infusions cortisol and ACTH levels were similar on the two study days. Administration of metoclopramide (10 mg) after 17 h induced a significant increase in cortisol levels during dopamine infusion (p less than 0...

  1. PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation

    Institute of Scientific and Technical Information of China (English)

    Peihua Sun; Jingru Wang; Weihua Gu; Wei Cheng; Guo-zhang Jin; Eitan Friedman; Jie Zheng; Xuechu Zhen

    2009-01-01

    The present study aims to define the role of postsynaptic density (PSD)-95 in the regulation of dopamine (DA) receptor function. We found that PSD-95 physically associates with either D1 or D2 DA receptors in co-transfected HEK-293 cells. Stimulation of DA receptors altered the association between D1 receptor and PSD-95 in a time-depen-dent manner. Functional assays indicated that PSD-95 co-expression did not affect D1 receptor-stimulated cAMP pro-duction, Gs-protein activation or receptor desensitization. However, PSD-95 accelerated the recovery of internalized membrane receptors by promoting receptor recycling, thus resulting in enhanced resensitization of internalized D1 receptors. Our results provide a novel mechanism for regulating DA receptor recycling that may play an important role in postsynaptic DA functional modulation and synaptic neuroplasticity.

  2. Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder

    Directory of Open Access Journals (Sweden)

    Dudley Anne G

    2005-04-01

    Full Text Available Abstract Background Methylphenidate (MPH is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD, yet the mechanisms underlying its therapeutic actions remain unclear. Recent studies have identified an oral, MPH dose regimen which when given to rats produces drug plasma levels similar to those measured in humans. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC, a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. The receptor mechanisms underlying the enhancing effects of MPH were explored by challenging the MPH response with the noradrenergic α2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390. Results MPH produced an inverted U dose response whereby moderate doses (1.0–2.0 mg/kg, p.o. significantly improved delayed alternation performance, while higher doses (2.0–3.0 mg/kg, p.o. produced perseverative errors in many animals. The enhancing effects of MPH were blocked by co-administration of either the α2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own. Conclusion The administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic α2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.

  3. Evaluation of D1 and D2 dopamine receptor segregation in the developing striatum using BAC transgenic mice.

    Directory of Open Access Journals (Sweden)

    Dominic Thibault

    Full Text Available The striatum is predominantly composed of medium spiny neurons (MSNs that send their axons along two parallel pathways known as the direct and indirect pathways. MSNs from the direct pathway express high levels of D1 dopamine receptors, while MSNs from the indirect pathway express high levels of D2 dopamine receptors. There has been much debate over the extent of colocalization of these two major dopamine receptors in MSNs of adult animals. In addition, the ontogeny of the segregation process has never been investigated. In this paper, we crossed bacterial artificial chromosome drd1a-tdTomato and drd2-GFP reporter transgenic mice to characterize these models and estimate D1-D2 co-expression in the developing striatum as well as in striatal primary cultures. We show that segregation is already extensive at E18 and that the degree of co-expression further decreases at P0 and P14. Finally, we also demonstrate that cultured MSNs maintain their very high degree of D1-D2 reporter protein segregation, thus validating them as a relevant in vitro model.

  4. Synthesis of carbon-11 labelled SCH 39166, a new selective dopamine D-1 receptor ligand, and preliminary PET investigations

    Energy Technology Data Exchange (ETDEWEB)

    Halldin, Christer; Farde, Lars; Sedvall, Goeran (Karolinska Hospital, Stockholm (Sweden). Dept. of Psychiatry and Psychology); Barnett, Allen (Schering-Plough Corp., Bloomfield, NJ (USA))

    1991-01-01

    SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1-b)azepine ) is a new more selective dopamine D-1 receptor antagonist than the widely used SCH 23390. ({sup 11}C)SCH 39166 was prepared by N-methylation of the desmethyl compound SCH 40853 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo(d)naphtho -(2,1-b)azepine) with ({sup 11}C)methyl iodide. Reaction in acetone with subsequent straight-phase semi-preparative HPLC resulted in 20-30% radiochemical yield (from EOB and decay-corrected) with a total synthesis time of 35-40 min and a radiochemical purity >99%. The specific activity obtained at EOS was about 1500 Ci/mmol (55 GBq/{mu}mol). ({sup 11}C)SCH 39166 was injected into a Cynomolgus monkey. PET-analysis demonstrated accumulation in the striatum, a region known to have a high density of dopamine D-1 receptors. In a displacement experiment, radioactivity in the striatum was markedly reduced after injection of 6 mg unlabelled SCH 23390, thus demonstrating the specificity and reversibility of ({sup 11}C)SCH 39166 binding to dopamine D-1 receptors. (author).

  5. D1 dopamine receptor signaling is modulated by the R7 RGS protein EAT-16 and the R7 binding protein RSBP-1 in Caenoerhabditis elegans motor neurons.

    Directory of Open Access Journals (Sweden)

    Khursheed A Wani

    Full Text Available Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1 required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.

  6. D1 dopamine receptor signaling is modulated by the R7 RGS protein EAT-16 and the R7 binding protein RSBP-1 in Caenoerhabditis elegans motor neurons.

    Science.gov (United States)

    Wani, Khursheed A; Catanese, Mary; Normantowicz, Robyn; Herd, Muriel; Maher, Kathryn N; Chase, Daniel L

    2012-01-01

    Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior.

  7. Altered functioning of both renal dopamine D1 and angiotensin II type 1 receptors causes hypertension in old rats.

    Science.gov (United States)

    Chugh, Gaurav; Lokhandwala, Mustafa F; Asghar, Mohammad

    2012-05-01

    Activation of renal dopamine D1 (D1R) and angiotensin II type 1 receptors (AT(1)Rs) influences the activity of proximal tubular sodium transporter Na,K-ATPase and maintains sodium homeostasis and blood pressure. We reported recently that diminished D1R and exaggerated AT(1)R functions are associated with hypertension in old Fischer 344 × Brown Norway F1 (FBN) rats, and oxidative stress plays a central role in this phenomenon. Here we studied the mechanisms of age-associated increase in oxidative stress on diminished D1R and exaggerated AT(1)R functions in the renal proximal tubules of control and antioxidant Tempol-treated adult and old FBN rats. Although D1R numbers and D1R agonist SKF38393-mediated stimulation of [(35)S]-GTPγS binding (index of D1R activation) were lower, G protein-coupled receptor kinase 4 (kinase that uncouples D1R) levels were higher in old FBN rats. Tempol treatment restored D1R numbers and G protein coupling and reduced G protein-coupled receptor kinase 4 levels in old FBN rats. Angiotensin II-mediated stimulation of [(35)S]-GTPγS binding and Na,K-ATPase activity were higher in old FBN rats, which were also restored with Tempol treatment. We also measured renal AT(1)R function in adult and old Fischer 344 (F344) rats, which, despite exhibiting an age-related increase in oxidative stress and diminished renal D1R function, are normotensive. We found that diuretic and natriuretic responses to candesartan (indices of AT(1)R function) were similar in F344 rats, a likely explanation for the absence of age-associated hypertension in these rats. Perhaps, alterations in both D1R (diminished) and AT(1)R (exaggerated) functions are necessary for the development of age-associated hypertension, as seen in old FBN rats.

  8. Requirement of PSD-95 for dopamine D1 receptor modulating glutamate NR1a/NR2B receptor function

    Institute of Scientific and Technical Information of China (English)

    Wei-hua GU; Shen YANG; Wei-xing SHI; Guo-zhang JIN; Xue-chu ZHEN

    2007-01-01

    Aim: To elucidate the role of scaffold protein postsynaptic density (PSD)-95 in the dopamine D1 receptor (D1R)-modulated NR 1a/NR2B receptor response.Methods: The human embryonic kidney 293 cells expressing D1R (tagged with the enhanced yellow fluorescent protein) and NR1a/NR2B with or without co-expres-sion of PSD-95 were used in the experiments. The Ca2+ influx measured by imaging technique was employed to monitor N-methyl-D-aspartic acid receptors (NMDAR) function.Results: The application of dopamine (DA, 100 μmol/L) did not alter glutamate/glycine (Glu/Gly)-induced NMDAR-mediated Ca2+ influx in cells only expressing the D1R/NR1a/NR2B receptor. However, DA increased Glu/Gly-induced Ca2+ influx in a concentration-dependent manner while the cells were co-expressed with PSD-95. D1.R-stimulated Ca2+ influx was inhibited by a selective DIR antagonist SCH23390. Moreover, pre-incubation with either the protein kinase A (PKA) inhibitor H89, or the protein kinase C (PKC) inhibitor chelerythrine attenuated D1R-enhanced Ca2+ influx induced by the N-methyl-D-aspartie acid (NMDA) agonist. The results clearly indicate that D1R-modulated NR1a/NR2B receptor function depends on PSD-95 and is subjected to the regulation of PKA and PKC.Conclusion: The present study provides the fast evidence that PSD-95 is essential in D iR-regulated NR1a/NR2B receptor function.

  9. Adolescent changes in dopamine D1 receptor expression in orbitofrontal cortex and piriform cortex accompany an associative learning deficit.

    Science.gov (United States)

    Garske, Anna K; Lawyer, Chloe R; Peterson, Brittni M; Illig, Kurt R

    2013-01-01

    The orbitofrontal cortex (OFC) and piriform cortex are involved in encoding the predictive value of olfactory stimuli in rats, and neural responses to olfactory stimuli in these areas change as associations are learned. This experience-dependent plasticity mirrors task-related changes previously observed in mesocortical dopamine neurons, which have been implicated in learning the predictive value of cues. Although forms of associative learning can be found at all ages, cortical dopamine projections do not mature until after postnatal day 35 in the rat. We hypothesized that these changes in dopamine circuitry during the juvenile and adolescent periods would result in age-dependent differences in learning the predictive value of environmental cues. Using an odor-guided associative learning task, we found that adolescent rats learn the association between an odor and a palatable reward significantly more slowly than either juvenile or adult rats. Further, adolescent rats displayed greater distractibility during the task than either juvenile or adult rats. Using real-time quantitative PCR and immunohistochemical methods, we observed that the behavioral deficit in adolescence coincides with a significant increase in D1 dopamine receptor expression compared to juvenile rats in both the OFC and piriform cortex. Further, we found that both the slower learning and increased distractibility exhibited in adolescence could be alleviated by experience with the association task as a juvenile, or by an acute administration of a low dose of either the dopamine D1 receptor agonist SKF-38393 or the D2 receptor antagonist eticlopride. These results suggest that dopaminergic modulation of cortical function may be important for learning the predictive value of environmental stimuli, and that developmental changes in cortical dopaminergic circuitry may underlie age-related differences in associative learning.

  10. Adolescent changes in dopamine D1 receptor expression in orbitofrontal cortex and piriform cortex accompany an associative learning deficit.

    Directory of Open Access Journals (Sweden)

    Anna K Garske

    Full Text Available The orbitofrontal cortex (OFC and piriform cortex are involved in encoding the predictive value of olfactory stimuli in rats, and neural responses to olfactory stimuli in these areas change as associations are learned. This experience-dependent plasticity mirrors task-related changes previously observed in mesocortical dopamine neurons, which have been implicated in learning the predictive value of cues. Although forms of associative learning can be found at all ages, cortical dopamine projections do not mature until after postnatal day 35 in the rat. We hypothesized that these changes in dopamine circuitry during the juvenile and adolescent periods would result in age-dependent differences in learning the predictive value of environmental cues. Using an odor-guided associative learning task, we found that adolescent rats learn the association between an odor and a palatable reward significantly more slowly than either juvenile or adult rats. Further, adolescent rats displayed greater distractibility during the task than either juvenile or adult rats. Using real-time quantitative PCR and immunohistochemical methods, we observed that the behavioral deficit in adolescence coincides with a significant increase in D1 dopamine receptor expression compared to juvenile rats in both the OFC and piriform cortex. Further, we found that both the slower learning and increased distractibility exhibited in adolescence could be alleviated by experience with the association task as a juvenile, or by an acute administration of a low dose of either the dopamine D1 receptor agonist SKF-38393 or the D2 receptor antagonist eticlopride. These results suggest that dopaminergic modulation of cortical function may be important for learning the predictive value of environmental stimuli, and that developmental changes in cortical dopaminergic circuitry may underlie age-related differences in associative learning.

  11. [sup 123]I-SCH 23982 is not suitable for dopamine D1 receptor imaging in vivo in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Verhoeff, N.P.L.G.; Fennema, P.; Royen, E.A. van (Academic Medical Centre, Amsterdam (Netherlands). Dept. of Nuclear Medicine); Bekier, A. (Kantonsspital, St Gallen (Switzerland). Inst. for Nuclear Medicine); Beer, H.-F.; Schubiger, P.A. (Paul Scherrer Inst. (PSI), Villigen (Switzerland))

    1993-02-01

    The tracer [sup 123]I-SCH 23982 was tested with regard to its ability to image dopamine D1 receptor in the human brain in vivo with single photon emission computed tomography (SPECT). The tracer did not reach equilibrium with regard to its bindign to dopamine D1 receptors, presumably owing to fast metabolism to hydrophilic products and deiodination. It is concluded that [sup 123]I-SCH 23982 is not suitable for dopamine D1 receptor imaging with SPECT in the human brain. (author).

  12. Altered ratio of D1 and D2 dopamine receptors in mouse striatum is associated with behavioral sensitization to cocaine.

    Directory of Open Access Journals (Sweden)

    Dawn Thompson

    Full Text Available BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT and G protein coupled receptor associated sorting protein-1 (GASP-1 knock out (KO mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization.

  13. Augmented D1 dopamine receptor signaling and immediate-early gene induction in adult striatum following prenatal cocaine

    Science.gov (United States)

    Tropea, Thomas F.; Guerriero, Réjean M.; Willuhn, Ingo; Unterwald, Ellen M.; Ehrlich, Michelle E.; Steiner, Heinz; Kosofsky, Barry E.

    2009-01-01

    Background Prenatal exposure to cocaine can impede normal brain development triggering a range of neuroanatomical and behavioral anomalies that are evident throughout life. Mouse models have been especially helpful in delineating neuro-teratogenic consequences following prenatal exposure tococaine. The present study employed a mouse model to investigate alterations in D1 dopamine receptor signaling and downstream immediate-early gene induction in the striatum of mice exposed to cocaine in utero. Methods Basal, forskolin- and D1 receptor agonist-induced cAMP levels were measured ex vivo in the adult male striatum in mice exposed to cocaine in utero. Further studies assessed cocaine-induced zif 268 and homer 1 expression in the striatum of juvenile (P15), adolescent (P36), and adult (P60) male mice. Results The D1 dopamine receptor agonist SKF82958 induced significantly higher levels of cAMP in adult male mice treated with cocaine in utero compared to saline controls. No effects of the prenatal treatment were found for cAMP formation induced by forskolin. Following an acute cocaine challenge (15 mg/kg, i.p.), these mice showed greater induction of zif 268 and homer 1, an effect that was most robust in the medial part of the mid-level striatum and became more pronounced with increasing age. Conclusions Together these findings indicate abnormally enhanced D1 receptor signal transduction in adult mice following prenatal cocaine exposure. Such changes in dopamine receptor signaling may underlie aspects of long-lasting neuro-teratogenic effects evident in some humans following in utero exposure to cocaine, and identify the striatum as one target potentially vulnerable to gestational cocaine exposure. PMID:18275938

  14. Involvement of dopamine D1/D5 and D2 receptors in context-dependent extinction learning and memory reinstatement

    Directory of Open Access Journals (Sweden)

    Marion Agnes Emma Andre

    2016-01-01

    Full Text Available Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context ‘A’ to associate a goal arm with a food reward, despite low reward probability (acquisition phase. On day 4, extinction learning (unrewarded occurred, that was reinforced by a context change (‘B’. On day 5, re-exposure to the (unrewarded ‘A’-context took place (renewal of context ‘A’, followed by extinction of context ‘A’. In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context ‘B’. By contrast, a D1/D5-agonist impaired renewal in context ’A’. Extinction in the ‘A’ context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context ‘B or renewal in context ‘A’, although extinction of the renewal effect was impaired on day 5, compared to controls.Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning.

  15. Involvement of Dopamine D1/D5 and D2 Receptors in Context-Dependent Extinction Learning and Memory Reinstatement

    Science.gov (United States)

    André, Marion Agnès Emma; Manahan-Vaughan, Denise

    2016-01-01

    Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context “A”) to associate a goal arm with a food reward, despite low reward probability (acquisition phase). On day 4, extinction learning (unrewarded) occurred, that was reinforced by a context change (“B”). On day 5, re-exposure to the (unrewarded) “A” context took place (renewal of context “A”, followed by extinction of context “A”). In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal) on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context “B”. By contrast, a D1/D5-agonist impaired renewal in context “A”. Extinction in the “A” context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context “B” or renewal in context “A”, although extinction of the renewal effect was impaired on day 5, compared to controls. Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning. PMID:26834599

  16. The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model­

    Science.gov (United States)

    VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K.; Karel, Peter; Shan, Ling; van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R.; Cuppen, Edwin; Ellenbroek, Bart A.

    2016-01-01

    ABSTRACT Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. PMID:27483345

  17. Dopamine D2/D3 but not dopamine D1 receptors are involved in the rapid antidepressant-like effects of ketamine in the forced swim test.

    Science.gov (United States)

    Li, Yan; Zhu, Zhuo R; Ou, Bao C; Wang, Ya Q; Tan, Zhou B; Deng, Chang M; Gao, Yi Y; Tang, Ming; So, Ji H; Mu, Yang L; Zhang, Lan Q

    2015-02-15

    Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine.

  18. Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

    Science.gov (United States)

    Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

    2016-07-01

    Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

  19. Dopamine D1 and D2 receptor ligands modulate the behaviour of mice in the elevated plus-maze.

    Science.gov (United States)

    Rodgers, R J; Nikulina, E M; Cole, J C

    1994-12-01

    To further our understanding of the potential role of dopamine in mechanisms of anxiety, the effects of four dopamine receptor ligands were examined in an ethological version of the murine elevated plus-maze test. The D1 receptor partial agonist, SKF 38393 (2.5-20.0 mg/kg), had minimal behavioural activity in this test, whereas the selective D1 receptor antagonist, SCH 23390 (0.025-0.2 mg/kg), had dose-dependent but behaviourally nonspecific effects. Quinpirole (0.0625-0.5 mg/kg), a D2 receptor agonist, had no effects at low doses but severely disrupted locomotion and exploration at the highest doses tested. In marked contrast to the lack of effect or nonspecific effects seen with the other ligands tested, the D2 receptor antagonist, sulpiride (2.5-20.0 mg/kg), produced an unambiguous anxiolytic-like profile under present test conditions. Although none of the doses tested adversely affected general activity, clear antianxiety effects were observed on both traditional and novel (i.e., risk assessment) behavioural measures. Data are discussed in relation to the relative importance of D1 and D2 receptor mechanisms in plus-maze anxiety, and the need to further assess D2 involvement through the use of more selective compounds.

  20. PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation.

    Science.gov (United States)

    Karunakaran, Smitha; Chowdhury, Ananya; Donato, Flavio; Quairiaux, Charles; Michel, Christoph M; Caroni, Pico

    2016-03-01

    Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.

  1. 1-Stepholidine increases the frequency of sEPSC via the activation of D1 dopamine signaling pathway in rat prelimbic cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Ming GAO; Chang-liang LIU; Shen YANG; Xue-chu ZHEN; Guo-zhang JIN

    2007-01-01

    Aim: To investigate the effect ofl-stepholidine (SPD) on the frequency of spon-taneous excitatory postsynaptic currents (sEPSC) in the pyramidal cells between layers Ⅴ and Ⅵ in the prelimbic cortex (PL). Methods: A whole-cell patch clamp in rat brain slices was used. Results: SPD significantly increased the frequency of sEPSC in a concentration-dependent manner. A selective D1 dopamine receptor antagonist SCH23390 blocked SPD-mediated effects, whereas the D1 agonist SKF38393, but not the D2/3 antagonist sulpiride, mimicked SPD-mediated increase in the frequency of sEPSC. Moreover, both protein kinase A (PKA) inhibitor N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide hydrochloride and protein kinase C (PKC) inhibitor chelerythrine attenuated the effect of SPD on sEPSC. Conclusion: SPD elicits its effect on the frequency of sEPSC on the PL pyramidal cells via presynaptic D1 receptors, and is dependent on PKA and PKC signaling pathways.

  2. Berberine is a dopamine D1- and D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immune responses.

    Science.gov (United States)

    Kawano, Masaaki; Takagi, Rie; Kaneko, Atsushi; Matsushita, Sho

    2015-12-15

    Berberine is an herbal alkaloid with various biological activities, including anti-inflammatory and antidepressant effects. Here, we examined the effects of berberine on dopamine receptors and the ensuing anti-inflammatory responses. Berberine was found to be an antagonist at both dopamine D1- and D2-like receptors and ameliorates the development of experimentally induced colitis in mice. In lipopolysaccharide-stimulated immune cells, berberine treatment modified cytokine levels, consistent with the effects of the dopamine receptor specific antagonists SCH23390 and L750667. Our findings indicate that dopamine receptor antagonists suppress innate and adaptive immune responses, providing a foundation for their use in combatting inflammatory diseases.

  3. Investigation of the association between dopamine D1 receptor gene polymorphisms and essential hypertension in a group of Turkish subjects.

    Science.gov (United States)

    Orun, Oya; Nacar, Cevdet; Cabadak, Hülya; Tiber, Pınar Mega; Doğan, Yüksel; Güneysel, Özlem; Fak, Ali Serdar; Kan, Beki

    2011-01-01

    Dopamine has been shown to influence blood pressure by regulating renal sodium excretion through direct interaction with the dopamine receptors, especially with the Dopamine D1 receptor (DRD1). To better understand the role of polymorphisms in those effects, we investigated the association between two polymorphic sites in the DRD1 promoter region (A-48G, G-94A) and essential hypertension in the Turkish population. The DRD1 variants were genotyped by restriction fragment length polymorphism (RFLP) analysis. A total of 205 unrelated individuals were enrolled in the study. We found that genotype distributions and allele frequencies of the control and hypertensive subjects were very similar and did not show any significant difference with respect to blood pressure (BP) and hypertension. Contribution of the gene variances in BP or hypertension by sex differences and dependence on body mass index (BMI) were also evaluated. Distribution of genotypes and allele frequencies were found to be in line with previous reports. However, increments detected in hypertensive subjects were far from being statistically significant.

  4. Dopamine D1 Receptor-Mediated Transmission Maintains Information Flow Through the Cortico-Striato-Entopeduncular Direct Pathway to Release Movements.

    Science.gov (United States)

    Chiken, Satomi; Sato, Asako; Ohta, Chikara; Kurokawa, Makoto; Arai, Satoshi; Maeshima, Jun; Sunayama-Morita, Tomoko; Sasaoka, Toshikuni; Nambu, Atsushi

    2015-12-01

    In the basal ganglia (BG), dopamine plays a pivotal role in motor control, and dopamine deficiency results in severe motor dysfunctions as seen in Parkinson's disease. According to the well-accepted model of the BG, dopamine activates striatal direct pathway neurons that directly project to the output nuclei of the BG through D1 receptors (D1Rs), whereas dopamine inhibits striatal indirect pathway neurons that project to the external pallidum (GPe) through D2 receptors. To clarify the exact role of dopaminergic transmission via D1Rs in vivo, we developed novel D1R knockdown mice in which D1Rs can be conditionally and reversibly regulated. Suppression of D1R expression by doxycycline treatment decreased spontaneous motor activity and impaired motor ability in the mice. Neuronal activity in the entopeduncular nucleus (EPN), one of the output nuclei of the rodent BG, was recorded in awake conditions to examine the mechanism of motor deficits. Cortically evoked inhibition in the EPN mediated by the cortico-striato-EPN direct pathway was mostly lost during suppression of D1R expression, whereas spontaneous firing rates and patterns remained unchanged. On the other hand, GPe activity changed little. These results suggest that D1R-mediated dopaminergic transmission maintains the information flow through the direct pathway to appropriately release motor actions.

  5. Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children

    Institute of Scientific and Technical Information of China (English)

    ICTsai; CHLee; CCKuo; HTHsu; YALi; CITsai

    2005-01-01

    Objective Recent research suggests that Tourette's syndrome (TS) may result from a defect in the dopamine system. The dopamine 1 receptor (DRD 1) gene is a candidate gene in the study of the etiology of neuropsychiatric diseases that may involve dopaminergic abnormalities. We sought to test the hypothesis that the DRD 1 gene might play a role in TS.Methods By performing an association study, we collected an independent sample of patients from the midland region of Taiwan and investigated whether DRD 1 gene polymorphisms can be used as markers of susceptibility to TS. A total of 148 children with TS and 83 normal control subjects were included in the study. A polymerase chain reaction was used to identify the A/G polymorphism of the DRD 1 gene. Genotypes and allelic frequencies for the DRD 1 gene polymorphisms in both groups were compared.Results The results showed that genotypes and allelic frequencies for the DRD 1 gene polymorphisms in both groups were not significantly different.Conclusion These data suggest that DRD 1 gene may not be a useful marker for prediction of the susceptibility of TS.

  6. Coincident activation of NMDA and dopamine D1 receptors within the nucleus accumbens core is required for appetitive instrumental learning.

    Science.gov (United States)

    Smith-Roe, S L; Kelley, A E

    2000-10-15

    The nucleus accumbens, a brain structure ideally situated to act as an interface between corticolimbic information-processing regions and motor output systems, is well known to subserve behaviors governed by natural reinforcers. In the accumbens core, glutamatergic input from its corticolimbic afferents and dopaminergic input from the ventral tegmental area converge onto common dendrites of the medium spiny neurons that populate the accumbens. We have previously found that blockade of NMDA receptors in the core with the antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol) abolishes acquisition but not performance of an appetitive instrumental learning task (Kelley et al., 1997). Because it is currently hypothesized that concurrent dopamine D(1) and glutamate receptor activation is required for long-term changes associated with plasticity, we wished to examine whether the dopamine system in the accumbens core modulates learning via NMDA receptors. Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect. Infusion of the combined low doses had no effect on indices of feeding and motor activity, suggesting a specific effect on learning. We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning. Such an interaction is likely to promote intracellular events and gene regulation necessary for synaptic plasticity and is supported by a number of cellular models.

  7. Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population

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    Yao J

    2014-04-01

    Full Text Available Jun Yao, Mei Ding, Jiaxin Xing, Jinfeng Xuan, Hao Pang, Yuqing Pan, Baojie WangInstitute of Forensic Medicine, China Medical University, Shenyang, People's Republic of ChinaObjective: Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia.Materials and methods: We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls.Results: A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction.Conclusion: It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted.Keywords: dopamine D1 receptor, paranoid schizophrenic, single-nucleotide study, association, genetic

  8. Intrahippocampal administration of D2 but not D1 dopamine receptor antagonist suppresses the expression of conditioned place preference induced by morphine in the ventral tegmental area.

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    Haghparast, Abbas; Esmaeili, Mohammad-Hossein; Taslimi, Zahra; Kermani, Mojtaba; Yazdi-Ravandi, Saeid; Alizadeh, Amir-Mohammad

    2013-04-29

    The ventral tegmental area (VTA) as a major source of dopamine neurons projecting to cortical and limbic regions has a crucial role in reward and addiction. The current study assessed the role of D1 and D2 receptors within the dorsal hippocampus (CA1) in the expression of conditioned place preference (CPP) by intra-VTA morphine in the rats. In the present study, 160 adult male albino Wistar rats weighing 220-290g were bilaterally implanted by two cannulae into the CA1 and VTA. The CPP paradigm was done and animal displacement, conditioning score and locomotor activity were recorded. For blocking the dopamine D1/D2 receptors in the dorsal hippocampus, SCH23390 (0.02, 0.05, 0.2 and 0.5μg per side) or sulpiride (0.25, 0.75, 1.5 and 3μg per side) were microinjected into the CA1, just 5min before the CPP test on the post-conditioning day. All animals received intra-VTA morphine (1μg per side) during 3-days conditioning phase. Our results showed that sulpiride (1.5 and 3μg) but not SCH23390 in the dorsal hippocampus significantly decreased the expression of CPP induced by intra-VTA morphine (phippocampus have a key role in the expression of CPP induced by morphine at the level of the VTA and there is a relationship between dopaminergic D2 receptors and opioidergic systems in these areas in reward circuit.

  9. Distinct motor impairments of dopamine D1 and D2 receptor knockout mice revealed by three types of motor behavior

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    Toru eNakamura

    2014-07-01

    Full Text Available Both D1R and D2R knock out (KO mice of the major dopamine receptors show significant motor impairments. However, there are some discrepant reports, which may be due to the differences in genetic background and experimental procedures. In addition, only few studies directly compared the motor performance of D1R and D2R KO mice. In this paper, we examined the behavioral difference among N10 congenic D1R and D2R KO, and wild type (WT mice. First, we examined spontaneous motor activity in the home cage environment for consecutive five days. Second, we examined motor performance using the rota-rod task, a standard motor task in rodents. Third, we examined motor ability with the Step-Wheel task in which mice were trained to run in a motor-driven turning wheel adjusting their steps on foothold pegs to drink water. The results showed clear differences among the mice of three genotypes in three different types of behavior. In monitoring spontaneous motor activities, D1R and D2R KO mice showed higher and lower 24 h activities, respectively, than WT mice. In the rota-rod tasks, at a low speed, D1R KO mice showed poor performance but later improved, whereas D2R KO mice showed a good performance at early days without further improvement. When first subjected to a high speed task, the D2R KO mice showed poorer rota-rod performance at a low speed than the D1R KO mice. In the Step-Wheel task, across daily sessions, D2R KO mice increased the duration that mice run sufficiently close to the spout to drink water, and decreased time to touch the floor due to missing the peg steps and number of times the wheel was stopped, which performance was much better than that of D1R KO mice. These incongruent results between the two tasks for D1R and D2R KO mice may be due to the differences in the motivation for the rota-rod and Step-Wheel tasks, aversion- and reward-driven, respectively. The Step-Wheel system may become a useful tool for assessing the motor ability of WT

  10. Mechanism for cocaine blocking the transport of dopamine: insights from molecular modeling and dynamics simulations.

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    Huang, Xiaoqin; Gu, Howard H; Zhan, Chang-Guo

    2009-11-12

    Molecular modeling and dynamics simulations have been performed to study how cocaine inhibits dopamine transporter (DAT) for the transport of dopamine. The computationally determined DAT-ligand binding mode is totally different from the previously proposed overlap binding mode in which cocaine- and dopamine-binding sites are the same (Beuming, T.; et al. Nat. Neurosci. 2008, 11, 780-789). The new cocaine-binding site does not overlap with, but is close to, the dopamine-binding site. Analysis of all results reveals that when cocaine binds to DAT, the initial binding site is likely the one modeled in this study because this binding site can naturally accommodate cocaine. Then cocaine may move to the dopamine-binding site after DAT makes some necessary conformational change and expands the binding site cavity. It has been demonstrated that cocaine may inhibit the transport of dopamine through both blocking the initial DAT-dopamine binding and reducing the kinetic turnover of the transporter following the DAT-dopamine binding. The relative contributions to the phenomenological inhibition of the transport of dopamine from blocking the initial binding and reducing the kinetic turnover can be different in different types of assays. The obtained general structural and mechanistic insights are consistent with available experimental data and could be valuable for guiding future studies toward understanding cocaine's inhibiting of other transporters.

  11. Modulation of Postnatal Neurogenesis by Perinatal Asphyxia: Effect of D1 and D2 Dopamine Receptor Agonists.

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    Tapia-Bustos, A; Perez-Lobos, R; Vío, V; Lespay-Rebolledo, C; Palacios, E; Chiti-Morales, A; Bustamante, D; Herrera-Marschitz, M; Morales, P

    2017-01-01

    Perinatal asphyxia (PA) is associated to delayed cell death, affecting neurocircuitries of basal ganglia and hippocampus, and long-term neuropsychiatric disabilities. Several compensatory mechanisms have been suggested to take place, including cell proliferation and neurogenesis. There is evidence that PA can increase postnatal neurogenesis in hippocampus and subventricular zone (SVZ), modulated by dopamine, by still unclear mechanisms. We have studied here the effect of selective dopamine receptor agonists on cell death, cell proliferation and neurogenesis in organotypic cultures from control and asphyxia-exposed rats. Hippocampus and SVZ sampled at 1-3 postnatal days were cultured for 20-21 days. At day in vitro (DIV) 19, cultures were treated either with SKF38393 (10 and 100 µM, a D1 agonist), quinpirole (10 µM, a D2 agonist) or sulpiride (10 μM, a D2 antagonist) + quinpirole (10 μM) and BrdU (10 μM, a mitosis marker) for 24 h. At DIV 20-21, cultures were processed for immunocytochemistry for microtubule-associated protein-2 (MAP-2, a neuronal marker), and BrdU, evaluated by confocal microscopy. Some cultures were analysed for cell viability at DIV 20-21 (LIVE/DEAD kit). PA increased cell death, cell proliferation and neurogenesis in hippocampus and SVZ cultures. The increase in cell death, but not in cell proliferation, was inhibited by both SKF38393 and quinpirole treatment. Neurogenesis was increased by quinpirole, but only in hippocampus, in cultures from both asphyxia-exposed and control-animals, effect that was antagonised by sulpiride, leading to the conclusion that dopamine modulates neurogenesis in hippocampus, mainly via D2 receptors.

  12. 5' UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism.

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    Kim, Dai-Jin; Park, Byung Lae; Yoon, Sujung; Lee, Hae-Kook; Joe, Keun-Ho; Cheon, Young-Hoon; Gwon, Do-Hoon; Cho, Sung-Nam; Lee, Hye Won; NamGung, Suk; Shin, Hyoung Doo

    2007-06-15

    Multiple dopamine receptors in the dopaminergic system may be prime candidates for genetic influence on alcohol abuse and dependence due to their involvement in reward and reinforcing mechanisms. Genetic polymorphisms in dopamine receptor genes are believed to influence the development and/or severity of alcoholism. To examine the genetic effects of the Dopamine Receptor D1 (DRD) gene family (DRD1-DRD5) in the Korean population, 11 polymorphisms in the DRD gene family were genotyped and analyzed in 535 alcohol-dependent subjects and 273 population controls. Although none of the polymorphisms of DRD1-5 genes were found to be associated with the risk of alcoholism, one 5' UTR polymorphism in the DRD1 (DRD1-48A>G) gene was significantly associated with severity of alcohol-related problem, as measured by the Alcohol Use Disorders Identification Test (AUDIT) in a gene dose-dependent manner, i.e., 24.37 (+/-8.19) among patients with -48A/A genotype, 22.37 (+/-9.49) among those with -48A/G genotype, and 17.38 (+/-8.28) among those with -48G/G genotype (P=0.002). The genetic effects of DRD1-48A>G were further analyzed with other phenotypes among alcohol-dependent subjects. Interestingly, the DRD1-48A>A genotype was also found to be associated with novelty seeking (NC), harm avoidance (HA), and persistence (P) (P =0.01, 0.02, and 0.003, respectively). The information derived from this study could be valuable for understanding the genetic factors involved in alcoholic phenotypes and genetic distribution of the DRD gene family, and could facilitate further investigation in other ethnic groups.

  13. Distribution of D1 and D2-dopamine receptors in calcium-binding-protein expressing interneurons in rat anterior cingulate cortex.

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    Xu, Lei; Zhang, Xue-Han

    2015-04-25

    Dopamine plays an important role in cognitive functions including decision making, attention, learning and memory in the anterior cingulate cortex (ACC). However, little is known about dopamine receptors (DAR) expression patterns in ACC neurons, especially GABAergic interneurons. The aim of the present study was to investigate the expression of the most abundant DAR subtypes, D1 receptors (D1Rs) and D2 receptors (D2Rs), in major types of GABAergic interneurons in rat ACC, including parvalbumin (PV)-, calretinin (CR)-, and calbindin D-28k (CB)-containing interneurons. Double immunofluorescence staining and confocal scanning were used to detect protein expression in rat brain sections. The results showed a high proportion of PV-containing interneurons express D1Rs and D2Rs, while a low proportion of CR-positive interneurons express D1Rs and D2Rs. D1R- and D2R-expressing PV interneurons are more prevalently distributed in deep layers than superficial layers of ACC. Moreover, we found the proportion of D2Rs expressed in CR cells is much greater than that of D1Rs. These regional and interneuron type-specific differences of D1Rs and D2Rs indicate functionally distinct roles for dopamine in modulating ACC activities via stimulating D1Rs and D2Rs.

  14. -94 G/A polymorphism in the dopamine D1 receptor gene is associated with schizophrenia in a Chinese Han population from Shandong province

    Institute of Scientific and Technical Information of China (English)

    Zhaoyun Du; Guangxin Wang; Yuebing Zhang; Yiren Cheng; Chuanan Zhu

    2011-01-01

    The correlation between-94 G/A polymorphism in the dopamine D1 receptor gene and schizophrenia remains poorly understood despite extensive research.This study sought to evaluate the genotypes and allele frequencies of the-94 G/A polymorphism in the dopamine D1 receptor gene by real-time PCR using TaqMan fluorescent probes.One hundred and sixty-two patients with schizophrenia and 101 healthy controls living in Shandong province of China were evaluated.Experimental results showed that the G/A genotype distribution was significantly higher in the schizophrenia patients than in healthy controls.The frequencies of G allele and A allele were not significantly different between the schizophrenia patients and the controls.Thus,the-94 G/A polymorphism in the dopamine D1 receptor gene was found to be associated with schizophrenia in a Chinese Han population from Shandong province.

  15. Dopamine D1 Receptor Immunoreactivity on Fine Processes of GFAP-Positive Astrocytes in the Substantia Nigra Pars Reticulata of Adult Mouse

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    Nagatomo, Katsuhiro; Suga, Sechiko; Saitoh, Masato; Kogawa, Masahito; Kobayashi, Kazuto; Yamamoto, Yoshio; Yamada, Katsuya

    2017-01-01

    Substantia nigra pars reticulata (SNr), the major output nucleus of the basal ganglia, receives dopamine from dendrites extending from dopaminergic neurons of the adjacent nucleus pars compacta (SNc), which is known for its selective degeneration in Parkinson's disease. As a recipient for dendritically released dopamine, the dopamine D1 receptor (D1R) is a primary candidate due to its very dense immunoreactivity in the SNr. However, the precise location of D1R remains unclear at the cellular level in the SNr except for that reported on axons/axon terminals of presumably striatal GABAergic neurons. To address this, we used D1R promotor-controlled, mVenus-expressing transgenic mice. When cells were acutely dissociated from SNr of mouse brain, prominent mVenus fluorescence was detected in fine processes of glia-like cells, but no such fluorescence was detected from neurons in the same preparation, except for the synaptic bouton-like structure on the neurons. Double immunolabeling of SNr cells dissociated from adult wild-type mice brain further revealed marked D1R immunoreactivity in the processes of glial fibrillary acidic protein (GFAP)-positive astrocytes. Such D1R imunoreactivity was significantly stronger in the SNr astrocytes than that in those of the visual cortex in the same preparation. Interestingly, GFAP-positive astrocytes dissociated from the striatum demonstrated D1R immunoreactivity, either remarkable or minimal, similarly to that shown in neurons in this nucleus. In contrast, in the SNr and visual cortex, only weak D1R immunoreactivity was detected in the neurons tested. These results suggest that the SNr astrocyte may be a candidate recipient for dendritically released dopamine. Further study is required to fully elucidate the physiological roles of divergent dopamine receptor immunoreactivity profiles in GFAP-positive astrocytes. PMID:28203148

  16. The Role of Dorsal Hippocampal Dopamine D1-Type Receptors in Social Learning, Social Interactions, and Food Intake in Male and Female Mice.

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    Matta, Richard; Tiessen, Angela N; Choleris, Elena

    2017-03-29

    The neurobiological mechanisms underlying social learning (ie, in which an animal's learning is influenced by another) are slowly being unraveled. Previous work with systemic treatments shows that dopamine (DA) D1-type receptors mediate social learning in the social transmission of food preferences (STFP) in mice. This study examines the involvement of one brain region underlying this effect. The ventral tegmental area has dopaminergic projections to many limbic structures, including the hippocampus-a site important for social learning in the STFP in rodents. In this study, adult male and female CD-1 mice received a dorsal hippocampal microinfusion of the D1-like receptor antagonist SCH23390 at 1, 2, 4, or 6 μg/μl 15 min before a 30 min social interaction with a same-sex conspecific, in which mice had the opportunity to learn a socially transmitted food preference. Results show that social learning was blocked in female mice microinfused with 6 μg/μl, and in males infused with 1, 4, or 6 μg/μl of SCH23390. This social learning impairment could not be explained by changes in total food intake, or olfactory discrimination. A detailed analysis of the social interactions also revealed that although SCH23390 did not affect oronasal investigation for either sex, drug treatments affected other social behaviors in a sex-specific manner; there was primarily a reduction in agonistic-related behaviors among males, and social investigatory-related behaviors among females. Thus, this study shows that dorsal hippocampal D1-type receptors mediate social learning and social behaviors in male and female mice.Neuropsychopharmacology advance online publication, 29 March 2017; doi:10.1038/npp.2017.43.

  17. Roles of dopamine D1 and D2 receptors in the acquisition and expression of fat-conditioned flavor preferences in rats.

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    Dela Cruz, J A D; Icaza-Cukali, D; Tayabali, H; Sampson, C; Galanopoulos, V; Bamshad, D; Touzani, K; Sclafani, A; Bodnar, R J

    2012-03-01

    Sugars and fats elicit innate and learned flavor preferences with the latter mediated by flavor-flavor (orosensory) and flavor-nutrient (post-ingestive) processes. Systemic dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC), but not opioid antagonists blocked the acquisition and expression of flavor-flavor preferences conditioned by sugars. In addition, systemic D1, but not D2 or opioid antagonists blocked the acquisition of flavor-nutrient preferences conditioned by intragastric (IG) sugar infusions. Given that DA antagonists reduce fat intake, the present study examined whether systemic D1 or D2 antagonists altered the acquisition and/or expression of conditioned flavor preferences (CFP) produced by pairing one novel flavor (CS+, e.g., cherry) with a 3.5% corn oil (CO: fat) solution relative to another flavor (CS-, e.g., grape) paired with a 0.9% CO solution. In an expression study, food-restricted rats were trained to drink either flavored 3.5% or 0.9% CO solutions on alternate days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), SCH (50-800 nmol/kg) or RAC (50-800 nmol/kg). The rats displayed a robust CS+ preference following VEH treatment (87-88%) the expression of which was attenuated by treatment with moderate doses of RAC, and to a lesser degree, SCH. In an acquisition study, six groups of rats received VEH, SCH (25, 50, 200 nmol/kg) or RAC (50, 200 nmol/kg) 0.5 h prior to 1-bottle training trials with CS+ flavored 3.5% and CS- flavored 0.9% (CS-) CO solutions. A seventh Limited VEH group was trained with its training intakes limited to that of the SCH and RAC groups. Subsequent two-bottle tests were conducted with the CS+ and CS- flavors presented in 0.9% CO without injections. Significant and persistent CS+ preferences were observed in VEH (75-82%), Limited VEH (70-88%), SCH25 (75-84%), SCH50 (64-87%), SCH200 (78-91%) and RAC200 (74-91%) groups. In

  18. Regulation of the ERK pathway in the dentate gyrus by in vivo dopamine D1 receptor stimulation requires glutamatergic transmission.

    Science.gov (United States)

    Gangarossa, Giuseppe; Valjent, Emmanuel

    2012-11-01

    Acute systemic administration of the dopamine D1/D5 receptors (D1Rs) agonist, SKF81297, activates the extracellular signal-regulated protein kinases (ERK) pathway selectively in the granule cells of the dentate gyrus. In this study, we examined the mechanisms involved in this regulation and investigated the molecular components that could promote ERK-dependent transcription and translation. SKF81297 induced phosphorylation of ERK and histone H3 required intact glutamatergic transmission. Blockade of glutamate release achieved by the mGluR2/3 agonist, LY354740 or the selective adenosine A1R agonist, CCPA as well as neurotoxic lesions of lateral entorhinal cortex reduced the ability of SKF81297 to induce ERK activation in the dentate gyrus. This activation required the combined stimulation of NR2B-containing NMDARs, mGluR1 and mGluR5. SKF81297 evoked phosphorylation of the ribosomal protein S6 (rpS6) selectively at the Ser235/236 site while the Ser240/244 site remains unchanged. The SKF81297 induced increased phosphorylation of rpS6 was dependent on PKC and ERK/p90RSK activation. Surprisingly, administration of D1Rs agonist suppressed mTORC1/p70S6K pathway suggesting an mTOR-independent regulation of rpS6 phosphorylation. Taken together, our results show that intact glutamatergic transmission plays a major role in the regulation of ERK-dependent phosphorylation of histone H3 and rpS6 observed in the mouse dentate gyrus after systemic administration of SKF81297.

  19. Effects of the D1 dopamine receptor agonist dihydrexidine (DAR-0100A) on working memory in schizotypal personality disorder.

    Science.gov (United States)

    Rosell, Daniel R; Zaluda, Lauren C; McClure, Margaret M; Perez-Rodriguez, M Mercedes; Strike, K Sloan; Barch, Deanna M; Harvey, Philip D; Girgis, Ragy R; Hazlett, Erin A; Mailman, Richard B; Abi-Dargham, Anissa; Lieberman, Jeffrey A; Siever, Larry J

    2015-01-01

    Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive

  20. Dopamine D1-D2 receptor heteromer in dual phenotype GABA/glutamate-coexpressing striatal medium spiny neurons: regulation of BDNF, GAD67 and VGLUT1/2.

    Directory of Open Access Journals (Sweden)

    Melissa L Perreault

    Full Text Available In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs coexpress D1 and D2 receptors (D1R and D2R along with the neuropeptides dynorphin (DYN and enkephalin (ENK. These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1-D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R-D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc, ventral tegmental area (VTA, caudate putamen and substantia nigra (SN. Additionally, activation of the D1R-D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction.

  1. Possible role of dopamine D1-like and D2-like receptors in behavioural activation and evaluation of response efficacy in the forced swimming test.

    Science.gov (United States)

    D'Aquila, Paolo S; Galistu, Adriana

    2012-03-01

    Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats ingesting a sucrose solution, we suggested that the behavioural activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and its level is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated evaluation process. The aim of this study was to test this hypothesis on the forced swimming test response. The effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01-0.04 mg/kg) and raclopride (0.025-0.25 mg/kg) administered before a 15-min exposure to forced swimming, and the response to a second session performed 24 h later, were examined. SCH 23390 dose-dependently reduced climbing scores in the first session and increased them in the second session, but the within-session decline of this measure was similar to that observed in the control group in both sessions. Raclopride-treated subjects showed a slightly reduced level of climbing scores at the beginning of the first session, but persisted in emitting this costly behavioural response up to the end of the session, while no effects were observed in the second session. These results, along with our results examining licking for sucrose, are consistent with the hypothesis that behavioural activation and response effort allocation are directly mediated by dopamine D1-like receptor stimulation, but the level of this activation is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated mechanism of response efficacy evaluation.

  2. Time-resolved FRET binding assay to investigate hetero-oligomer binding properties: proof of concept with dopamine D1/D3 heterodimer.

    Science.gov (United States)

    Hounsou, Candide; Margathe, Jean-François; Oueslati, Nadia; Belhocine, Abderazak; Dupuis, Elodie; Thomas, Cécile; Mann, André; Ilien, Brigitte; Rognan, Didier; Trinquet, Eric; Hibert, Marcel; Pin, Jean-Philippe; Bonnet, Dominique; Durroux, Thierry

    2015-02-20

    G protein-coupled receptors (GPCRs) have been described to form hetero-oligomers. The importance of these complexes in physiology and pathology is considered crucial, and heterodimers represent promising new targets to discover innovative therapeutics. However, there is a lack of binding assays to allow the evaluation of ligand affinity for GPCR hetero-oligomers. Using dopamine receptors and more specifically the D1 and D3 receptors as GPCR models, we developed a new time-resolved FRET (TR-FRET) based assay to determine ligand affinity for the D1/D3 heteromer. Based on the high-resolution structure of the dopamine D3 receptor (D3R), six fluorescent probes derived from a known D3R partial agonist (BP 897) were designed, synthesized and evaluated as high affinity and selective ligands for the D3/D2 receptors, and for other dopamine receptor subtypes. The highest affinity ligand 21 was then employed in the development of the D1/D3 heteromer assay. The TR-FRET was monitored between a fluorescent tag donor carried by the D1 receptor (D1R) and a fluorescent acceptor D3R ligand 21. The newly reported assay, easy to implement on other G protein-coupled receptors, constitutes an attractive strategy to screen for heteromer ligands.

  3. Role of NMDA, opioid and dopamine D1 and D2 receptor signaling in the acquisition of a quinine-conditioned flavor avoidance in rats.

    Science.gov (United States)

    Rotella, Francis M; Badalia, Arzman; Duenas, Sean M; Hossain, Maruf; Saeed, Shermeen; Touzani, Khalid; Sclafani, Anthony; Bodnar, Richard J

    2014-04-10

    A conditioned flavor preference (CFP) can be produced by pairing a flavor (conditioned stimulus, CS+) with the sweet taste of fructose. Systemic dopamine (DA) D1, D2 and NMDA, but not opioid, receptor antagonists significantly reduce the acquisition of the fructose-CFP. A conditioned flavor avoidance (CFA) can be produced by pairing a CS+flavor with the bitter taste of quinine. To evaluate whether fructose-CFP and quinine-CFA share common neurochemical substrates, the present study determined the systemic effects of DA D1 (SCH23390: SCH), DA D2 (raclopride: RAC), NMDA (MK-801) or opioid (naltrexone: NTX) receptor antagonists on the acquisition of quinine-CFA. In Experiment 1, food-restricted male rats were trained over 8 alternating one-bottle sessions to drink an 8% fructose+0.2% saccharin solution (FS) mixed with one flavor (CS-, e.g., grape) and a different flavor (CS+, e.g., cherry) mixed in a solution (FSQ) containing fructose+saccharin and quinine at 0.001-0.030% concentrations. In six subsequent two-bottle choice tests (1-3: two sessions each) with the CS- and CS+ flavors presented in FS solutions, only rats trained with 0.03% quinine displayed a CS+ avoidance in Test 1. In Experiment 2, rats received vehicle (Veh), SCH (200 nmol/kg), RAC (200 nmol/kg), MK-801 (100 μg/kg) or NTX (1 mg/kg) 30 min prior to the 8 one-bottle training sessions with CS-/FS and CS+/FSQ (0.03% quinine) solutions. An additional vehicle group (Veh 0.06%) was trained with a CS+/FSQ containing 0.06% quinine. In the two-bottle choice tests, the Veh and RAC groups avoided the CS+ flavor in Test 1 only, whereas the SCH, MK801, and NTX groups significantly avoided the CS+ in Tests 1-3. The Veh.06% group trained avoided the CS+ in Tests 1 and 2, but not Test 3. In Experiment 3, Veh and SCH groups were trained as in Experiment 2, but were tested with CS flavors presented in 0.2% saccharin solutions. The SCH group avoided the CS+ flavor in Tests 1-3 while the Veh group avoided the CS+ in Test

  4. Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor.

    Science.gov (United States)

    Brenhouse, Heather C; Thompson, Britta S; Sonntag, Kai C; Andersen, Susan L

    2015-08-01

    Extinction of behaviors in response to drug-associated cues and prevention of reinstatement are integral for addiction treatment, and can reverse or ameliorate the harmful consequences of drug use. The mechanisms controlling extinction and reinstatement involve prefrontal cortical dopamine receptors, which change in expression and activity during the juvenile and adolescent transitions until they mature in adulthood. Little is known about the role that PFC D1 dopamine receptors play in extinction of drug-paired associations early in life. We used extinction of place preferences for cocaine in juvenile male and female rats following genetic, cell-specific overexpression of D1 on glutamatergic cells in the PFC. All subjects needed to demonstrate cocaine preferences for inclusion in the extinction studies. Here, male juveniles with a preference to 10 mg/kg cocaine took longer to extinguish preferences compared to both male adults and female juveniles. Female juveniles extinguished more rapidly than male juveniles at 20 mg/kg cocaine. Overexpression of D1 in juvenile males significantly facilitated extinction relative to juvenile male controls, whereas D1 prolonged expression of extinction in adults overexpressing D1 and adolescents who naturally have elevated D1 expression. These data suggest that an immature D1 profile in juveniles prevented the learning of new associations, and D1 overexpression may provide sufficient activity to facilitate extinction learning. D1 overexpression reduced reinstatement to a priming dose of cocaine in juvenile males. Together, these data show D1 expression may re-program motivational circuitry to facilitate extinction learning during juvenility that is normally unavailable to juveniles and that sex differences exist.

  5. Dopamine D1 receptor imaging in the rodent and primate brain using the isoquinoline (+)-[{sup 11}C]A-69024 and positron emission tomography

    Energy Technology Data Exchange (ETDEWEB)

    Besret, L.; Herard, A.S.; Guillermier, M.; Hantraye, P. [CNRS, URA 2210, F-91406 Orsay (France); Dolle, F.; Demphel, S.; Hinnen, F.; Coulon, C.; Ottaviani, M.; Bottlaender, M. [CEA, DSV, I2BM, SHFJ, Lab Imagerie Mol Expt, F-91406 Orsay (France); Herard, A.S.; Guillermier, M.; Hantraye, P. [CEA, DSV, I2BM, Mol Imaging Res Ctr, F-92265 Fontenay Aux Roses (France); Kassiou, M. [Univ Sydney, Discipline Med Radiat Sci, Sydney, NSW 2006 (Australia); Kassiou, M. [Univ Sydney, Brain and Mind Res Inst, Sydney, NSW 2050 (Australia); Kassiou, M. [Univ Sydney, Sch Chem, Sydney, NSW 2006 (Australia)

    2008-07-01

    In vivo pharmacokinetic and brain binding characteristics of (+)-[{sup 11}C]A-69024, a high-affinity-D1-selective dopamine receptor antagonist, were assessed with micro-PET and {beta}-microprobes in the rat and PET in the baboon. The biodistribution of (+)-[{sup 11}C]A-69024 in rats and baboons showed a rapid brain uptake (reaching a maximal value at 5 and 15 min postinjection in rats and baboons, respectively), followed by a slow wash out. The region/cerebellum concentration ratio was characterized by a fourfold higher uptake in striatum and a twofold higher uptake in cortical regions, consistent with in vivo specific binding of the radiotracer in these cerebral regions. Furthermore, this specific (+)-[{sup 11}C]A-69024 binding significantly correlated with the reported in vitro distribution of dopamine D1-receptors. Finally, the specific uptake of the tracer in the striatum and cortical regions was completely prevented by either a pretreatment with large doses of nonradioactive {+-}A-69024 or of the D1-selective antagonist SCH23390, resulting in a similar uptake in the reference region (cerebellum) and in other brain regions. Thus, (+)-[{sup 11}C]A-69024 appears to be a specific and enantioselective radioligand to visualize and quantify brain dopamine D1 receptors in vivo using positron emission tomography. (authors)

  6. Differentiation of forebrain and hippocampal dopamine 1-class receptors, D1R and D5R, in spatial learning and memory.

    Science.gov (United States)

    Sariñana, Joshua; Tonegawa, Susumu

    2016-01-01

    Activation of prefrontal cortical (PFC), striatal, and hippocampal dopamine 1-class receptors (D1R and D5R) is necessary for normal spatial information processing. Yet the precise role of the D1R versus the D5R in the aforementioned structures, and their specific contribution to the water-maze spatial learning task remains unknown. D1R- and D5R-specific in situ hybridization probes showed that forebrain restricted D1R and D5R KO mice (F-D1R/D5R KO) displayed D1R mRNA deletion in the medial (m)PFC, dorsal and ventral striatum, and the dentate gyrus (DG) of the hippocampus. D5R mRNA deletion was limited to the mPFC, the CA1 and DG hippocampal subregions. F-D1R/D5R KO mice were given water-maze training and displayed subtle spatial latency differences between genotypes and spatial memory deficits during both regular and reversal training. To differentiate forebrain D1R from D5R activation, forebrain restricted D1R KO (F-D1R KO) and D5R KO (F-D5R KO) mice were trained on the water-maze task. F-D1R KO animals exhibited escape latency deficits throughout regular and reversal training as well as spatial memory deficits during reversal training. F-D1R KO mice also showed perseverative behavior during the reversal spatial memory probe test. In contrast, F-D5R KO animals did not present observable deficits on the water-maze task. Because F-D1R KO mice showed water-maze deficits we tested the necessity of hippocampal D1R activation for spatial learning and memory. We trained DG restricted D1R KO (DG-D1R KO) mice on the water-maze task. DG-D1R KO mice did not present detectable spatial memory deficit, but did show subtle deficits during specific days of training. Our data provides evidence that forebrain D5R activation plays a unique role in spatial learning and memory in conjunction with D1R activation. Moreover, these data suggest that mPFC and striatal, but not DG D1R activation are essential for spatial learning and memory.

  7. D1多巴胺受体与原发性高血压%D1 Dopamine Receptor and Essential Hypertension

    Institute of Scientific and Technical Information of China (English)

    李震; 曾春雨; 杨成明

    2006-01-01

    多巴胺可通过对肾脏水钠重吸收的调节作用,进而发挥对血压调控的影响,多巴胺功能障碍在原发性高血压发生过程中发挥重要的作用.在多巴胺受体的5个亚型中,D1受体的作用尤其引人注目.在体内钠负荷过载的情况下,刺激肾脏D1受体可调节超过50%的钠排量.原发性高血压状态下D1受体功能障碍,其发生的原因与D1 受体/G蛋白效应物复合体失偶联有关,而其失偶联的机制归因于G蛋白激酶4变异体存在所引起的G蛋白激酶活性增高.

  8. 多巴胺D1受体在Sf9昆虫细胞中的表达及左旋氯代斯阔任对重组D1受体的激动作用%Expression of dopamine D1 receptor in Sf9 insect cells and agonism ofl-12-chloroscoulerine on recombinant D1 receptor

    Institute of Scientific and Technical Information of China (English)

    和友; 金文桥; 申庆祥; 陈新建; 金国章

    2003-01-01

    目的:在Sf9昆虫细胞中表达D1受体,并研究左旋氯代斯阔任对重组D1受体的激动作用.方法:构建含D1受体cDNA的重组杆状病毒,以其感染Sf9昆虫细胞得到D1受体表达.[3H]SCH23390受体结合检测重组D1受体的药理特性.[3H]SCH23390受体结合和cAMP测定实验检测左旋氯代斯阔任对重组D1受体的激动作用.结果:在Sf9昆虫细胞中成功表达D1受体,[3H]SCH23390与重组D1受体最大结合量(Bmax)为(0.94±0.06)nmol/g蛋白,[3H]SCH23390与重组D1受体的结合解离常数(Kd)为(1.9±0.3)nmol/L,其药理特性与小牛纹状体脑匀浆所得结果一致.左旋氯代斯阔任对重组D1受体有高亲和力,解离常数Ki为(6.3±1.4)nmol/L;并剂量依赖地引起胞内cAMP增加,EC50为0.72μmol/L(95%可信限为0.67-0.77 μmol/L),表现出D1激动作用.结论:在杆状病毒/昆虫细胞Sf9中,成功建立了D1受体异源表达系统.在细胞分子水平,直接证实了左旋氯代斯阔任对D1受体的激动作用.%AIM: To express dopamine D1 receptor in baculovirus-Sf9 cell system, and to investigate the effects ofl-12-chloroscoulerine (l-CSL) on the recombinant D1 receptor (D1R). METHODS: The recombinant baculovirus,Autographa californica nuclear polyhedrosis virus bearing D1R (AcNPV- D1R) was generated, and then was usedto produce recombinant D1R in Sf9 insect cells. Expression of D1R in Sf9 cells was monitored by [3H]SCH23390binding assay. The effects ofl-CSL on recombinant D1R were investigated by [3H]SCH23390 binding assay andcAMP assay. RESULTS: The recombinant baculovirus AcNPV bearing DiR cDNA was generated, and wassuccessfully expressed in Sf9 insect cells. The expression level of (Bmax) was (0.94±0.06) nmol/g protein. The Kdvalue of [3H]SCH23390 was (1.9±0.3) nmol/L, which was consistent with the previous results from calf striutamtissues. l-CSL had a high affinity to recombinant D1R with Ki value of (6.3±1.4) nmol/L, and increased theintracellular cAMP level in a

  9. Effects of the selective dopamine D(1) antagonists NNC 01-0112 and SCH 39166 on latent inhibition in the rat.

    Science.gov (United States)

    Trimble, Karen M; Bell, Robert; King, David J

    2002-09-01

    Dopamine D(1) receptor blockade does not appear to be a prerequisite for antipsychotic activity since many clinically effective antipsychotics have little or no affinity for this receptor subtype. Clozapine, however, which has minimal liability for extrapyramidal symptoms, possesses affinities of similar order for D(1) and D(2) receptors. In earlier animal models used to predict antipsychotic effect, selective D(1) antagonists have shown effects similar to standard antipsychotics with preferential D(2) or mixed D(1)/D(2) antagonism. We investigated the effects of haloperidol (0.1 mg/kg) and two selective D(1) antagonists, NNC 01-0112 (0.05, 0.1 and 0.2 mg/kg) and SCH 39166 (0.02, 0.2 and 2.0 mg/kg), on latent inhibition (LI) in rats. LI is a behavioural paradigm in which repeated nonreinforced preexposure to a stimulus retards subsequent associations to that stimulus. Disrupted LI has been suggested as a model for the attentional deficits in schizophrenia. Using preexposure to a flashing light stimulus, which subsequently served as a conditioned stimulus for suppression of water licking, we demonstrated a clear LI effect with haloperidol but with neither of the two D(1) antagonists. Since selective D(1) antagonists are not clinically effective, these results add further credibility for the relevance of LI as an animal model of psychosis.

  10. Dopamine D1 and D2 Receptors Make Dissociable Contributions to Dorsolateral Prefrontal Cortical Regulation of Rule-Guided Oculomotor Behavior

    Directory of Open Access Journals (Sweden)

    Susheel Vijayraghavan

    2016-07-01

    Full Text Available Studies of neuromodulation of spatial short-term memory have shown that dopamine D1 receptor (D1R stimulation in dorsolateral prefrontal cortex (DLPFC dose-dependently modulates memory activity, whereas D2 receptors (D2Rs selectively modulate activity related to eye movements hypothesized to encode movement feedback. We examined localized stimulation of D1Rs and D2Rs on DLPFC neurons engaged in a task involving rule representation in memory to guide appropriate eye movements toward or away from a visual stimulus. We found dissociable effects of D1R and D2R on DLPFC physiology. D1R stimulation degrades memory activity for the task rule and increases stimulus-related selectivity. In contrast, D2R stimulation affects motor activity tuning only when eye movements are made to the stimulus. Only D1R stimulation degrades task performance and increases impulsive responding. Our results suggest that D1Rs regulate rule representation and impulse control, whereas D2Rs selectively modulate eye-movement-related dynamics and not rule representation in the DLPFC.

  11. Dopamine D1-dependent trafficking of striatal N-methyl-D-aspartate glutamate receptors requires Fyn protein tyrosine kinase but not DARPP-32.

    Science.gov (United States)

    Dunah, Anthone W; Sirianni, Ana C; Fienberg, Allen A; Bastia, Elena; Schwarzschild, Michael A; Standaert, David G

    2004-01-01

    Interactions between dopaminergic and glutamatergic systems in the striatum are thought to underlie both the symptoms and adverse effects of treatment of Parkinson's disease. We have previously reported that activation of the dopamine D1 receptor triggers a rapid redistribution of striatal N-methyl-d-aspartate (NMDA) receptors between intracellular and postsynaptic sub-cellular compartments. To unravel the signaling pathways underlying this trafficking, we studied mice with targeted disruptions of either the gene that encodes the dopamine- and cAMP-regulated phosphoprotein (DARPP-32), a potent and selective inhibitor of protein phosphatase-1, or the protein tyrosine kinase Fyn. In striatal tissue from DARPP-32-depleted mice, basal tyrosine and serine phosphorylation of striatal NMDA receptor subunits NR1, NR2A, and NR2B was normal, and activation of dopamine D1 receptors with the agonist SKF-82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine] produced redistribution of NMDA receptors from vesicular compartments (P3 and LP2) to synaptosomal membranes (LP1). In the Fyn knockout mice, basal tyrosine phosphorylation of NR2A and NR2B was drastically reduced, whereas serine phosphorylation of these NMDA subunits was unchanged. In the Fyn knockout mice, the dopamine D1 receptor agonist failed to induce subcellular redistribution of NMDA receptors. In addition, Fyn-depleted mice lesioned with 6-hydroxydopamine also failed to exhibit l-DOPA-induced behavioral sensitization, but this may be caused, at least in part, by resistance of these mice to the neurotoxic lesion. These findings suggest a novel mechanism for the trafficking of striatal NMDA receptors by signaling pathways that are independent of DARPP-32 but require Fyn protein tyrosine kinase. Strategies that prevent NMDA receptor subcellular redistribution through inhibition of Fyn kinase may prove useful in the treatment of Parkinson's disease.

  12. Oxidative stress causes renal dopamine D1 receptor dysfunction and hypertension via mechanisms that involve nuclear factor-kappaB and protein kinase C.

    Science.gov (United States)

    Banday, Anees Ahmad; Fazili, Fatima Rizwan; Lokhandwala, Mustafa F

    2007-05-01

    Renal dopamine, via activation of D1 receptors, plays a role in maintaining sodium homeostasis and BP. There exists a defect in renal D1 receptor function in hypertension, diabetes, and aging, conditions that are associated with oxidative stress. However, the exact underlying mechanism of the oxidative stress-mediated impaired D1 receptor signaling and hypertension is not known. The effect of oxidative stress on renal D1 receptor function was investigated in healthy animals. Male Sprague-Dawley rats received tap water (vehicle) and 30 mM L-buthionine sulfoximine (BSO), an oxidant, with and without 1 mM tempol for 2 wk. Compared with vehicle, BSO treatment caused oxidative stress and increase in BP, which was accompanied by defective D1 receptor G-protein coupling and loss of natriuretic response to SKF38393. BSO treatment also increased NF-kappaB nuclear translocation, protein kinase C (PKC) activity and expression, G-protein-coupled receptor kinase-2 (GRK-2) membranous translocation, and D1 receptor serine phosphorylation. In BSO-treated rats' supplementation of tempol decreased oxidative stress, normalized BP, and restored D1 receptor G-protein coupling and natriuretic response to SKF38393. Tempol also normalized NF-kappaB translocation, PKC activity and expression, GRK-2 sequestration, and D1 receptor serine phosphorylation. In conclusion, these results show that oxidative stress activates NF-kappaB, causing an increase in PKC activity, which leads to GRK-2 translocation and subsequent D1 receptor hyper-serine phosphorylation and uncoupling. The functional consequence of this phenomenon was the inability of SKF38393 to inhibit Na/K-ATPase activity and promote sodium excretion, which may have contributed to increase in BP. Tempol reduced oxidative stress and thereby restored D1 receptor function and normalized BP.

  13. Dopamine receptor D1 and postsynaptic density gene variants associate with opiate abuse and striatal expression levels.

    Science.gov (United States)

    Jacobs, M M; Ökvist, A; Horvath, M; Keller, E; Bannon, M J; Morgello, S; Hurd, Y L

    2013-11-01

    Opioid drugs are highly addictive and their abuse has a strong genetic load. Dopamine-glutamate interactions are hypothesized to be important for regulating neural systems central for addiction vulnerability. Balanced dopamine-glutamate interaction is mediated through several functional associations, including a physical link between discs, large homolog 4 (Drosophila) (DLG4, PSD-95) and dopamine receptor 1 (DRD1) within the postsynaptic density to regulate DRD1 trafficking. To address whether genetic associations with heroin abuse exist in relation to dopamine and glutamate and their potential interactions, we evaluated single-nucleotide polymorphisms of key genes within these systems in three populations of opiate abusers and controls, totaling 489 individuals from Europe and the United States. Despite significant differences in racial makeup of the separate samples, polymorphisms of DRD1 and DLG4 were found to be associated with opiate abuse. In addition, a strong gene-gene interaction between homer 1 homolog (Drosophila) (HOMER1) and DRD1 was predicted to occur in Caucasian subjects. This interaction was further analyzed by evaluating DRD1 genotype in relation to HOMER1b/c protein expression in postmortem tissue from a subset of Caucasian subjects. DRD1 rs265973 genotype correlated with HOMER1b/c levels in the striatum, but not cortex or amygdala; the correlation was inversed in opiate abusers as compared with controls. Cumulatively, these results support the hypothesis that there may be significant, genetically influenced interactions between glutamatergic and dopaminergic pathways in opiate abusers.

  14. Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis

    Science.gov (United States)

    Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modula...

  15. 左旋千金藤啶碱增加离体大鼠心肌收缩力的作用%Effect of(-)-stepholidine on enhancing cardiac muscle contraction mediated by dopamine D1 receptor

    Institute of Scientific and Technical Information of China (English)

    周淑媛; 施铮; 刘峥; 胡慧升; 李晓冬; 金国章; 陈龙

    2009-01-01

    目的:观察左旋千金藤啶碱((-)-Stepholidine SPD)对离体心脏心肌收缩力的影响,分析其增加心肌收缩力是否直接作用于心脏多巴胺D1受体.方法:采用Langendorff离体灌流装置及膜片钳技术,观察左旋千金藤啶碱(1μM、10 μM、100μM)对大鼠离体心脏左心室收缩力各参数及对左心室心肌细胞L型钙电流的影响;再分析给予选择性多巴胺受体阻断剂SCH23390、H_1受体阻断剂非索非那定、β受体阻断剂普萘洛尔以及α1受体阻断剂哌唑嗪对SPD增加心肌收缩力的影响.结果:SPD以剂量依赖的方式显著增加心肌收缩力及左心室心肌细胞L型钙电流.SCH23390可明显阻断SPD心肌收缩效应,普萘洛尔、哌唑嗪和非索非那定则无此作用.结论:左旋千金藤啶碱(SPD)可显著地增加大鼠离体工作心脏心肌收缩力,其作用机制是通过心脏多巴胺D_1受体增加L型钙电流而发挥作用.%Objective:The present study was undertaken to investigate the effect of (-)-Stepholidine (SPD) on enhancing L-type Ca~(2+) current and contraction of cardiac muscle in isolated rat heart mediated by dopamine D_1 receptor and to examine whether SPD has a direct effect on the heart dopamine D_1 receptors.Methods:Normal adult rat working hearts by Langendorff and patch clamp techniques were applied to investigate the effects of SPD on left ventricular pressure and L-type Ca~(2+) current.Results:SPD significantly increased the cardiac muscle contraction and L-type Ca~(2+) current in a dose-dependent manner.The selective dopamine D_1 receptor antagonist SCH23390 (1 μM) blocked the SPD induced heart contraction effect.However,β-receptor antagonist propranolol (1 μM),αl-receptor antagonist prazosin (1 μM) and Hl-receptor antagonist Fexofenadine (1 μM) had no effects in blocking SPD induced heart contractions.Conclusions:SPD exerted its effect on enhancing contraction of isolated rat heart through activating heart dopamine D_1

  16. The tight junction protein ZO-2 blocks cell cycle progression and inhibits cyclin D1 expression.

    Science.gov (United States)

    Gonzalez-Mariscal, Lorenza; Tapia, Rocio; Huerta, Miriam; Lopez-Bayghen, Esther

    2009-05-01

    ZO-2 is an adaptor protein of the tight junction that belongs to the MAGUK protein family. ZO-2 is a dual localization protein that in sparse cultures is present at the cell borders and the nuclei, whereas in confluent cultures it is concentrated at the cell boundaries. Here we have studied whether ZO-2 is able to regulate the expression of cyclin D1 (CD1) and cell proliferation. We have demonstrated that ZO-2 negatively regulates CD1 transcription by interacting with c-Myc at an E box present in CD1 promoter. We have further found that ZO-2 transfection into epithelial MDCK cells triggers a diminished expression of CD1 protein and decreases the rate of cell proliferation in a wound-healing assay.

  17. β-Lactotensin derived from bovine β-lactoglobulin exhibits anxiolytic-like activity as an agonist for neurotensin NTS(2) receptor via activation of dopamine D(1) receptor in mice.

    Science.gov (United States)

    Hou, I-Ching; Suzuki, Chihiro; Kanegawa, Norimasa; Oda, Ayako; Yamada, Ayako; Yoshikawa, Masaaki; Yamada, Daisuke; Sekiguchi, Masayuki; Wada, Etsuko; Wada, Keiji; Ohinata, Kousaku

    2011-11-01

    β-Lactotensin (His-Ile-Arg-Leu) is a bioactive peptide derived from bovine milk β-lactoglobulin, acting as a natural agonist for neurotensin receptors. We found that β-lactotensin exhibited anxiolytic-like activity in an elevated plus-maze test after its intraperitoneal (i.p.) administration in mice. β-Lactotensin was also orally active. The anxiolytic-like activity of β-lactotensin after i.p. administration was blocked by levocabastine, an antagonist for the neurotensin NTS(2) receptor. β-Lactotensin had anxiolytic-like activity in wild-type but not Ntsr2-knockout mice. β-Lactotensin increased intracellular Ca(2+) flux in glial cells derived from wild-type mice but not Ntsr2 knockout mice. These results suggest that β-lactotensin acts as an NTS(2) receptor agonist having anxiolytic-like activity. The anxiolytic-like activity of β-lactotensin was also blocked by SCH23390 and SKF83566, antagonists for dopamine D(1) receptor, but not by raclopride, an antagonist for D(2) receptor. Taken together, β-lactotensin may exhibit anxiolytic-like activity via NTS(2) receptor followed by D(1) receptor.

  18. Individual differences in ethanol locomotor sensitization are associated with dopamine D1 receptor intra-cellular signaling of DARPP-32 in the nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Karina Possa Abrahao

    Full Text Available In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as "sensitized" and the 33% with the lowest levels as "non-sensitized". The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of

  19. A "genome-to-lead" approach for insecticide discovery: pharmacological characterization and screening of Aedes aegypti D(1-like dopamine receptors.

    Directory of Open Access Journals (Sweden)

    Jason M Meyer

    2012-01-01

    Full Text Available BACKGROUND: Many neglected tropical infectious diseases affecting humans are transmitted by arthropods such as mosquitoes and ticks. New mode-of-action chemistries are urgently sought to enhance vector management practices in countries where arthropod-borne diseases are endemic, especially where vector populations have acquired widespread resistance to insecticides. METHODOLOGY/PRINCIPAL FINDINGS: We describe a "genome-to-lead" approach for insecticide discovery that incorporates the first reported chemical screen of a G protein-coupled receptor (GPCR mined from a mosquito genome. A combination of molecular and pharmacological studies was used to functionally characterize two dopamine receptors (AaDOP1 and AaDOP2 from the yellow fever mosquito, Aedes aegypti. Sequence analyses indicated that these receptors are orthologous to arthropod D(1-like (Gα(s-coupled receptors, but share less than 55% amino acid identity in conserved domains with mammalian dopamine receptors. Heterologous expression of AaDOP1 and AaDOP2 in HEK293 cells revealed dose-dependent responses to dopamine (EC(50: AaDOP1 = 3.1±1.1 nM; AaDOP2 = 240±16 nM. Interestingly, only AaDOP1 exhibited sensitivity to epinephrine (EC(50 = 5.8±1.5 nM and norepinephrine (EC(50 = 760±180 nM, while neither receptor was activated by other biogenic amines tested. Differential responses were observed between these receptors regarding their sensitivity to dopamine agonists and antagonists, level of maximal stimulation, and constitutive activity. Subsequently, a chemical library screen was implemented to discover lead chemistries active at AaDOP2. Fifty-one compounds were identified as "hits," and follow-up validation assays confirmed the antagonistic effect of selected compounds at AaDOP2. In vitro comparison studies between AaDOP2 and the human D(1 dopamine receptor (hD(1 revealed markedly different pharmacological profiles and identified amitriptyline and doxepin as AaDOP2

  20. Mechanism of over-activation in direct pathway mediated by dopamine D1 receptor in rats with levodopa-induced dyskinesias

    Institute of Scientific and Technical Information of China (English)

    Xue-Bing CAO; Qiang GUAN; Yan XU; Lan WANG; Sheng-Gang SUN

    2006-01-01

    Objective To study the changes of prodynorphin (PDyn) gene expression and dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) phosphorylation in rats with levodopa-induced dyskinesias (LID), and to explore the mechanism of over-activation in direct pathway mediated by dopamine D1 receptor. Methods Parkinson's disease (PD) rats were received levodopa (10 mg/kg, i.p.) for 28 d to get the LID rats. According to the behavior scale, LID rats were divided into mild (n=8) and severe (n=16) groups. On day 29, 8 rats in severe LID group were given an acute intraperitoneal injection of MK-801 (0.1 mg/kg) 15 min before levodopa treatment (MK-801 group, n=8). The normal rats received same course and dosage of levodopa as the control group (n=8). Hybridization in situ was used to measure the expression of PDyn mRNA in striatum. Protein and mRNA levels of total DARPP-32 and phospho-Thr-34 DARPP-32 level were measured by immunoblotting and RT-PCR, respectively. Results The levels of PDyn mRNA and phospho-Thr-34DARPP-32 increased significantly in LID rats compared with control rats (P<0.01), and they also increased markedly in severe LID group compared with mild group (P<0.01). Conclusion Phospho-Thr-34 DARPP-32 level was increased in LID rats, which contributed to the over-activation of direct pathway mediated by dopamine D1 receptor.

  1. Nicotine restores morphine-induced memory deficit through the D1 and D2 dopamine receptor mechanisms in the nucleus accumbens.

    Science.gov (United States)

    Azizbeigi, Ronak; Ahmadi, Shamseddin; Babapour, Vahab; Rezayof, Ameneh; Zarrindast, Mohammad Reza

    2011-08-01

    Involvement of the dopamine D1 and D2 receptors in the nucleus accumbens (NAc) with interaction between morphine and nicotine on inhibitory avoidance (IA) memory was investigated. A step-through type of inhibitory avoidance tasks was used to assess memory in male Wistar rats. The results showed that subcutaneous (s.c.) administration of morphine (7.5 mg/kg) after training decreased retrieval of IA memory in the animals when tested 24 h later. Pre-test administration of the same dose of morphine significantly reversed the deficiency in retrieval. The results also showed that pre-test administration of nicotine (0.2 and 0.4 mg/kg, s.c.) by itself mimicked the effect of pre-test morphine, and lower doses of nicotine (0.1 and 0.2 mg/kg) also improved the effect of a low dose of morphine (2.5 mg/kg) on retrieval of IA memory. Pre-test intra-NAc administration of the dopamine D1 receptor antagonist, SCH 23390 (0.001 and 0.01 µg/rat), and the dopamine D2 receptor antagonist, sulpiride (0.5 and 1 µg/rat) caused no significant effects on IA memory by themselves, but both prevented reinstatement of the retrieval of IA memory by the effective dose of nicotine (0.4 mg/kg). It can be concluded that the dopaminergic mechanism(s) in the NAc is a crosslink for the effect of morphine and nicotine on reinstatement of retrieval of IA memory impaired by post-training administration of morphine.

  2. Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action.

    Science.gov (United States)

    Bay-Richter, Cecilie; O'Tuathaigh, Colm M P; O'Sullivan, Gerard; Heery, David M; Waddington, John L; Moran, Paula M

    2009-04-01

    Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.

  3. Spinal D1-like dopamine receptors modulate NMDA receptor-induced hyperexcitability and NR1 subunit phosphorylation at serine 889.

    Science.gov (United States)

    Aira, Zigor; Barrenetxea, Teresa; Buesa, Itsaso; Martínez, Endika; Azkue, Jon Jatsu

    2016-04-01

    Activation of the N-methyl-d-aspartate receptor (NMDAR) in dorsal horn neurons is recognized as a fundamental mechanism of central sensitization and pathologic pain. This study assessed the influence of dopaminergic, D1-like receptor-mediated input to the spinal dorsal horn on NMDAR function. Spinal superfusion with selective NMDAR agonist cis-ACPD significantly increased C-fiber-evoked field potentials in rats subjected to spinal nerve ligation (SNL), but not in sham-operated rats. Simultaneous application of D1LR antagonist SCH 23390 dramatically reduced hyperexcitability induced by cis-ACPD. Furthermore, cis-ACPD-induced hyperexcitability seen in nerve-ligated rats could be mimicked in unin-jured rats during stimulation of D1LRs by agonist SKF 38393 at subthreshold concentration. Phosphorylation of NMDAR subunit NR1 at serine 889 at postsynaptic sites was found to be increased in dorsal horn neurons 90 min after SNL, as assessed by increased co-localization with postsynaptic marker PSD-95. Increased NR1 phosphorylation was attenuated in the presence of SCH 23390 in the spinal superfusate. The present results support that D1LRs regulate most basic determinants of NMDAR function in dorsal horn neurons, suggesting a potential mechanism whereby dopaminergic input to the dorsal horn can modulate central sensitization and pathologic pain.

  4. Roles of adrenergic α1 and dopamine D1 and D2 receptors in the mediation of the desynchronization effects of modafinil in a mouse EEG synchronization model.

    Directory of Open Access Journals (Sweden)

    Chang-Rui Chen

    Full Text Available BACKGROUND: Synchronized electroencephalogram (EEG activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R and dopamine (DA D1 and D2 receptors (D1Rs and D2Rs on modafinil-induced desynchronization in mice. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p. completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg and the D2R antagonist raclopride (2 mg/kg, i.p.. CONCLUSIONS/SIGNIFICANCE: These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.

  5. In vitro and in vivo testing of the dopamine D1 ligand [123I]SCH 23982 with respect to its potential application in SPET investigations.

    Science.gov (United States)

    Beer, H F; Lin, S; Bläuenstein, P; Hasler, P; Schubiger, P A; Maier, A; Lichtensteiger, W; Oettli, R; Bekier, A; Weder, B

    1993-07-01

    [123I]SCH 23982, a dopamine D1 ligand, was labelled in a large scale process and then tested in vitro for binding to rat brain sections and membranes. Because of the promising values of KD = 1.5 x 10(-10) M and Bmax = 0.7 x 10(-11) mol/g, in vivo evaluation was performed on rats and normal volunteers to test its possible usefulness for SPET imaging. In competition experiments, a higher binding in the presence of sulpiride was found while ketanserin displaced [123I]SCH 23982 only at a 10,000-fold excess. Differences between rats and men were seen with respect to their metabolism. SPET investigations failed because the washout of [123I]SCH 23982 was too rapid.

  6. D1 and D2 dopamine receptor antagonists decrease behavioral bout duration, without altering the bout's repeated behavioral components, in a naturalistic model of repetitive and compulsive behavior.

    Science.gov (United States)

    Hoffman, Kurt L; Rueda Morales, Rafael I

    2012-04-21

    Nest building behavior in the pregnant female rabbit (Oryctolagus cuniculus) is a model for compulsive behavior in Obsessive Compulsive Disorder (OCD). This behavior comprises a cycle of repeated, stereotyped components (collecting straw, entering nest box and depositing the straw there, returning to collect more straw), which itself is repeated 80+ times in a single bout that lasts approximately 50min. The bout, in turn, is repeated if necessary, according to the rabbit's perception of whether or not the nest is finished. We administered SCH23390 (5-100μg/kg; D1/D5 antagonist) or raclopride (0.05-1.0mg/kg; D2/D3 antagonist), subcutaneously to day 28 pregnant female rabbits, 30 or 60min before placing straw inside their home cage. At doses that minimally affected ambulatory behavior in open field (5-12.5μg/kg SCH23390, 0.5-1.0mg/kg raclopride), both antagonists dramatically reduced bout duration while not significantly affecting the initiation of straw carrying behavior, the sequential performance of the individual cycle components, maximum cycle frequency, or the total number of bouts performed. These results point to an important role for dopamine neurotransmission for the prolonged expression of a normal, repetitive and compulsive-like behavior. Moreover, the finding that dopamine receptor antagonists decrease the time spent engaged in repetitive behavior (without significantly altering the form of the repetitive behavior itself) suggests a possible explanation for why neuroleptics can be clinically effective for treating OCD.

  7. Dopamine modulates hemocyte phagocytosis via a D1-like receptor in the rice stem borer, Chilo suppressalis.

    Science.gov (United States)

    Wu, Shun-Fan; Xu, Gang; Stanley, David; Huang, Jia; Ye, Gong-Yin

    2015-07-16

    Dopamine (DA) is a signal moiety bridging the nervous and immune systems. DA dysregulation is linked to serious human diseases, including addiction, schizophrenia, and Parkinson's disease. However, DA actions in the immune system remain incompletely understood. In this study, we found that DA modulates insect hemocyte phagocytosis using hemocytes prepared from the rice stem borer (RSB), Chilo suppressalis. We investigated whether insect hemocytes are capable of de novo DA production. Here we show that exposing hemocytes to lipopolysaccharide (LPS) led to induction of DA-generating enzymes. Exogenous DA induced rapid phosphorylation of extracellular signal-regulated kinase (ERK) in naïve hemocytes. Activation of ERK was inhibited by preincubating with a DOP1 receptor antagonist. Thus, DA signaling via the DOP1 receptor may contribute to early hemocyte activation. DA synthesized and released from hemocytes may act in an autocrine mechanism to stimulate or maintain phagocytic activity. Consistent with this hypothesis, we found that inhibition of DA synthesis with α-methyl-DL-tyrosine methyl ester hydrochloride or blockage of DOP1 receptor with antagonist SCH23390 impaired hemocyte phagocytosis. Topical DA application also significantly decreased RSB mortality following challenge with the insect pathogenic fungus, Beauveria bassiana. We infer that a DA-dependent signaling system operates in hemocytes to mediate phagocytotic functions.

  8. Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons

    Directory of Open Access Journals (Sweden)

    Christopher J Evans

    2012-03-01

    Full Text Available The striatum can be divided into the DLS (dorsolateral striatum and the VMS (ventromedial striatum, which includes NAcC (nucleus accumbens core and NAcS (nucleus accumbens shell. Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons based on their location, expression of DA (dopamine D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala2-MePhe4-Gly(ol5]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances compared with cells in the VMS. RMPs (resting membrane potentials were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials. Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.

  9. Detailed analysis of food-reinforced operant lever pressing distinguishes effects of a cannabinoid CB1 inverse agonist and dopamine D1 and D2 antagonists.

    Science.gov (United States)

    McLaughlin, P J; Winston, K M; Swezey, L A; Vemuri, V K; Makriyannis, A; Salamone, J D

    2010-07-01

    Overt similarities exist between the effects of systemic cannabinoid CB1 inverse agonists and dopamine (DA) antagonists on appetitive behavior. The present set of studies was undertaken to apply a fine-grained analysis of food-reinforced operant lever pressing in rats in order to compare the pattern of effects produced by administration of the CB1 inverse agonist AM 251 and those induced by the DA D1 antagonist SKF 83566, and the D2 antagonist raclopride. Three groups of rats were trained on a fixed-ratio 5 (FR5) schedule and administered these compounds over a range of doses expected to suppress responding. All three drugs produced a dose-related suppression of total lever pressing. In addition to main effects of dose, regression analyses were performed to determine which of several response timing- and rate-related variables correlated most strongly with overall responding in each group. It was found that total session time spent pausing from responding was significantly better at predicting responding in the AM 251 group, while both DA antagonists produced significantly stronger regression coefficients (versus AM 251) from fast responding measures. These results suggest that, while several similarities exist, CB1, D1, and D2 antagonists are not identical in their pattern of suppression of food-maintained lever pressing.

  10. Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms.

    Science.gov (United States)

    Acevedo, JeanMarie; Santana-Almansa, Alexandra; Matos-Vergara, Nikol; Marrero-Cordero, Luis René; Cabezas-Bou, Ernesto; Díaz-Ríos, Manuel

    2016-02-01

    Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A1 and A(2A) receptors. The effects of caffeine at the level of the lumbar spinal central pattern generator (CPG) network for hindlimb locomotion are lacking. We assessed the effects of caffeine to the locomotor function of the spinal CPG network via extracellular ventral root recordings using the isolated neonatal mouse spinal cord preparation. Addition of caffeine and of an A1 receptor antagonist significantly decreased the cycle period accelerating the ongoing locomotor rhythm, while decreasing burst duration reversibly in most preparations suggesting the role of A1 receptors as the primary target of caffeine. Caffeine and an A1 receptor antagonist failed to stimulate ongoing locomotor activity in the absence of dopamine or in the presence of a D1 receptor antagonist supporting A1/D1 receptor-dependent mechanism of action. The use of caffeine or an A1 receptor blocker failed to stimulate an ongoing locomotor rhythm in the presence of a blocker of the cAMP-dependent protein kinase (PKA) supporting the need of this intracellular pathway for the modulatory effects of caffeine to occur. These results support a stimulant effect of caffeine on the lumbar spinal network controlling hindlimb locomotion through the inhibition of A1 receptors and subsequent activation of D1 receptors via a PKA-dependent intracellular mechanism.

  11. Differential effects of selective adenosine antagonists on the effort-related impairments induced by dopamine D1 and D2 antagonism.

    Science.gov (United States)

    Nunes, E J; Randall, P A; Santerre, J L; Given, A B; Sager, T N; Correa, M; Salamone, J D

    2010-09-29

    Mesolimbic dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. Previous work showed that adenosine A(2A) antagonists can reverse the effects of DA D(2) antagonists on effort-related choice. However, less is known about the effects of adenosine A(1) antagonists. Despite anatomical data showing that A(1) and D(1) receptors are co-localized on the same striatal neurons, it is uncertain if A(1) antagonists can reverse the effects DA D(1) antagonists. The present work systematically compared the ability of adenosine A(1) and A(2A) receptor antagonists to reverse the effects of DA D(1) and D(2) antagonists on a concurrent lever pressing/feeding choice task. With this procedure, rats can choose between responding on a fixed ratio 5 lever-pressing schedule for a highly preferred food (i.e. high carbohydrate pellets) vs. approaching and consuming a less preferred rodent chow. The D(1) antagonist ecopipam (0.2 mg/kg i.p.) and the D(2) antagonist eticlopride (0.08 mg/kg i.p.) altered choice behavior, reducing lever pressing and increasing lab chow intake. Co-administration of the adenosine A(1) receptor antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.375, 0.75, and 1.5 mg/kg i.p.), and 8-cyclopentyltheophylline (CPT; 3.0, 6.0, 12.0 mg/kg i.p.) failed to reverse the effects of either the D(1) or D(2) antagonist. In contrast, the adenosine A(2A) antagonist KW-6002 (0.125, 0.25 and 0.5 mg/kg i.p.) was able to produce a robust reversal of the effects of eticlopride, as well as a mild partial reversal of the effects of ecopipam. Adenosine A(2A) and DA D(2) receptors interact to regulate effort-related choice behavior, which may have implications for the treatment of psychiatric symptoms such as psychomotor

  12. ABT-431: the diacetyl prodrug of A-86929, a potent and selective dopamine D1 receptor agonist: in vitro characterization and effects in animal models of Parkinson's disease.

    Science.gov (United States)

    Shiosaki, K; Jenner, P; Asin, K E; Britton, D R; Lin, C W; Michaelides, M; Smith, L; Bianchi, B; Didomenico, S; Hodges, L; Hong, Y; Mahan, L; Mikusa, J; Miller, T; Nikkel, A; Stashko, M; Witte, D; Williams, M

    1996-01-01

    (-)-Trans 9,10-hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5- azacyclopent-1-ena[c]phenanthrene hydrochloride (A-86929) is a potent and selective full agonist at the dopamine (DA) D1-like receptor. Judging by its binding affinities to the D1 and D2 classes of receptors, the compound is approximately 20-fold D1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D1-selective. A-86929 has moderate to weak (Ki > 1 microM) affinity at other monoaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce the prodrug, (-)-trans 9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia- 5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431), which is more chemically stable yet is rapidly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotation in rats bearing unilateral 6-hydroxydopamine lesions, with ED50 values of 0.24 mumol/kg s.c. and 0.54 mumol/kg s.c., respectively. A-86929 and ABT-431 improved behavioral disability scores and increased locomotor activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mumol/kg s.c.). When administered three times daily for 30 consecutive days to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parkinson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct-acting D2-selective agonists. Stimulation of the D2 receptor, which is associated with all current DA agonist-based therapies, may contribute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which

  13. A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

    Science.gov (United States)

    Marchant, Nathan J; Kaganovsky, Konstantin

    2015-06-01

    In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.

  14. 多巴胺D1和D2受体敲除对类风湿关节炎小鼠模型的影响%The influence of dopamine D1 and D2 receptor knockout on the mice model of rheumatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    邓乔文; 蔡唤唤; 王小琴; 邱一华

    2016-01-01

    目的:探讨多巴胺D1受体敲除(dopamine D1 receptor gene knockout, D1R-/-)和多巴胺D2受体敲除(dopamine D2 receptor gene knockout, D2R-/-)对类风湿关节炎小鼠模型的影响。方法:以D1R-/-和D2R-/-小鼠为实验对象,用鸡Ⅱ型胶原(typeⅡcollagen, CⅡ)乳剂制作胶原诱导性关节炎(collagen-induced arthritis, CIA)小鼠模型。用免疫荧光染色法检测该小鼠模型关节滑膜组织CD4+T细胞上多巴胺D1受体(dopamine D1 receptor, D1R)和多巴胺D2受体(dopamine D2 receptor, D2R)的表达;用蛋白免疫印迹法检测滑膜组织中CD4+T细胞相关转录因子的表达。结果:CIA造模组关节滑膜组织中CD4+T细胞上有D2R的表达。D2R敲除后,CD4+T细胞相关转录因子T-bet、GATA-3、ROR-γt、Foxp3的蛋白表达上调;D1R敲除后,CD4+T细胞相关转录因子T-bet、GATA-3、ROR-γt、Foxp3的蛋白表达与野生组无明显差异。结论:D2R敲除后,CIA的症状加重。%Objective: To study the effect of dopamine D1 receptor(D1R) and dopamine D2 receptor(D2R) gene knockout on collagen-induced arthritis(CIA) mice model. Methods: Dopamine D1 receptor gene knockout mice(D1R-/-) and dopamine D2 receptor gene knockout mice(D2R-/-) were used in this experiment. CIA model was established using chicken type Ⅱcollagen(CⅡ) and co-localization of D1R or D2R with CD4 +T cells in joint synovial tissue were performed by immunofluorescence staining. Transcription factors related to CD4+T cell were determined by Western Blot analysis. Results:Study confirmed that dopamine D2 receptor expressed on CD4 +T cells in synovial tissue from CIA model. After D2R knockout, transcription factors T-bet, GATA-3, ROR-γt and Foxp3 related to CD4 +T cells expression were increased;however, there was no obvious difference in protein expression between D1R-/- CIA model mice and wild type CIA model mice. Conclusion:CIA model get worse with D2R-/- mice.

  15. Role of Dopamine Receptors Subtypes, D1-Like and D2-Like, within the Nucleus Accumbens Subregions, Core and Shell, on Memory Consolidation in the One-Trial Inhibitory Avoidance Task

    Science.gov (United States)

    Manago, Francesca; Castellano, Claudio; Oliverio, Alberto; Mele, Andrea; De Leonibus, Elvira

    2009-01-01

    Recent evidence demonstrated that dopamine within the nucleus accumbens mediates consolidation of both associative and nonassociative memories. However, the specific contribution of the nucleus accumbens subregions, core and shell, and of D1 and D2 receptors subtypes has not been yet clarified. The aim of this study was, therefore, to directly…

  16. Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.

    Science.gov (United States)

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Rakesh; Shukla, Shubha

    2016-12-14

    Parkinson's disease is accompanied by nonmotor symptoms including cognitive impairment, which precede the onset of motor symptoms in patients and are regulated by dopamine (DA) receptors and the mesocorticolimbic pathway. The relative contribution of DA receptors and astrocytic glutamate transporter (GLT-1) in cognitive functions is largely unexplored. Similarly, whether microglia-derived increased immune response affects cognitive functions and neuronal survival is not yet understood. We have investigated the effect of acetyl-L-carnitine (ALCAR) on cognitive functions and its possible underlying mechanism of action in 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian rats. ALCAR treatment in 6-OHDA-lesioned rats improved memory functions as confirmed by decreased latency time and path length in the Morris water maze test. ALCAR further enhanced D1 receptor levels without altering D2 receptor levels in the hippocampus and prefrontal cortex (PFC) regions, suggesting that the D1 receptor is preferentially involved in the regulation of cognitive functions. ALCAR attenuated microglial activation and release of inflammatory mediators through balancing proinflammatory and anti-inflammatory cytokines, which subsequently enhanced the survival of mature neurons in the CA1, CA3, and PFC regions and improved cognitive functions in hemiparkinsonian rats. ALCAR treatment also improved glutathione (GSH) content, while decreasing oxidative stress indices, inducible nitrogen oxide synthase (iNOS) levels, and astrogliosis resulting in the upregulation of GLT-1 levels. Additionally, ALCAR prevented the loss of dopaminergic (DAergic) neurons in ventral tagmental area (VTA)/substantia nigra pars compacta (SNpc) regions of 6-OHDA-lesioned rats, thus maintaining the integrity of the nigrostriatal pathway. Together, these results demonstrate that ALCAR treatment in hemiparkinsonian rats ameliorates neurodegeneration and cognitive deficits, hence suggesting its therapeutic potential in

  17. The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.

    Science.gov (United States)

    Björkholm, Carl; Marcus, Monica M; Konradsson-Geuken, Åsa; Jardemark, Kent; Svensson, Torgny H

    2017-02-09

    Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

  18. Role of D1/D2 dopamine receptors in the CA1 region of the rat hippocampus in the rewarding effects of morphine administered into the ventral tegmental area.

    Science.gov (United States)

    Esmaeili, Mohammad-Hossein; Kermani, Mojtaba; Parvishan, Asghar; Haghparast, Abbas

    2012-05-16

    Considerable evidences show that the VTA, as a major source of dopamine neurons projecting to cortical and limbic regions, has a major role in cognitive and motivating aspects of addiction. The current study assessed the ability of the selective D1 receptor antagonist SCH 23390 and D2 receptor antagonist sulpiride administrated into the CA1 region of hippocampus (dorsal hippocampus) to alter the rewarding effects of intra-VTA administration of morphine using the conditioned place preference (CPP). After bilaterally implantation of cannulae into the CA1 and/or VTA in adult male Wistar rats weighing 210-310 g, dose-response effects of different doses of intra-VTA morphine (0.03, 0.1, 0.3, 1 and 3 μg/side) on CPP paradigm were evaluated and animal displacement, conditioning score and locomotor activity were recorded by Ethovision software. In the next experiments, SCH 23390 (0.02, 0.05, 0.2 and 0.5 μg/side) or sulpiride (0.25, 0.75, 1.5 and 3 μg/side) were injected into the CA1, 5 min after intra-VTA injection of morphine during 3 days conditioning phase. Our results showed that intra-VTA morphine dose-dependently induces CPP in rats. Moreover, the blocking D1 and D2 receptors in the dorsal hippocampus decreased intra-VTA morphine-induced CPP significantly (Phippocampus have a key role in the development of CPP induced by morphine at the level of the VTA. It seems that there is an interaction between dopaminergic and opioidergic systems in these areas in reward circuit.

  19. Dopamine D1 and opioid receptor antagonists differentially reduce the acquisition and expression of fructose-conditioned flavor preferences in BALB/c and SWR mice.

    Science.gov (United States)

    Kraft, Tamar T; Yakubov, Yakov; Huang, Donald; Fitzgerald, Gregory; Natanova, Elona; Sclafani, Anthony; Bodnar, Richard J

    2015-11-01

    Sugar appetite is influenced by unlearned and learned preferences in rodents. The present study examined whether dopamine (DA) D1 (SCH23390: SCH) and opioid (naltrexone: NTX) receptor antagonists differentially altered the expression and acquisition of fructose-conditioned flavor preferences (CFPs) in BALB/c and SWR mice. In expression experiments, food-restricted mice alternately (10 sessions, 1h) consumed a flavored (e.g., cherry) 8% fructose+0.2% saccharin solution (CS+) and a differently-flavored (e.g., grape) 0.2% saccharin solution (CS-). Two-bottle CS choice tests (1h) occurred 0.5h following vehicle: SCH (200 or 800 nmol/kg) or NTX (1 or 5mg/kg). SCH, but not NTX significantly reduced CS+ preference in both strains. In acquisition experiments, 0.5h prior to 10 acquisition training sessions, vehicle, SCH (50 nmol/kg), NTX (1 mg/kg) or Limited Control vehicle treatments were administered, followed by two-bottle CS choice tests without injections. SCH and NTX reduced training intakes in both strains. BALB/c mice displayed hastened extinction of the fructose-CFP following training with SCH, but not NTX. SCH eliminated fructose-CFP acquisition in SWR mice, whereas NTX hastened extinction of the CFP. These results are compared to previous drug findings obtained with sucrose-CFPs in SWR and BALB/c mice, and are discussed in terms of differential effects of these sugars on oral and post-oral conditioning.

  20. 胖Zucker大鼠肠系膜动脉多巴胺D1受体介导的血管舒张功能受损及其机制%Impaired dopamine D1 receptor-mediated vasorelaxation of mesenteric arteries in obese Zucker rats and its underlying mechanisms

    Institute of Scientific and Technical Information of China (English)

    符金娟; 韩愈; 王震; 关蔚蔚; 刘渔凯; 杨迪; 黄河飞; 杨素菲; 曾春雨

    2014-01-01

    × 10-5 mol/L)pretreatment.Pre-incubated the mesenteric arteries with D1 receptor antagonist (SCH23390,1 × 10-7 mol/L) for 30 min to identify the specificity of D1 receptor-mediated vasorelaxation.D1 receptor expression of mesenteric arteries was tested by Western blot.Result Compared with lean Zucker rats,obese rats showed higher blood pressure and had obviously lower vasorelaxation subjected to Fenoldopam at 3× 10-6mol/L [(63.43±13.79)% vs (20.75± 8.60) %,P<0.01].Fenoldopam-induced vasorelaxation was endothelium-independent,as there was no different for this vasorelaxation in mesenteric arteries with or without intact endothelium (all P>0.05).Fenoldoparn induced vasorelaxation of all rats was blocked by SCH23390,which by itself had no effect on the mesenteric artery.Further,D1 receptor protein expression was found to be higher in the artery of lean Zucker rats than that of obese Zucker rats [(1.26±0.04)% vs (0.74±0.06)%,P<0.01].Conclusions Impaired dopamine D1 receptormediated vasorelaxation is observed in mesenteric artery of obese rather than lean Zucker rats,possibly due to the decreased expression of D1 receptor in resistance artery,which might be associated with high blood pressure in obese Zucker rats.

  1. Possible role of dopamine D1-like and D2-like receptors in behavioural activation and "contingent" reward evaluation in sodium-replete and sodium-depleted rats licking for NaCl solutions.

    Science.gov (United States)

    D'Aquila, Paolo S; Rossi, Roberta; Rizzi, Antonella; Galistu, Adriana

    2012-03-01

    Based on the different effects of the dopamine D1-like and D2-like receptor antagonists SCH 23390 and raclopride on the measures of licking microstructure in rats, we suggested that the level of activation of reward-associated responses depends on dopamine D1-like receptor stimulation, and is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated reward evaluation. To further test this hypothesis, we examined the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, 250μg/kg) and of the dopamine D1-like receptor antagonist SCH 23390 (0, 10, 20 and 40μg/kg) on the microstructure of licking for two different NaCl solutions (0.9% and 2.7%) in rats in sodium-replete status and in the sodium-depleted status induced by the diuretic drug furosemide. Rats were exposed to each solution for 180 seconds after the first lick. Both in sodium-replete and in sodium-depleted status, SCH 23390 produced a decrease of burst number, a measure of behavioural activation, without affecting their size, a measure of reward evaluation. Raclopride reduced burst number but appeared also to exert some effects on burst size. Sodium depletion resulted in an increased intake for both NaCl solutions due to an increase in burst number and size, and in a reduced sensitivity to the effect of raclopride on lick number. These results are not in contrast with the proposed hypothesis and are consistent with previous evidence suggesting a role for dopamine D2-like receptors in the increased NaCl appetite induced by sodium depletion.

  2. NMDA and dopamine D1 receptors within NAc-shell regulate IEG proteins expression in reward circuit during cocaine memory reconsolidation.

    Science.gov (United States)

    Li, Y; Ge, S; Li, N; Chen, L; Zhang, S; Wang, J; Wu, H; Wang, X; Wang, X

    2016-02-19

    Reactivation of consolidated memory initiates a memory reconsolidation process, during which the reactivated memory is susceptible to strengthening, weakening or updating. Therefore, effective interference with the memory reconsolidation process is expected to be an important treatment for drug addiction. The nucleus accumbens (NAc) has been well recognized as a pathway component that can prevent drug relapse, although the mechanism underlying this function is poorly understood. We aimed to clarify the regulatory role of the NAc in the cocaine memory reconsolidation process, by examining the effect of applying different pharmacological interventions to the NAc on Zif 268 and Fos B expression in the entire reward circuit after cocaine memory reactivation. Through the cocaine-induced conditioned place preference (CPP) model, immunohistochemical and immunofluorescence staining for Zif 268 and Fos B were used to explore the functional activated brain nuclei after cocaine memory reactivation. Our results showed that the expression of Zif 268 and Fos B was commonly increased in the medial prefrontal cortex (mPFC), the infralimbic cortex (IL), the NAc-core, the NAc-shell, the hippocampus (CA1, CA2, and CA3 subregions), the amygdala, the ventral tegmental area (VTA), and the supramammillary nucleus (SuM) following memory reconsolidation, and Zif 268/Fos B co-expression was commonly observed (for Zif 268: 51-68%; for Fos B: 52-66%). Further, bilateral NAc-shell infusion of MK 801 and SCH 23390, but not raclopride or propranolol, prior to addictive memory reconsolidation, decreased Zif 268 and Fos B expression in the entire reward circuit, except for the amygdala, and effectively disturbed subsequent CPP-related behavior. In summary, N-methyl-d-aspartate (NMDA) and dopamine D1 receptors, but not dopamine D2 or β adrenergic receptors, within the NAc-shell, may regulate Zif 268 and Fos B expression in most brain nuclei of the reward circuit after cocaine memory reactivation

  3. Roles of NMDA and dopamine D1 and D2 receptors in the acquisition and expression of flavor preferences conditioned by oral glucose in rats.

    Science.gov (United States)

    Dela Cruz, J A D; Coke, T; Icaza-Cukali, D; Khalifa, N; Bodnar, R J

    2014-10-01

    Animals learn to prefer flavors associated with the intake of sugar (sucrose, fructose, glucose) and fat (corn oil: CO) solutions. Conditioned flavor preferences (CFP) have been elicited for sugars based on orosensory (flavor-flavor: e.g., fructose-CFP) and post-ingestive (flavor-nutrient: e.g., intragastric (IG) glucose-CFP) processes. Dopamine (DA) D1, DA D2 and NMDA receptor antagonism differentially eliminate the acquisition and expression of fructose-CFP and IG glucose-CFP. However, pharmacological analysis of fat (CO)-CFP, mediated by both flavor-flavor and flavor-nutrient processes, indicated that acquisition and expression of fat-CFP were minimally affected by systemic DA D1 and D2 antagonists, and were reduced by NMDA antagonism. Therefore, the present study examined whether systemic DA D1 (SCH23390), DA D2 (raclopride) or NMDA (MK-801) receptor antagonists altered acquisition and/or expression of CFP induced by oral glucose that should be mediated by both flavor-flavor and flavor-nutrient processes. Oral glucose-CFP was elicited following by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in 8% glucose and another flavor (CS-, e.g., grape) mixed in 2% glucose. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 days. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 2% glucose occurred 0.5 h after systemic administration of vehicle (VEH), SCH23390 (50-800 nmol/kg), raclopride (50-800 nmol/kg) or MK-801 (50-200 μg/kg). Rats displayed a robust CS+ preference following VEH treatment (94-95%) which was significantly though marginally attenuated by SCH23390 (67-70%), raclopride (77%) or MK-801 (70%) at doses that also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH, SCH23390 (50-400 nmol/kg), raclopride (50-400 nmol/kg) or MK-801 (100 μg/kg) 0.5 h prior to ten 1-bottle training trials with CS+/8%G and CS-/2%G training solutions that was

  4. Dopamine D1 and opioid receptor antagonism effects on the acquisition and expression of fat-conditioned flavor preferences in BALB/c and SWR mice.

    Science.gov (United States)

    Kraft, Tamar T; Yakubov, Yakov; Huang, Donald; Fitzgerald, Gregory; Acosta, Vanessa; Natanova, Elona; Touzani, Khalid; Sclafani, Anthony; Bodnar, Richard J

    2013-09-01

    Sugar and fat appetites are influenced by unlearned and learned responses to orosensory and post-ingestive properties which are mediated by dopamine (DA) and opioid transmitter systems. In BALB and SWR mice, acquisition and expression of sucrose conditioned flavor preferences (CFP) are differentially affected by systemic DA D1 (SCH23390: SCH) and opioid (naltrexone: NTX) antagonism. The present study examined whether fat-CFP occurred in these strains using preferred (5%) and less preferred (0.5%) Intralipid solutions, and how SCH and NTX altered its expression and acquisition. Food-restricted mice drank flavored (CS+, e.g., cherry) 5% and flavored (CS-, e.g., grape) 0.5% Intralipid solutions in alternate 1 h/day sessions. Six two-bottle tests with both CS flavors presented in 0.5% Intralipid occurred. Robust and comparable fat-CFP was observed in both strains. In Experiment 2, vehicle (Veh), SCH (50-800 nmol/kg) or NTX (1-5 mg/kg) were administered prior to two-bottle testing in an identical paradigm. Expression of fat-CFP was significantly reduced by SCH and NTX in BALB mice, and only by SCH in SWR mice. NTX produced significantly greater inhibition of fat-CFP expression in BALB versus SWR mice. In Experiment 3, separate groups of BALB and SWR mice received Veh, SCH (50 nmol/kg) or NTX (1 mg/kg) injections prior to daily one-bottle CS+ and CS- training sessions to assess acquisition effects. Six two-bottle CS+ vs. CS- choice tests were then conducted. Fat-CFP acquisition was significantly reduced in SWR mice by SCH, but not NTX, and was only mildly affected by both antagonists in BALB mice. SCH produced significantly greater inhibition of fat-CFP acquisition in SWR versus BALB mice. The pattern of SCH effects upon the expression and acquisition of fat-CFP in BALB and SWR mice was quite similar to that observed for sucrose-CFP, suggesting similar DA D1 receptor involvement in sugar- and fat-CFP in these mouse strains.

  5. D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

    Science.gov (United States)

    Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

    2016-10-01

    The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine.

  6. Clebopride enhances contractility of the guinea pig stomach by blocking peripheral D2 dopamine receptor and alpha-2 adrenoceptor

    Energy Technology Data Exchange (ETDEWEB)

    Takeda, K.; Taniyama, K.; Kuno, T.; Sano, I.; Ishikawa, T.; Ohmura, I.; Tanaka, C. (Kobe Univ. School of Medicine, (Japan))

    1991-05-01

    The mechanism of action of clebopride on the motility of guinea pig stomach was examined by the receptor binding assay for bovine brain membrane and by measuring gastric contractility and the release of acetylcholine from the stomach. The receptor binding assay revealed that clebopride bound to the D2 dopamine receptor with a high affinity and to the alpha-2 adrenoceptor and 5-HT2 serotonin receptor with relatively lower affinity, and not to D1 dopamine, alpha-1 adrenergic, muscarinic acetylcholine, H1 histamine, or opioid receptor. In strips of the stomach, clebopride at 10{sup {minus} 8} M to 10{sup {minus} 5} M enhanced the electrical transmural stimulation-evoked contraction and the release of acetylcholine. This enhancement was attributed to the blockade of the D2 dopamine receptor and alpha-2 adrenoceptor because: (1) Maximum responses obtained with specific D2 dopamine receptor antagonist, domperidone, and with specific alpha-2 adrenoceptor antagonist, yohimbine, were smaller than that with clebopride, and the sum of the effects of these two specific receptor antagonists is approximately equal to the effect of clebopride. (2) The facilitatory effect of clebopride was partially eliminated by pretreatment of the sample with domperidone or yohimbine, and the facilitatory effect of clebopride was not observed in preparations treated with the combination of domperidone and yohimbine. Clebopride also antagonized the inhibitory effects of dopamine and clonidine on the electrical transmural stimulation-evoked responses. These results indicate that clebopride acts on post ganglionic cholinergic neurons at D2 and alpha-2 receptors in this preparation to enhance enteric nervous system stimulated motility.

  7. Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons.

    Science.gov (United States)

    Qian, Kun; Yu, Na; Tucker, Kristal R; Levitan, Edwin S; Canavier, Carmen C

    2014-12-01

    Dopamine neurons in freely moving rats often fire behaviorally relevant high-frequency bursts, but depolarization block limits the maximum steady firing rate of dopamine neurons in vitro to ∼10 Hz. Using a reduced model that faithfully reproduces the sodium current measured in these neurons, we show that adding an additional slow component of sodium channel inactivation, recently observed in these neurons, qualitatively changes in two different ways how the model enters into depolarization block. First, the slow time course of inactivation allows multiple spikes to be elicited during a strong depolarization prior to entry into depolarization block. Second, depolarization block occurs near or below the spike threshold, which ranges from -45 to -30 mV in vitro, because the additional slow component of inactivation negates the sodium window current. In the absence of the additional slow component of inactivation, this window current produces an N-shaped steady-state current-voltage (I-V) curve that prevents depolarization block in the experimentally observed voltage range near -40 mV. The time constant of recovery from slow inactivation during the interspike interval limits the maximum steady firing rate observed prior to entry into depolarization block. These qualitative features of the entry into depolarization block can be reversed experimentally by replacing the native sodium conductance with a virtual conductance lacking the slow component of inactivation. We show that the activation of NMDA and AMPA receptors can affect bursting and depolarization block in different ways, depending upon their relative contributions to depolarization versus to the total linear/nonlinear conductance.

  8. Cerebral hippocampal neuronal apoptosis following kainic acid-induced epilepsy and the intervention of antagonists of dopamine D1 and D2 receptors%红藻氨酸致痫后脑海马神经元凋亡与黑质多巴胺受体D1及D2拮抗剂的干预作用

    Institute of Scientific and Technical Information of China (English)

    王松青; 陈海棠; 柯以铨; 徐如祥; 姜晓丹; 张怡然; 陈利锋

    2005-01-01

    dopamine D2 receptors injected in substantia nigra, hippocampal cell apoptosis was aggravated (P =0.00).CONCLUSION: Injection of SCH23390, the antagonist of dopamine D1 receptors in substantia nigra cannot block kainic acid inducing epilepsy and epileptic electroencephalic activity is not weakened remarkably. Injection of haloperidol, the antagonist of dopamine D2 receptors enhances epileptic electroencephalic activity in kainic acid induced epilepsy and increases cell apoptosis remarkably in cerebral hippocampal CA3 area. It is to explain that it is dopamine D2 acceptor that is involved in regulation of temporal epilepsy in substantia nigra rather than D1 acceptor.%背景:多巴胺在中枢神经系统内与癫痫的发生及传导有密切关系,它的不同作用是特异的受体决定的.目的:建立颞叶癫痫模型.探讨黑质内给予多巴胺D1受体拮抗剂SCH23390及D2受体拮抗剂氟哌啶醇对红藻氨酸所致的颞叶癫痫发作和脑电活动的影响.设计:随机对照的验证性实验.单位:南方医科大学附属珠江医院神经医学研究实验室.材料:实验于2004-08/12在解放军第一军医大学珠江医院全军神经医学研究所进行,选择成年雄性SD大鼠30只,体质量250~300g.方法:①30只大鼠随机分为生理盐水对照组6只,红藻氨酸组6只和实验组18只,实验组大鼠又分为3个亚组,多巴胺D1受体拮抗剂SCH23390+红藻氨酸组,多巴胺D2受体拮抗剂氟哌啶醇+红藻氨酸组,生理盐水+红藻氨酸组,每组6只.生理盐水对照组单独右侧脑室注入生理盐水2 μL,红藻氨酸组予右侧脑室注入红藻氨酸2 μL,实验各组分别给予多巴胺D1受体拮抗剂SCH23390、多巴胺D2受体拮抗剂氟哌啶醇、生理盐水1 μL注入右侧黑质,同时红藻氨酸2 μL注入右侧脑室.②观察项目:实验各组给药后第0.5,1,2,6,24小时脑电图变化[以未出现癫痫样行为时脑电图为对照,当出现尖波、棘波、尖(棘)慢综合波、多棘

  9. D1-like dopamine receptor suppresses neuropeptide Y-induced proliferation in vascular smooth muscle cells%多巴胺D1类受体对神经肽Y受体介导的促血管平滑肌细胞增殖的影响

    Institute of Scientific and Technical Information of China (English)

    周永巧; 曾春雨; 王震; 刘莉; 王微; 韩愈; 陈彩宇; 任红梅; 何多芬; 杨剑

    2012-01-01

    Objective To determine the effect of D,-like dopamine receptor on neuropeptide Y ( NPY)-mediated proliferation in primary cultured vascular smooth muscle cells ( VSMCs) derived from thoracic aorta of Sprague-Dawley( SD) rats. Methods After VSMCs were isolated from SD rat thoracic aorta and identified by morphology and immunocytocchemistry, the cells at passage 4 to 8 were treated by 10 -8 to 10 -11 mol/L NPY in presence or absence of D,-like receptor agonist fenoldopam ( 10 -8 mol/L), blocker BIBP3226 (10-6mol/L), or antagonist SCH23390 (10-8mol/L)to observe NPY-mediated proliferation in VSMCs. The proliferation of VSMCs was investigated by [3H]-TdR incorporation and MTT assay. Results NPY resulted in an increased proliferation of VSMCs in a concentration-dependent manner, with a maximal proliferative amplitude of (77 ±9)% (P<0.05). D1-like receptor agonist, fenoldopam, completely blocked the NPY Y1-mediated proliferation in VSMCs, although the agonist had no effect on the proliferation of VSMCs by itself, which might be through protein kinase A pathway. Conclusion Activation of D, -like receptor inhibits NPY Y1-mediated proliferation in VSMCs,which might be involved in the pathogenesis of cardiovascular diseases.%目的 探讨多巴胺D1类受体对神经肽Y( neuropeptide Y,NPY)受体介导的Sprague-Dawley (SD)大鼠原代血管平滑肌细胞(vascular smooth muscle cells,VSMCs)增殖的影响.方法 以NPY( 10-8~10-11mol/L)刺激SD大鼠胸主动脉培养的VSMCs,观察在D1类多巴胺受体激动剂Fenoldopam( 10-8 mol/L)存在的情况下,神经肽Y促VSMCs增殖作用的变化.细胞增殖的检测采用[3H]胸腺嘧啶核苷([ 3H]-TdR)掺入率的变化表示及MTT方法.结果 NPY呈浓度依赖性促进SD大鼠VSMCs的异常增殖,最高增殖幅度达(77±9)%(P<0.05),该增殖作用由NPY Y,受体亚型介导.多巴胺D1类受体激动剂Fenoldopam对VSMCs无增殖影响,但Fenoldopam可抑制NPY Y1亚型受体介导VSMCs的增殖作用,该作

  10. 北极狐多巴胺受体D1基因的克隆测序%Cloning and Sequencing of Dopamine Receptor D1 Gene of Arctic Fox

    Institute of Scientific and Technical Information of China (English)

    王光圣; 白秀娟

    2007-01-01

    为了获得北极狐多巴胺受体D1基因序列,给北极狐自咬行为提供理论依据.采用聚合酶链式反应方法,从北极狐耳组织扩增出多巴胺受体D1基因的部分外显子序列,并对其进行克隆测序,将该序列提交到Genebank上.Genebank中的Blast分析表明,北极狐多巴胺D1受体基因与家狗(Canis familiaris)的同源性为99%,与牛(Bos taurus)的同源性为93%,与人(Homo sapiens)的同源性为92%.

  11. Dopamine D1 A receptor in the marginal division of rat neostriatum was involved in the learning and memory function%大鼠纹状体边缘区的多巴胺受体D1A参与了学习记忆功能

    Institute of Scientific and Technical Information of China (English)

    周莹; 蔡业峰; 李东风; 肖鹏; 舒斯云

    2012-01-01

    目的:研究多巴胺受体D1A在纹状体边缘区的分布及其是否参与了大鼠的学习记忆过程.方法:先用免疫组织化学方法观察多巴胺受体D1A在纹状体边缘区的分布,再向纹状体边缘区内立体定位微量注射多巴胺受体D1A拮抗剂SCH-23390(1%,0.1μl/侧)或等量的生理盐水,检测大鼠注射前后Y-迷宫结果的变化.结果:多巴胺受体D1A免疫组化阳性产物广泛分布于大脑皮层、海马、杏仁核、Meynert基核、下丘脑等处的胞体和突起上.在纹状体内,多巴胺受体D1A的阳性产物广泛而不均匀地分布于神经元的细胞核内,密度最大的区域在纹状体的尾内侧边缘.在纹状体尾内侧边缘,分布有多层密集平行排列的多巴胺受体D1A强阳性的椭圆形胞核,围绕苍白球外侧边缘,沿背腹方向呈带状分布,细胞核形态与位置和边缘区一致.行为实验证明,边缘区微量注射多巴胺受体D1A拮抗剂SCH-23390后,显著降低了大鼠的长期学习记忆能力.结论:大鼠脑纹状体边缘区神经元内存在多巴胺受体D1A,它们参与了成年SD大鼠的长期学习记忆功能.%Objective; To study the distribution of dopamine D1A receptor in the marginal division (MrD) of the rat striatum and its influence on the rat's learning and memory process. Methods; The immunohistochemistry method was used to investigate the distribution of dopamine D1A receptor in the MrD of rat striatum by using D1A receptor polyclone antibody. The Y-maze trained adult SD rats were accepted intra-MrD microjection of SCH-23390 (1 μg/side) or same volume of saline respectively and were tested by Y-maze again to observe whether the dopamine D1A receptor associated to learning and memory function of the rat. Results; The immunorealtivities of dopamine D1A receptor were observed widely distributed in the neurons of cerebral cortex, hippocampus, amygdala and hypothalamus. The immunoreactivities of dopamine Dl A receptors were

  12. Differential Involvement of Dopamine D1 Receptor and MEK Signaling Pathway in the Ventromedial Prefrontal Cortex in Consolidation and Reconsolidation of Recognition Memory

    Science.gov (United States)

    Maroun, Mouna; Akirav, Irit

    2009-01-01

    We investigated MEK and D1 receptors in the ventromedial prefrontal cortex (vmPFC) in consolidation and reconsolidation of recognition memory in rats nonhabituated to the experimental context (NH) or with reduced arousal due to extensive prior habituation (H). The D1 receptor antagonist enhanced consolidation and impaired reconsolidation in NH but…

  13. Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning.

    Science.gov (United States)

    Parker, Jones G; Zweifel, Larry S; Clark, Jeremy J; Evans, Scott B; Phillips, Paul E M; Palmiter, Richard D

    2010-07-27

    During Pavlovian conditioning, phasic dopamine (DA) responses emerge to reward-predictive stimuli as the subject learns to anticipate reward delivery. This observation has led to the hypothesis that phasic dopamine signaling is important for learning. To assess the ability of mice to develop anticipatory behavior and to characterize the contribution of dopamine, we used a food-reinforced Pavlovian conditioning paradigm. As mice learned the cue-reward association, they increased their head entries to the food receptacle in a pattern that was consistent with conditioned anticipatory behavior. D1-receptor knockout (D1R-KO) mice had impaired acquisition, and systemic administration of a D1R antagonist blocked both the acquisition and expression of conditioned approach in wild-type mice. To assess the specific contribution of phasic dopamine transmission, we tested mice lacking NMDA-type glutamate receptors (NMDARs) exclusively in dopamine neurons (NR1-KO mice). Surprisingly, NR1-KO mice learned at the same rate as their littermate controls. To evaluate the contribution of NMDARs to phasic dopamine release in this paradigm, we performed fast-scan cyclic voltammetry in the nucleus accumbens of awake mice. Despite having significantly attenuated phasic dopamine release following reward delivery, KO mice developed cue-evoked dopamine release at the same rate as controls. We conclude that NMDARs in dopamine neurons enhance but are not critical for phasic dopamine release to behaviorally relevant stimuli; furthermore, their contribution to phasic dopamine signaling is not necessary for the development of cue-evoked dopamine or anticipatory activity in a D1R-dependent Pavlovian conditioning paradigm.

  14. Ca2+-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and dopamine D1 receptors regulate GluA1 trafficking in striatal neurons.

    Science.gov (United States)

    Tukey, David S; Ziff, Edward B

    2013-12-06

    Regulation of striatal medium spiny neuron synapses underlies forms of motivated behavior and pathological drug seeking. A primary mechanism for increasing synaptic strength is the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into the postsynapse, a process mediated by GluA1 AMPAR subunit phosphorylation. We have examined the role of converging glutamate and dopamine inputs in regulating biochemical cascades upstream of GluA1 phosphorylation. We focused on the role of Ca(2+)-permeable AMPARs (CPARs), which lack the GluA2 AMPAR subunit. Under conditions that prevented depolarization, stimulation of CPARs activated neuronal nitric oxide synthase and production of cGMP. CPAR-dependent cGMP production was sufficient to induce synaptic insertion of GluA1, detected by confocal microscopy, through a mechanism dependent on GluA1 Ser-845 phosphorylation. Dopamine D1 receptors, in contrast, stimulate GluA1 extra synaptic insertion. Simultaneous activation of dopamine D1 receptors and CPARs induced additive increases in GluA1 membrane insertion, but only CPAR stimulation augmented CPAR-dependent GluA1 synaptic insertion. This incorporation into the synapse proceeded through a sequential two-step mechanism; that is, cGMP-dependent protein kinase II facilitated membrane insertion and/or retention, and protein kinase C activity was necessary for synaptic insertion. These data suggest a feed-forward mechanism for synaptic priming whereby an initial stimulus acting independently of voltage-gated conductance increases striatal neuron excitability, facilitating greater neuronal excitation by a subsequent stimulus.

  15. Dopamine receptors and hypertension.

    Science.gov (United States)

    Banday, Anees Ahmad; Lokhandwala, Mustafa F

    2008-08-01

    Dopamine plays an important role in regulating renal function and blood pressure. Dopamine synthesis and dopamine receptor subtypes have been shown in the kidney. Dopamine acts via cell surface receptors coupled to G proteins; the receptors are classified via pharmacologic and molecular cloning studies into two families, D1-like and D2-like. Two D1-like receptors cloned in mammals, the D1 and D5 receptors (D1A and D1B in rodents), are linked to adenylyl cyclase stimulation. Three D2-like receptors (D2, D3, and D4) have been cloned and are linked mainly to adenylyl cyclase inhibition. Activation of D1-like receptors on the proximal tubules inhibits tubular sodium reabsorption by inhibiting Na/H-exchanger and Na/K-adenosine triphosphatase activity. Reports exist of defective renal dopamine production and/or dopamine receptor function in human primary hypertension and in genetic models of animal hypertension. In humans with essential hypertension, renal dopamine production in response to sodium loading is often impaired and may contribute to hypertension. A primary defect in D1-like receptors and an altered signaling system in proximal tubules may reduce dopamine-mediated effects on renal sodium excretion. The molecular basis for dopamine receptor dysfunction in hypertension is being investigated, and may involve an abnormal posttranslational modification of the dopamine receptor.

  16. (-)-Stepholodine induced enhancement of cardiac muscle contractions mediated by D1 receptors

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shu-yuan; LIU Zheng; HU Hui-sheng; SHI Zhen; CHEN Long

    2008-01-01

    Objective To investigate the effect of (-)-Stepholidine (SPD) on enhancing D1 receptor mediated contraction of cardiac muscle in isolated rat heart and to examine whether SPD has a direct effect on the heart dopamine D1 receptors. SPD an active ingredient of the Chinese herb Stephania intermedia, binds to dopamine D1 and D2 like receptors. Biochemical, electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D(1/5) agonist and a D(2/4) antagonist, which could indicate unique antipsychotic properties. Methods Normal adult rat working hearts were isolated by Langendorff technique. Results SPD significantly increased the cardiac muscle contraction in a dose-dependent manner. The selective D1 dopamine receptor antagonist SCH23390 (1 μM) blocked the SPD induced heart contraction, however, neither the β-receptor antagonist propranolol (1 μM) nor the α1-receptor antagonist prazosin (1 μM) had any effect on blocking SPD induced heart contractions. Moreover, the L-type Ca2+ channel inhibitor nimodipine (1 μM) completely blocked the effect of SPD on cardiac muscle contraction. Conclusions SPD show the effect on enhancing contraction of isolated rat heart through activating L-type Ca2+ channel mediated by heart D1 receptors.

  17. MPTP Impairs Dopamine D1 Receptor-Mediated Survival of Newborn Neurons in Ventral Hippocampus to Cause Depressive-Like Behaviors in Adult Mice

    Science.gov (United States)

    Zhang, Tingting; Hong, Juan; Di, Tingting; Chen, Ling

    2016-01-01

    Parkinson’s disease (PD) is characterized by motor symptoms with depression. We evaluated the influence of dopaminergic depletion on hippocampal neurogenesis process to explore mechanisms of depression production. Five consecutive days of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice (MPTP-mice) reduced dopaminergic fibers in hippocampal dentate gyrus (DG). MPTP-mice exhibited depressive-like behaviors later for 2–3 weeks. BrdU was injected 4 h after last-injection of MPTP. BrdU-positive (BrdU+) cells in dorsal (d-DG) and ventral (v-DG) DG were examined on day 1 (D1), 7 (D7), 14 (D14) and 21 (D21) after BrdU injection. Fewer D7-, D14- and D21-BrdU+ cells or BrdU+/NeuN+ cells, but not D1-BrdU+ cells, were found in v-DG of MPTP-mice than in controls. However, the number of BrdU+ cells in d-DG did not differ between the both. Loss of doublecortin-positive (DCX+) cells was observed in v-DG of MPTP-mice. Protein kinase A (PKA) and Ca2+/cAMP-response element binding protein (CREB) phosphorylation were reduced in v-DG of MPTP-mice, which were reversed by D1-like receptor (D1R) agonist SKF38393, but not D2R agonist quinpirole. The treatment of MPTP-mice with SKF38393 on days 2–7 after BrdU-injection reduced the loss of D7- and D21-BrdU+ cells in v-DG and improved the depressive-like behaviors; these changes were sensitive to PKA inhibitor H89. Moreover, the v-DG injection of SKF38393 in MPTP-mice could reduce the loss of D21-BrdU+ cells and relieve the depressive-like behaviors. In control mice, the blockade of D1R by SCH23390 caused the reduction of D21-BrdU+ cells in v-DG and the depressive-like behaviors. Our results indicate that MPTP-reduced dopaminergic depletion impairs the D1R-mediated early survival of newborn neurons in v-DG, producing depressive-like behaviors.

  18. Dopamine D1/D5, but not D2/D3, receptor dependency of synaptic plasticity at hippocampal mossy fiber synapses that is enabled by patterned afferent stimulation, or spatial learning

    Directory of Open Access Journals (Sweden)

    Hardy Hagena

    2016-09-01

    Full Text Available Although the mossy fiber (MF synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH-CA1 and perforant path (PP-dentate gyrus (DG synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP and long-term depression (LTD. These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data

  19. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat

    DEFF Research Database (Denmark)

    Axel, Anne Marie Dixen; Mikkelsen, Jens D; Hansen, Henrik H

    2010-01-01

    Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management...... antagonist), or ritanserin (0.03 mg/kg, 5-HT(2A/C) receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate alpha(1) adrenoceptor and DA D(1) receptor function....... is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being...

  20. The orexin-1 receptor antagonist SB-334867 blocks the effects of antipsychotics on the activity of A9 and A10 dopamine neurons: implications for antipsychotic therapy.

    Science.gov (United States)

    Rasmussen, Kurt; Hsu, Mei-Ann; Yang, Yili

    2007-04-01

    Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day x 21 days, s.c.) or olanzapine (10 mg/kg/day x 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.

  1. [Effects of dopamine and adenosine on regulation of water-electrolyte exchange in Amoeba proteus].

    Science.gov (United States)

    Bagrov, Ia Iu; Manusova, N B

    2014-01-01

    Dopamine and adenosine both regulate transport of sodium chloride in the renal tubules in mammals. We have studied the effect of dopamine and adenosine on spontaneous activity of contractile vacuole of Amoeba proteous. Both substances stimulated contractile vacuole. The effect of dopamine was suppressed by D2 receptor antagonist, haloperidol, but not by D1 antagonist, SCH 39166. Adenylate cyclase inhibitor, 2.5-dideoxyadenosine, suppressed the effect of dopamine, but not of adenosine. Inhibitor of protein kinase C, staurosporine, in contrast, blocked the effect of adenosine, but not dopamine. Notably, dopamine opposed effect of adenosine and vice versa. These results suggest that similar effects of dopamine and adenosine could be mediated by different intracellulare mechanisms.

  2. Systemic catechol-O-methyl transferase inhibition enables the D1 agonist radiotracer R-[11C]SKF 82957

    DEFF Research Database (Denmark)

    Palner, Mikael; McCormick, Patrick; Parkes, Jun;

    2010-01-01

    R-[(11)C]-SKF 82957 is a high-affinity and potent dopamine D(1) receptor agonist radioligand, which gives rise to a brain-penetrant lipophilic metabolite. In this study, we demonstrate that systemic administration of catechol-O-methyl transferase (COMT) inhibitors blocks this metabolic pathway...

  3. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning

    Science.gov (United States)

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  4. Methylphenidate and cocaine have a similar in vivo potency to block dopamine transporters in the human brain

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D. [Brookhaven National Lab., Upton, NY (United States)]|[State Univ. of New York, Stony Brook, NY (United States). Dept. of Psychiatry; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1999-05-28

    The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Though cocaine and methylphenidate have similar in vitro affinities for DAT the abuse of methylphenidate in humans is substantially lower than of cocaine. To test if differences in in vivo potency at the DAT between these two drugs could account for the differences in their abuse liability the authors compared the levels of DAT occupancies that they had previously reported separately for intravenous methylphenidate in controls and for intravenous cocaine in cocaine abusers. DAT occupancies were measured with Positron Emission Tomography using [{sup 11}C]cocaine, as a DAT ligand, in 8 normal controls for the methylphenidate study and in 17 active cocaine abusers for the cocaine study. The ratio of the distribution volume of [{sup 11}C]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd+1, was used as measure of DAT availability. Parallel measures were obtained to assess the cardiovascular effects of these two drugs. Methylphenidate and cocaine produced comparable dose-dependent blockage of DAT with an estimated ED{sub 50} for methylphenidate of 0.07 mg/kg and for cocaine of 0.13 mg/kg. Both drugs induced similar increases in heart rate and blood pressure but the duration of the effects were significantly longer for methylphenidate than for cocaine.

  5. Differential effects of a selective dopamine D1-like receptor agonist on motor activity and c-fos expression in the frontal-striatal circuitry of SHR and Wistar-Kyoto rats

    Directory of Open Access Journals (Sweden)

    Diaz Heijtz Rochellys

    2006-05-01

    Full Text Available Abstract Background Molecular genetic studies suggest the dopamine D1 receptor (D1R may be implicated in attention-deficit/hyperactivity disorder (ADHD. As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. Methods We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg, on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR, the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived. Results SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum of SHR when compared to WKY rats

  6. Dopamine receptor and hypertension.

    Science.gov (United States)

    Zeng, Chunyu; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2005-01-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and reactive oxygen and by interacting with vasopressin, renin-angiotensin, and the sympathetic nervous system. Decreased renal dopamine production and/or impaired dopamine receptor function have been reported in hypertension. Disruption of any of the dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) results in hypertension. In this paper, we review the mechanisms by which hypertension develops when dopamine receptor function is perturbed.

  7. Differential effects of dopamine receptor D1-type and D2-type antagonists and phase of the estrous cycle on social learning of food preferences, feeding, and social interactions in mice.

    Science.gov (United States)

    Choleris, Elena; Clipperton-Allen, Amy E; Gray, Durene G; Diaz-Gonzalez, Sebastian; Welsman, Robert G

    2011-07-01

    The neurobiological bases of social learning, by which an animal can 'exploit the expertise of others' and avoid the disadvantages of individual learning, are only partially understood. We examined the involvement of the dopaminergic system in social learning by administering a dopamine D1-type receptor antagonist, SCH23390 (0.01, 0.05, and 0.1 mg/kg), or a D2-type receptor antagonist, raclopride (0.1, 0.3, and 0.6 mg/kg), to adult female mice prior to socially learning a food preference. We found that while SCH23390 dose-dependently inhibited social learning without affecting feeding behavior or the ability of mice to discriminate between differently flavored diets, raclopride had the opposite effects, inhibiting feeding but leaving social learning unaffected. We showed that food odor, alone or in a social context, was insufficient to induce a food preference, proving the specifically social nature of this paradigm. The estrous cycle also affected social learning, with mice in proestrus expressing the socially acquired food preference longer than estrous and diestrous mice. This suggests gonadal hormone involvement, which is consistent with known estrogenic regulation of female social behavior and estrogen receptor involvement in social learning. Furthermore, a detailed ethological analysis of the social interactions during which social learning occurs showed raclopride- and estrous phase-induced changes in agonistic behavior, which were not directly related to effects on social learning. Overall, these results suggest a differential involvement of the D1-type and D2-type receptors in the regulation of social learning, feeding, and agonistic behaviors that are likely mediated by different underlying states.

  8. 高血压患者多巴胺受体D1-A/G基因型与全麻围拔管期心血管反应的关系%Relationship between dopamine D1 receptor-48A/G genotypes and hemodynamic response to extubation in patients with essential hypertension

    Institute of Scientific and Technical Information of China (English)

    王军; 胡毅平; 孙含哲; 李筱; 穆会君

    2011-01-01

    目的 探讨原发性高血压患者多巴胺受体D1-48A/G基因型与全麻围拔管期心血管反应的关系.方法 有EH病史的腹部手术患者120例,用RFLP-PCR法测定多巴胺受体D1-48A/G基因型.按基因型均分为A、C组(均为 AG+GG型)和B组(从型).三组均以相同麻醉药诱导及维持.C组拔管前5 min泵注硝酸甘油1~1.5μg·kg-1·min-1控制性降压.于术毕、拔管后0、1.5、5、15 min记录收缩压(SBP)、舒张压(DBP)、心率(HR)和ECG.结果 拔管后0、1.5、5和15 min,SBP、DBP、HR,A、B组均明显高于术毕(P<0.01或P<0.05).拔管后0,1.5、5和15min,A组SBP明显高于C组,DBP明显高于B、C组(P<0.01).A组围拔管期心律失常明显多于B、C组(P<0.05).结论 AG型高血压患者围拔管期血液动力学变化明显,硝酸甘油对此有一定防治效果.%Objective To investigate the relationship between different dopamine D1 receptor48A/G genotypes and hemodynamic response to tracheal extubation in patients with essential hypertension(EH). Methods One hundred and twenty adult patients with EH undergoing abdominal surgery were divided into three groups with 40 cases each, in whom dopamine D1 receptor-48A/G genotype was detected by RFLP-PCR. Groups of A and C were the patients with AG+GG genotype and group B with AA genotype. The patients in group C were treated with nitroglycerin for deliberate hypotension before extuhation. Anesthesia in all patients was induced and maintained with same techniques and drugs. SBP,DBP, HR and ECG were recorded at the end of surgery and at 0,1. 5,5,and 15 rain after extubation. Results Compared with those at the end of operation,SBP,DBP and HR increased markedly in groups of A and B at 0,1.5, 5 and 15 min after extubation (P<0. 01 or P<0.05). At 0,1.5,5 and 15 rain after extubation,SBP was higher in group A than that in group C,and DBP was higher in group A than that in groups of B and C(P<0.01). The incidence of cardiac arrhythmias in group A was higher

  9. Effects of dopamine antagonists on methamphetamine-induced dopamine release in high and low alcohol preference rats.

    Science.gov (United States)

    Nishiguchi, Minori; Kinoshita, Hiroshi; Kasuda, Shogo; Takahashi, Montonori; Yamamura, Takehiko; Matsui, Kiyoshi; Ouchi, Harumi; Minami, Takako; Hishida, Shigeru; Nishio, Hajime

    2010-03-01

    The authors have previously shown that high alcohol preference rats (HAP) have a significantly higher sensitivity than low alcohol preference rats (LAP) for methamphetamine (MAP). In this study, changes in dopamine and serotonin release induced by MAP (1 mg/kg, intraperitoneally) after pre-treatment with D1 and D2 receptor antagonists were examined in the striatum of rats with different alcohol preferences to elucidate differences in receptor levels between the two rat strains. D1 receptor antagonist SCH23390 or D2 receptor antagonist haloperidol were administrated intracerebroventricularly 10 min before MAP stimulation. This study investigated the effect of methamphetamine-induced dopamine and serotonin release in striatum using microdialysis of freely moving rats coupled to ECD-HPLC. With haloperidol treatment both strains of rats showed a significantly greater maximum increase on MAP-induced dopamine release compared with respective control rats. However, after SCH23390 treatment only HAP rats showed a significantly greater increase in dopamine release compared with controls. SCH23390 blocks mainly D1 receptors only in the post-synaptic membrane, whereas haloperidol blocks D2 receptors in both the pre-synaptic and post-synaptic membranes. The MAP-induced increase in dopamine release following haloperidol pre-treatment was greater than SCH23390 pre-treatment in both strains. This result indicates that D2 receptors (autoreceptors) in the pre-synaptic membrane were blocked, leading to the elimination of the feedback function that regulates dopamine release. These data suggested that alcohol preference is associated with the action of MAP, and the dopaminergic mechanism, specifically the D1 system in the striatum, might have a different pathway dependent on alcohol preference.

  10. Effects of dopamine on adenylyl cyclase activity and amylase secretion in rat parotid tissue.

    Science.gov (United States)

    Hatta, S; Amemiya, N; Takemura, H; Ohshika, H

    1995-06-01

    Several previous studies have shown that dopamine causes amylase secretion from rat parotid tissue. However, the mechanism of this dopamine action is still unclear. The present study was designed to characterize dopamine action in rat parotid gland tissue by examining the effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release. Dopamine significantly enhanced accumulation of cyclic AMP in parotid slices and stimulated adenylyl cyclase activity in parotid membrane preparations. It also significantly stimulated amylase release from parotid slices. The stimulatory effects of dopamine on cyclic AMP accumulation, adenylyl cyclase activity, and amylase release were effectively blocked with propranolol, a beta-adrenergic antagonist, but not by either SCH 23390, a preferential D1 antagonist, or butaclamol, a preferential D2 antagonist. No substantial specific binding sites for D1 receptors were detectable by [3H]SCH 23390 binding in parotid membranes. These results suggest that the stimulatory effect of dopamine on amylase secretion in rat parotid tissue is not mediated through specific D1 dopamine receptors but rather through beta-adrenergic receptors.

  11. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice

    OpenAIRE

    Wang, Xiaoyan; Villar, Van Anthony M.; Armando, Ines; Eisner, Gilbert M.; Felder, Robin A.; Pedro A. Jose

    2008-01-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D1-like (D1, D5) and D2-like (D2, D3, D4) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models...

  12. Research on hemodynamic response to endotracheal intubation in hypertensive patients of different dopamine D1 receptor genotypes%不同多巴胺D1受体基因型高血压患者气管插管反应的研究

    Institute of Scientific and Technical Information of China (English)

    王军; 王志萍; 黄东晓; 孙含哲; 穆会君

    2011-01-01

    研究不同多巴胺D1受体(DRD1)基因型48A/G原发性高血压患者全麻气管插管心血管反应.方法原发性高血压患者120例,ASAⅡ或Ⅲ级,按照基因型进行分组,A、C组为AG/GG型,B组为AA型,每组40例.C组气管插管前10 s静注乌拉地尔25 mg.于诱导前、诱导后、插管后0、1.5、5 min测定SBP、DBP、HR和ECG.结果 与诱导前比较,A、B组插管后0、1.5、5min SBP、DBP升高,HR显著增快(P<0.05或P<0.01),C组SBP、DBP升高不明显.插管后0、1.5、5 min A组DBP明显高于、HR快于B、C组(P<0.05或P<0.01).A组气管插管时心律失常发生率明显多于B、C组(P<0.05).结论AG/GG型原发性高血压患者气管插管时血流动力学变化明显,麻醉诱导前静注乌拉地尔可以起到预防作用.%Objective To investigate hemodynamic response to endotracheal intubation under general anesthesia in patients of different dopamine D1 receptor -48A/G genotypes with essential hypertension (EH). Methods One hundred and twenty patients with EH (ASA Ⅱ or Ⅲ) undergoing abdominal surgery were divided into three groups according to dopamine Dl receptor genotypes. The patients in group A and C were AG + GG genotype, and those in group B were AA genotype. 25mg Urapidil was intravenously injected 10s before intubation in group C. SBP, DBP, HR and ECG were recorded before and after induction, 0 min, 1. 5 min and 5 min after intubation. Results Compared with baseline level before induction, SBP, DBP and HR at 0 min, 1. 5 min, 5 min after intubation increased significantly in group A and B (P<0. 05 or P<0. 01), whereas SBP.DBP did not increase significantly in group C. DBP and HR in group A increased more significantly at 0 min, 1. 5 min, 5 min after intubation compared with group B and C (P<0. 05 or P<0. 01). The incidence of cardiac arrhythmias in group A was higher than that in group B and C (P<0. 05). Conclusion EH patients of AG/GG genotype show significant hemodynamic fluctuation during

  13. Study on Relationship between Dopamine D1 Receptor Gene Polymorphisms and Clozapine Efficacy in Male Schizophrenic Patients%男性精神分裂症患者服用氯氮平疗效与多巴胺D1受体基因多态性的相关性研究

    Institute of Scientific and Technical Information of China (English)

    陈颖; 吴娜; 瞿发林; 魏渊; 余海鹰; 汪广剑; 陈方斌

    2014-01-01

    Objective:To investigate the relationship between dopamine D1 receptor ( DRD1 ) gene polymorphisms and clozapine efficacy in male schizophrenic patients. Methods:Totally 46 male schizophrenic patients were treated by clozapine for 6-8 weeks. The clinical response was determined by the Positive and Negative Symptom Scale (PANSS). DRD1 gene rs265981, rs5326, rs4532, rs1799914, rs686 and rs4867798 polymorphisms were detected by the gene sequencing, while plasma clozapine levels were monitored during the treatment. Results:The total clinical efficacy of clozapine response group and the non-response group was compared, the distribution of rs265981 genotype TT, TC and CC and allele T and C had statistically significant differences (P=0. 025;P=0. 005), and the distribution of rs686 genotype CC, CT and TC and allele C and T had statistically significant differences ( P=0. 044;P=0. 010). The negative symptom of the response group was compared with that of the non-response group, the distribution of rs4532 gen-otype GG, GA and AA and allele G and A had statistically significant differences (P=0. 034; P=0. 013). Conclusion: The poly-morphisms of DRD1 gene rs265981 and rs686 may have influence on the clinical efficacy of clozapine, and rs4532 may have influence on the negative symptom.%目的::探讨中国男性精神分裂症患者多巴胺D1受体基因多态性对服用氯氮平后血药浓度与疗效的影响。方法:46例男性精神分裂症患者单一服用氯氮平治疗6~8周,采用阳性与阴性症状量表( PANSS)评定氯氮平的疗效。测定氯氮平血药浓度,并通过测定基因序列检测多巴胺D1受体上rs265981、rs5326、rs4532、rs1799914、rs686、rs4867798等6个SNP位点的基因型和等位基因频率。结果:氯氮平总疗效有效组与无效组相比,rs265981基因型TT、TC、CC及等位基因T、C的分布差异有统计学意义(P =0.025;P =0.005),rs686基因型 CC、CT、TC 及等位基因 C、T 的分

  14. Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice.

    Science.gov (United States)

    Wang, Xiaoyan; Villar, Van Anthony M; Armando, Ines; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2008-12-01

    Dopamine is important in the pathogenesis of hypertension because of abnormalities in receptor-mediated regulation of renal sodium transport. Dopamine receptors are classified into D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) subtypes, all of which are expressed in the kidney. Mice deficient in specific dopamine receptors have been generated to provide holistic assessment on the varying physiological roles of each receptor subtype. This review examines recent studies on these mutant mouse models and evaluates the impact of individual dopamine receptor subtypes on blood pressure regulation.

  15. 烟碱上调大鼠脑纹状体多巴胺D1受体mRNA表达诱导其行为改变%Chronic nicotine induces the changes of locomotor activities in rats by increasing the mRNA levels of dopamine D1 receptor in striatum

    Institute of Scientific and Technical Information of China (English)

    陈涛; 郭纪锋; 唐北沙; 廖小平; 文国强; 严新翔; 江泓; 张玉虎; 龙志刚; 欧阳锋

    2006-01-01

    反转录聚合酶链反应和设定的引物,得到多巴胺Di,D2受体及actin的扩增产物分别为350 bp,399 bp,218 bp,与预计值一致.③在大鼠纹状体内,烟碱组多巴胺D1受体mRNA表达比对照组上升23%(分别为98.63±1.13,65.29±1.45,P<0.01),两组多巴胺D2受体mRNA的表达差异无显著性意义(P>0.01).结论:烟碱可能通过上调大鼠纹状体多巴胺D1受体mRNA的表达而诱导大鼠行为改变.%BACKGROUND: Nicotine, which is a known central nervous system stimulant, appears to be the neuroprotective factor of Parkinson disease(PD). It has been reported that PD patients' symptoms such as trembling,rigor, hypokinesia are ameliorated during smoking, but its mechanism still keeps unclear.OBJECTIVE: To observe the effects of nicotine on gene expression levels of dopamine D1 and D2 receptors (D1R,D2R)in striatum of rats and analyze the possible mechanism of behavioral changes of rats induced by nicotine.DESIGN:Randomized and controlled experiment.SETTING:Institute of Neurology, Xiangya Hospital, Central South University.MATERIALS :Twenty-four SD rats aged at 10 weeks were chosen,weighing 180-200 g. Nicotine (Sigma),revert AidTM M-Mulv reverse transcriptase (MBI Fermentas,USA), polymerase chain reaction (RCR,Beckman),densitometric scanning imaging system (Stratagene Eagle Eye Ⅱ ,USA).METHODS :This experiment was carried out in the Laboratory of Institute of Neurology, Xiangya Hospital,Central South University from July 2001 to July 2002. These rats were divided into two groups: control group (n=12)and nicotine group(n=12). The level of D1 and D2 receptors on striatum of rats was estimated at the timepoint of thirty-minute after chronic nicotine administration (4 mg/kg per day s.c.), and the behavioral activities were also recorded at the same timepoint for thirty minutes. The functional behavioral activities recorded included: rearing up repeatedly, moving about, provoking, climbing, grooming, yawning, rotating, smelling

  16. 首发精神分裂症患者认知功能与多巴胺D1受体基因的关联研究%Association study of dopamine D1 receptor gene and cognitive function of first-episode schizophrenic patients

    Institute of Scientific and Technical Information of China (English)

    张晨; 李则挚; 吴志国; 陈俊; 彭代辉; 方贻儒; 禹顺英

    2011-01-01

    目的 探讨首发精神分裂症患者认知功能与多巴胺D1受体基因间的关系.方法 使用韦氏成人智力量表(WAIS-R)、韦氏记忆量表(WMS)、威斯康星卡片分类测验(WCST)评定112例首发精神分裂症患者和60例健康对照者的认知功能,并利用TaqMan荧光探针SNP基因分型技术对DRD1基因rs4532位点进行基因分型.结果 患者组与对照组间DRD1基因rs4532位点基因型及等位基因频率分布的差异无统计学意义(分别为x2=2.90,P=0.35;x2=0.01,P=0.93);WCST各指标在病例组与对照组之间存在显著性差异(P<0.01);携带rs4532G等位基因的精神分裂症患者WCST中持续性错误率显著高于不携带rs4532G等位基因的患者[分别为(60.9±13.2)%,(44.9±21.3)%,t=4.79,P=0.00002].结论 DRD1基因rs4532多态性位点可能与精神分裂症患者执行功能损害有关.%Objective To investigate the relationship between cognitive function of first-episode schizophrenic patients and dopamine D1 receptor gene. Methods A total of 112 first-episode schizophrenic patients and 60 healthy controls were evaluated with Wechsler adult intelligence scale ( WAIS-R), Wechsler memory scale (WMS) and Wisconsin card sort test (WCST) ,and genotyped one polymorphism (rs4532) within DRD1 gene using TaqMan SNP genotyping assay. Results There were no significant differences on the frequencies of the genotypes and alleles of rs4532 polymorphism between patients with schizophrenia and normal controls ( x2 =2.90, P=0.35; x2 = 0.01, P= 0. 93 ). There were significant differences in all index of WCST between two groups (P <0.01 ). Patients with rs4532G allele had worse WCST performance than those without G allele ((60.9 ± 13.2)%vs (44.9 ±21.3)%, t=4.79, P=0.00002). Conclusion Rs4532 polymorphism of DRD1 gene may be associated with executive function impairment in schizophrenic patients.

  17. Gene-gene interaction between genes of brain-derived neurotrophic factor and dopamine D1 receptor in schizophrenia%精神分裂症患者脑源性神经营养因子与多巴胺D1受体基因交互作用研究

    Institute of Scientific and Technical Information of China (English)

    卢卫红; 张晨; 易正辉; 吴志国; 陈俊; 方贻儒

    2013-01-01

    目的 探讨多巴胺D1受体(DRD1)与精神分裂症的关系是否与脑源性神经营养因子(BDNF)有关.方法 选取BDNF基因Val66Met位点(rs6562)以及DRD1基因5个标签单核苷酸多态性(SNP)(rs4532、rs5326、rs2168631、rs6882300和rs267418),采用TaqMan探针SNP基因分型技术对340例精神分裂症患者(患者组)和375名健康对照者(对照组)进行检验,使用多因子降维法软件(MDR)分析基因-基因交互作用.结果 以上6个SNP基因型及等位基因频率分布在患者组与对照组之间差异无统计学意义(Ps>0.0083);MDR分析结果显示,BDNF与DRD1基因交互作用存在于两位点模型(rs6265-rs5326)[OR=1.83,95%可信区间(CI):1.33~2.53;x2=13.91,P=0.0002],三位点模型(rs6265-rs4532-rs6882300)(OR=2.06,95% CI:1.53~2.78;x2=22.73,P<0.0001)及四位点模型(rs6265-rs5326-rs2168631-rs6882300)(OR =2.85,95% CI:2.09 ~ 3.89;x2=44.99,P<0.0001).结论 精神分裂症患者BDNF与DRD1基因存在交互作用,DRD1在精神分裂症发生过程中的作用可能与BDNF有关.%Objective To explore the impact of brain-derived neurotrophic factor(BDNF) on the contribution of dopamine D1 receptor (DRD1) to schizophrenia.Methods One single nucleotide polymorphism (SNP) (Va166Met,rs6562) within BDNF gene and five tag-SNPs (rs4532,rs5326,rs2168631,rs6882300 and rs267418) within DRD1 gene were genotyped in 340 schizophrenic patients and 375 healthy controls.The gene-gene interaction between BDNF and DRD1 was analyzed by Multifactor Dimensionality Reduction (MDR) software.Results There were no significant differences on the frequencies of the genotypes and alleles of the six SNPs between patients and controls (Ps > 0.0083).MDR revealed that the significance were shown in patterns with 2 SNPs (rs6265-rs5326; OR =1.83,95% CI:1.33-2.53,x2 =13.91,P =0.0002),3 SNPs (rs6265-rs4532-rs6882300 ; OR =2.06,95% CI:1.53-2.78,x2 =22.73,P < 0.0001) and 4 SNPs (rs6265-rs5326-rs2168631-rs6882300; OR =2.85,95

  18. 多巴胺D1受体基因与精神分裂症患者症状数量性状的关联分析%Association analysis between dopamine D1 receptor gene and symptom quantitative trait of schizophrenia

    Institute of Scientific and Technical Information of China (English)

    张晨; 吴志国; 邵阳; 李则挚; 禹顺英; 方贻儒

    2011-01-01

    Objective To explore the relationship between dopamine D1 receptor gene (DRD1)and symptom quantitative trait of schizophrenia. Methods Peripheral blood samples were collected from 211 schizophrenics and 247 healthy controls at our center. Five tag SNPs (single nucleotide polymorphisms) (rs4532, rs5326, rs2168631, rs6882300 & rs267418) within DRD1 gene were genotyped by TaqMan SNP genotyping assay. The positive and negative syndrome scale (PANSS) was used to quantify the phenotypes of schizophrenia. Results No significant differences existed in the frequencies of genotypes and alleles of DRD1 gene between the schizophrenics and normal controls ( Ps > 0.05 ); strong linkage disequilibrium was observed between rs4532 and rs5326 ( D'= 0.84 ); no significant difference of haplotypic distribution was identified between the patients and controls ( Ps > 0. 05 ); the patients with rs4532G allele had a higher negative subscale score than those without G allele (20.3 ± 3.3 vs 18.2 ± 3.9, P < 0. 01 ). Conclusion The rs4532 within DRD1 gene may be associated with negative symptom quantitative trait in schizophrenia.%目的 探讨多巴胺D1受体基因(DRD1)与精神分裂症患者症状数量性状的关联.方法 2006年1月至2007年12月在上海交通大学医学院附属精神卫生中心收集211例精神分裂症患者和247名健康对照者的临床资料及外周静脉血并提取DNA,采用TaqMan荧光探针SNP基因分型技术对DRD1基因的5个标签单核苷酸多态性(rs4532、rs5326、rs2168631、rs6882300及rs267418)进行检查,使用阳性和阴性症状量表(PANSS)评定患者疾病表型的数量性状.结果 患者组与对照组间DRD1基因5个标签SNP的基因型及等位基因频率分布的差异无统计学意义(Ps>0.05);rs4532-rs5326之间存在连锁不平衡(D'=0.84);单体型分析显示各单体型分布频率差异在病例组与对照组间差异无统计学意义(Ps>0.05);携带rs4532G等位基因患者的阴性症状分显

  19. Dopamine in the dorsal hippocampus impairs the late consolidation of cocaine-associated memory.

    Science.gov (United States)

    Kramar, Cecilia P; Chefer, Vladimir I; Wise, Roy A; Medina, Jorge H; Barbano, M Flavia

    2014-06-01

    Cocaine is thought to be addictive because it elevates dopamine levels in the striatum, reinforcing drug-seeking habits. Cocaine also elevates dopamine levels in the hippocampus, a structure involved in contextual conditioning as well as in reward function. Hippocampal dopamine promotes the late phase of consolidation of an aversive step-down avoidance memory. Here, we examined the role of hippocampal dopamine function in the persistence of the conditioned increase in preference for a cocaine-associated compartment. Blocking dorsal hippocampal D1-type receptors (D1Rs) but not D2-type receptors (D2Rs) 12 h after a single training trial extended persistence of the normally short-lived memory; conversely, a general and a specific phospholipase C-coupled D1R agonist (but not a D2R or adenylyl cyclase-coupled D1R agonist) decreased the persistence of the normally long-lived memory established by three-trial training. These effects of D1 agents were opposite to those previously established in a step-down avoidance task, and were here also found to be opposite to those in a lithium chloride-conditioned avoidance task. After returning to normal following cocaine injection, dopamine levels in the dorsal hippocampus were found elevated again at the time when dopamine antagonists and agonists were effective: between 13 and 17 h after cocaine injection. These findings confirm that, long after the making of a cocaine-place association, hippocampal activity modulates memory consolidation for that association via a dopamine-dependent mechanism. They suggest a dynamic role for dorsal hippocampal dopamine in this late-phase memory consolidation and, unexpectedly, differential roles for late consolidation of memories for places that induce approach or withdrawal because of a drug association.

  20. Actions of dopamine antagonists on stimulated striatal and limbic dopamine release: an in vivo voltammetric study.

    OpenAIRE

    Stamford, J. A.; Kruk, Z L; Millar, J.

    1988-01-01

    1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (c...

  1. Renal dopamine receptors and hypertension.

    Science.gov (United States)

    Hussain, Tahir; Lokhandwala, Mustafa F

    2003-02-01

    Dopamine has been recognized as an important modulator of central as well as peripheral physiologic functions in both humans and animals. Dopamine receptors have been identified in a number of organs and tissues, which include several regions within the central nervous system, sympathetic ganglia and postganglionic nerve terminals, various vascular beds, the heart, the gastrointestinal tract, and the kidney. The peripheral dopamine receptors influence cardiovascular and renal function by decreasing afterload and vascular resistance and promoting sodium excretion. Within the kidney, dopamine receptors are present along the nephron, with highest density on proximal tubule epithelial cells. It has been reported that there is a defective dopamine receptor, especially D(1) receptor function, in the proximal tubule of various animal models of hypertension as well as in humans with essential hypertension. Recent reports have revealed the site of and the molecular mechanisms responsible for the defect in D(1) receptors in hypertension. Moreover, recent studies have also demonstrated that the disruption of various dopamine receptor subtypes and their function produces hypertension in rodents. In this review, we present evidence that dopamine and dopamine receptors play an important role in regulating renal sodium excretion and that defective renal dopamine production and/or dopamine receptor function may contribute to the development of various forms of hypertension.

  2. Effects of D1-like Dopamine Receptor on Insulin Receptor-mediated Proliferation of Vascular Smooth Muscle Cells%多巴胺D1类受体对胰岛素受体介导的血管平滑肌细胞增殖的影响

    Institute of Scientific and Technical Information of China (English)

    韩愈; 曾春雨; 杨剑; 黄河飞; 石伟彬; 傅春江; 何多芬; 杨成明; 黄岚; 周林

    2007-01-01

    目的 观察多巴胺D1类受体对胰岛素受体介导的血管平滑肌细胞增殖的影响.方法 本研究以A10细胞为研究对象,观察刺激D1类受体对胰岛素促增殖作用的影响,并用免疫印迹研究D1类受体影响胰岛素作用的机制.细胞增殖作用采用[3H]胸腺嘧啶核苷(3H-TdR)掺入量表示.结果 胰岛素可促进A10细胞的增殖,该作用呈现浓度依赖性的.D1类受体激动剂Fenoldopam本身对A10细胞无增殖影响,但Fenoldopam通过D1类受体可完全阻断胰岛素介导的血管平滑肌细胞增殖作用.免疫印迹显示刺激D1类受体可降低胰岛素受体的蛋白表达,提示该机制可能参与了D1类受体对胰岛素受体作用的过程.结论 D1类受体对胰岛素受体介导的血管平滑肌细胞增殖具有抑制作用,该作用可能在高血压的发生发展中发挥一定作用.

  3. 电针联合多巴胺D1受体拮抗剂对脑缺血-再灌注后大鼠体感诱发电位及行为学的影响%Effects of Electroacupuncture plus Dopamine D1 Receptor Antagonist on Somatosensory Evoked Potentials and Behavioral Changes in Rats with Cerebral Ischemia-reperfusion

    Institute of Scientific and Technical Information of China (English)

    刘成勇; 徐鸣曙; 葛林宝

    2012-01-01

    目的:研究电针联合多巴胺D1受体(D1 Receptor,D1R)拮抗剂对脑缺血再灌注后大鼠体感诱发电位(Somatosensory Evoked Potential,SEP)及行为学的影响.方法:将40只雄性SD大鼠随机分为正常组、模型组、电针组、D1R拮抗剂组、电针+D1R拮抗剂组,每组8只.除正常组外,其余4组制作大鼠脑缺血-再灌注模型,模型成功后予相应处理.分别于处理前、造模即刻、实验结束时检查大鼠SEP,并进行神经功能缺损评分(Neural Function Defect Score,NFDS)和平衡木试验.结果:治疗后电针组、D1R拮抗剂组及电针+D1R拮抗剂组SEP均有明显恢复,与模型组差异均有统计学意义(P<0.05).模型组行为学评分有明显降低,与正常组有统计学差异(P<0.05).治疗后,电针组、D1R拮抗剂组及电针+D1R拮抗剂组有明显改善,与模型组差异均有统计学意义(P<0.05).结论:电针与D1R拮抗剂均能促进脑缺血损伤后神经功能恢复,具有脑保护作用,联合使用没有发生协同叠加作用.

  4. Dopamine-sensitive signaling mediators modulate psychostimulant-induced ultrasonic vocalization behavior in rats.

    Science.gov (United States)

    Williams, Stacey N; Undieh, Ashiwel S

    2016-01-01

    The mesolimbic dopamine system plays a major role in psychostimulant-induced ultrasonic vocalization (USV) behavior in rodents. Within this system, psychostimulants elevate synaptic concentrations of dopamine thereby leading to exaggerated activation of postsynaptic dopamine receptors within the D1-like and D2-like subfamilies. Dopamine receptor stimulation activate several transmembrane signaling systems and cognate intracellular mediators; downstream activation of transcription factors then conveys the information from receptor activation to appropriate modulation of cellular and physiologic functions. We previously showed that cocaine-induced USV behavior was associated with enhanced expression of the neurotrophin BDNF. Like cocaine, amphetamine also increases synaptic dopamine levels, albeit primarily through facilitating dopamine release. Therefore, in the present study we investigated whether amphetamine and cocaine similarly activate dopamine-linked signaling cascades to regulate intracellular mediators leading to induction of USV behavior. The results show that amphetamine increased the emission of 50 kHz USVs and this effect was blocked by SCH23390, a D1 receptor antagonist. Similar to cocaine, amphetamine increased BDNF protein expression in discrete brain regions, while pretreatment with K252a, a trkB neurotrophin receptor inhibitor, significantly reduced amphetamine-induced USV behavior. Inhibition of cyclic-AMP/PKA signaling with H89 or inhibition of PLC signaling with U73122 significantly blocked both the acute and subchronic amphetamine-induced USV behavior. In contrast, pharmacologic inhibition of either pathway enhanced cocaine-induced USV behavior. Although cocaine and amphetamine similarly modulate neurotrophin expression and USV, the molecular mechanisms by which these psychostimulants differentially activate dopamine receptor subtypes or other monoaminergic systems may be responsible for the distinct aspects of behavioral responses.

  5. 多巴胺D1类受体对血管平滑肌细胞胰岛素样生长因子1受体表达的影响%The Effect of D1 Dopamine Receptor on IGF-1 Receptor Expression in Vascular Smooth Muscle Cells

    Institute of Scientific and Technical Information of China (English)

    韩愈; 周林; 曾春雨; 于长青; 黄河飞; 何多芬; 石伟彬; 傅春江; 杨成明; 王旭开; 黄岚

    2008-01-01

    目的 观察多巴胺D1类受体对血管平滑肌细胞胰岛素样生长因子1(IGF-1)受体的影响.方法 以A10细胞为研究对象,免疫印迹观察刺激D1类受体对IGF-1受体表达的影响,并初步探讨D1类受体对IGF-1受体影响的机制.结果 刺激D1类受体可降低IGF-1受体的表达,D1类受体阻断剂可完全阻断D1类受体激动剂Fenoldopam对IGF-1受体的影响,免疫印迹显示运用蛋白激酶C(PKC)和促分裂原活化蛋白激酶(MAPK)阻断剂后,IGF-1受体表达恢复,提示PKC和MAPK途径可能参与了D1类受体对血管平滑肌细胞IGF-1受体的影响过程,在Wistar-Kyoto(WKY)大鼠和自发性高血压大鼠(SHR)血管平滑肌细胞中D1类受体激动剂Fenoldopam对IGF-1受体表达具有抑制作用,但该抑制作用在SHR细胞明显低于WKY细胞.结论 D1类受体对血管平滑肌细胞IGF-1受体表达具有抑制作用,该作用可能通过PKC和MAPK途径发挥一系列生理效应.

  6. Blockade of dopamine D(3) receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: similar actions of D(1) receptor agonists, but not of D(2) antagonists.

    Science.gov (United States)

    Loiseau, Florence; Millan, Mark J

    2009-01-01

    Though D(3) receptor antagonists can enhance cognitive function, their sites of action remain unexplored. This issue was addressed employing a model of social recognition in rats, and the actions of D(3) antagonists were compared to D(1) agonists that likewise possess pro-cognitive properties. Infusion of the highly selective D(3) antagonists, S33084 and SB277,011 (0.04-2.5 microg/side), into the frontal cortex (FCX) dose-dependently reversed the deficit in recognition induced by a delay. By contrast, the preferential D(2) antagonist, L741,626 (0.63-5.0) had no effect. The action of S33084 was regionally specific inasmuch as its injection into the nucleus accumbens or striatum was ineffective. A similar increase of recognition was obtained upon injection of the D(1) agonist, SKF81297 (0.04-0.63), into the FCX though it was also active (0.63) in the nucleus accumbens. These data suggest that D(3) receptors modulating social recognition are localized in FCX, and underpin their pertinence as targets for antipsychotic agents.

  7. Study on the Association between Dopamine D1 Receptor Gene Polymorphism and Primary Hypertension%原发性高血压与多巴胺受体D1基因多态性的相关性研究

    Institute of Scientific and Technical Information of China (English)

    袁公贤; 哈黛文

    2002-01-01

    目的探讨多巴胺受体D1基因-48A/G多态性与原发性高血压(PH)的相关性.方法运用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)方法,了解-48A/G基因型在PH组和正常血压对照(NT)组的分布情况.结果等位基因A、G在PH组和NT组的分布频率分别为0.78、0.22和0.86、0.14,基因频率分布符合Hardy-Weinderg平衡,样本具有群体代表性,两组人群的基因型和等位基因频率存在明显统计学差异(P<0.01,P<0.01).PH组中G等位基因、舒张压明显高于A等位基因(P<0.05).结论本组人群中,多巴胺受体D1基因-48A/G多态性与PH显著性相关.

  8. 多巴胺受体D1基因-48A/G多态性与原发性高血压病的关联研究%Correlation between Dopamine D1 Receptor Gene 48A/GPolymorphism and Essential Hypertension in a ChinesePoplulation

    Institute of Scientific and Technical Information of China (English)

    袁公贤; 哈黛文

    2002-01-01

    目的探讨多巴胺受体D1基因-48A/G多态性与原发性高血压病相关性.方法运用聚合酶链反应一限制性片段长度多态性法(PCR-RFLP)分析了解-48A/G基因型在原发性高血压病组和正常血压对照组的分布情况.结果等位基因A,G在原发性高血压病组和对照组的分布频率分别为0.78,0.22和0.86,0.14,基因频率分布符合Hardy-Weinberg平衡,样本具有群体代表性,两组人群的基因型和等位基因频率存在明显统计学差异(P<0.01,P<0.01).原发性高血压组中G等位基因,舒张压明显高于A等位基因(P<0.05).结论在中国人群中,多巴胺受体D1基因-48A/G多态性与原发性高血压病显著性相关.

  9. D1-dopamine receptor is involved in the modulation of the respiratory rhythmical discharge activity in the medulla oblongata slice preparation of neonatal rats in vitro%多巴胺D1受体参与新生鼠离体延髓脑片呼吸节律性放电的调节

    Institute of Scientific and Technical Information of China (English)

    焦勇钢; 吴中海

    2008-01-01

    本研究旨在探讨多巴胺D1受体在延髓离体脑片基本节律性呼吸放电调节中的作用.以改良的Kreb'S液(modified Kreb,s perfusion,MKS)恒温灌流Sprague-Dawley大鼠(0~3 d)离体延髓脑片标本,稳定记录到与之相连的舌卜神经根的呼吸节律性放电活动(respiratory rhythmical discharge activity,RRDA)后,第一组(n=5)先给予多巴胺Dl受体特异性激动剂[cis-(±)-1-(Aminomethyl)-3,4-dihydro-3-phenyl-1H-2-Benzopyran-5,6-Diolhy.drochlo-fide,A689301灌流10 min,用MKS洗脱后,再给予多巴胺D1受体特异性拮抗剂[R(+)-7-Chloro-8-hydroxy-3-methyl-1-pheny1-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride,SCH-23390]灌流10 min;第二组(n=5)先给予A68930持续灌流10 min后再给予A68930+SCH-23390持续灌流10 min;观察各时间点舌下神经根RRDA的变化.结果显示,给予A68930灌流后呼吸周期(respiratory cycle,RC)和呼气时程(expiratory time,TE)显著缩短,放屯积分幅度(integral amplitude,IA)增加,吸气时程(inspiratory time,TI)无明显变化;给予SCH-23390后RC、TE显著延长、TI显著缩短、IA减小,而且A68930的作用可以被SCH一23390部分逆转.这些观察结果提示多巴胺D1受体参与了哺乳动物基本呼吸频率和幅度的调节.

  10. 精神分裂症患者多巴胺D1受体基因-48A/G多态性与认知功能的关系%Association study between cognitive function in schizophrenics and dopamine D1 receptor gene -48A/G polymorphism

    Institute of Scientific and Technical Information of China (English)

    胡一文; 王高华; 顾剑

    2006-01-01

    目的 探讨精神分裂症患者多巴胺D1受体基因-48A/G多态性与认知功能的关系.方法 应用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP),检测103例精神分裂症患者多巴胺D1受体基因-48A/G多态性.采用威斯康星卡片分类测验(Wiscosin Card Sorting Test,WCST)和韦氏成人智力量表修订版(Wechsler Adult Intelligence Scale-RC,WAIS-RC)评估患者的认知功能.结果 其中分类数、错误应答数、持续应答数、非持续错误数、算术、数字广度(顺)、数字符号及木块图得分在AA基因型和AG+GG基因型两组患者间均无显著性差异(P>0.05),但持续错误数(t=2.321,P<0.05)和数字广度(逆)(t=3.042,P<0.01)在两组间有显著性差异,AA基因型患者持续错误数和数字广度(逆)得分明显高于AG+GG基因型患者.结论 精神分裂症患者D1受体基因-48A/G多态性与持续性错误数及数字广度(逆)相关,AA基因型精神分裂症患者较AG+GG基因型患者工作记忆受损更严重,但短时记忆能力要强于后者.

  11. Essential role of D1R in the regulation of mTOR complex1 signaling induced by cocaine.

    Science.gov (United States)

    Sutton, Laurie P; Caron, Marc G

    2015-12-01

    The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is involved in neuronal adaptions that underlie cocaine-induced sensitization and reward. mTOR exists in two functionally distinct multi-component complexes known as mTORC1 and mTORC2. In this study, we show that increased mTORC1 activity induced by cocaine is mediated by the dopamine D1 receptor (D1R). Specifically, cocaine treatment increased the phosphorylation on residues Thr2446 and Ser2481 but not on Ser2448 in the nucleus accumbens (NAc) and that this increase in phosphorylated mTOR levels was also apparent when complexed with its binding partner Raptor. Furthermore, the increase in phosphorylated mTOR levels, as well as phosphorylated 4E-BP1 and S6K, downstream targets of mTORC1 were blocked with SCH23390 treatment. Similar results were also observed in the dopamine-transporter knockout mice as the increase in phosphorylated mTOR Thr2446 and Ser2481 was blocked by SCH23390 but not with raclopride. To further validate D1R role in mTORC1 signaling, decrease in phosphorylated mTOR levels were observed in D1R knockout mice, whereas administration of SKF81297 elevated phosphorylated mTOR in the NAc. Lastly deletion of mTOR or Raptor in D1R expressing neurons reduced cocaine-induced locomotor activity. Together, our data supports a mechanism whereby mTORC1 signaling is activated by cocaine administration through the stimulation of D1R.

  12. Dopamine-deprived striatal GABAergic interneurons burst and generate repetitive gigantic IPSCs in medium spiny neurons.

    Science.gov (United States)

    Dehorter, Nathalie; Guigoni, Celine; Lopez, Catherine; Hirsch, June; Eusebio, Alexandre; Ben-Ari, Yehezkel; Hammond, Constance

    2009-06-17

    Striatal GABAergic microcircuits modulate cortical responses and movement execution in part by controlling the activity of medium spiny neurons (MSNs). How this is altered by chronic dopamine depletion, such as in Parkinson's disease, is not presently understood. We now report that, in dopamine-depleted slices of the striatum, MSNs generate giant spontaneous postsynaptic GABAergic currents (single or in bursts at 60 Hz) interspersed with silent episodes, rather than the continuous, low-frequency GABAergic drive (5 Hz) observed in control MSNs. This shift was observed in one-half of the MSN population, including both "D(1)-negative" and "D(1)-positive" MSNs. Single GABA and NMDA channel recordings revealed that the resting membrane potential and reversal potential of GABA were similar in control and dopamine-depleted MSNs, and depolarizing, but not excitatory, actions of GABA were observed. Glutamatergic and cholinergic antagonists did not block the GABAergic oscillations, suggesting that they were generated by GABAergic neurons. In support of this, cell-attached recordings revealed that a subpopulation of intrastriatal GABAergic interneurons generated bursts of spikes in dopamine-deprived conditions. This subpopulation included low-threshold spike interneurons but not fast-spiking interneurons, cholinergic interneurons, or MSNs. Therefore, a population of local GABAergic interneurons shifts from tonic to oscillatory mode when dopamine deprived and gives rise to spontaneous repetitive giant GABAergic currents in one-half the MSNs. We suggest that this may in turn alter integration of cortical signals by MSNs.

  13. Dopamine, hypertension and obesity.

    Science.gov (United States)

    Contreras, F; Fouillioux, C; Bolívar, A; Simonovis, N; Hernández-Hernández, R; Armas-Hernandez, M J; Velasco, M

    2002-03-01

    Dopamine, a neurotransmitter, precursor of noradrenaline, is responsible for cardiovascular and renal actions, such as increase in myocardial contractility and cardiac output, without changes in heart rate, producing passive and active vasodilatation, diuresis and natriuresis. These cardiovascular and renal actions take place through the interaction with dopamine receptors, D(1), D(2), D(3), D(4), and D(5). Recent findings point to the possibility of D(6) and D(7)receptors. Dopamine is known to influence the control of arterial pressure by influencing the central and peripheral nervous system and target organs such as kidneys and adrenal glands, in some types of hypertension. Although dopamine and its derivatives have been shown to have antihypertensive effects, these are still being studied; therefore it is important to explain some physiological and pharmacological aspects of dopamine, its receptors, and the clinical uses it could have in the treatment of arterial hypertension and more recently in obesity, based on evidence proving a clear association between obesity and the decrease in the expression of D(2) receptors in the brain of obese persons.

  14. Relationship between the dopamine D1 receptor gene polymorphism and the hypertensive disorder complicating pregnancy%多巴胺D1受体基因-48A/G多态性与妊娠高血压疾病的相关性研究

    Institute of Scientific and Technical Information of China (English)

    马少平; 卢爱妮; 廖予妹

    2006-01-01

    目的探讨多巴胺D1受体(DRD1)基因-48A/G多态性与妊娠高血压疾病(HDCP)的关联性.方法 运用限制性片段长度多态性-聚合酶链反应分析DRD1基因基因型AA、AG和GG在正常和HDCP孕妇组的分布.结果等位基因A、G在正常孕妇组和HDCP患者的分布频率分别为90.9%、9.1%和72.6%、27.4%,两组基因型频率和等位基因频率差异有统计学意义(P<0.01).结论在中国汉族人群中,DRD1基因多态性与HDCP相关,但其基因型分布与病情严重程度无相关性.

  15. Effects of D1 and D2 dopamine receptor agonists and antagonists on cerebral ischemia/reperfusion injury%多巴胺D1和D2受体激动剂和拮抗剂对脑缺血/再灌注损伤的影响

    Institute of Scientific and Technical Information of China (English)

    纵雪梅; 曾因明; 许铁; 吕建农

    2003-01-01

    实验应用开阔法、组织病理学方法、原位末端标记(in situterminal deoxynucleotidyl transferase-mediated de-oxy-UTP nick end labeling,TUNEL)法及免疫组织化学等方法,探讨多巴胺D1、D2受体激动剂和拮抗剂对沙土鼠前脑缺血/再灌注损伤海马CA1区神经元凋亡及凋亡相关基因bcl-2、bax表达的影响.结果显示:前脑缺血5 min可引起沙土鼠探索活动增加;再灌注3 d,海马CA1区约95%的锥体细胞凋亡;再灌注7 d,海马CA1区仅残存约2%-7%的存活锥体细胞;前脑缺血5 min可抑制bcl-2的表达并诱导bax表达增高;预先应用D2受体激动剂培高利特可减轻缺血后沙土鼠行为学异常、抑制海马CA1区锥体细胞凋亡、提高锥体细胞存活数、显著诱导bcl-2的表达并抑制bax的表达.预先应用SKF38393、SCH23390及螺哌隆对以上结果无明显影响.实验结果提示,培高利特具有确切的脑保护作用,诱导bcl-2并抑制bax的表达可能是其脑保护作用机制之一.

  16. Effects of buspirone on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Dhavalshankh, A G; Jadhav, S A; Gaikwad, R V; Gaonkar, R K; Thorat, V M; Balsara, J J

    2007-01-01

    Buspirone, a partial agonist of 5-hydroxytryptamine autoreceptors, selectively blocks presynaptic nigrostriatal D2 dopamine (DA) autoreceptors. At doses which antagonised action of apomorphine in biochemical presynaptic nigrostriatal D2 DA autoreceptor test systems buspirone neither induced catalepsy nor antagonised apomorphine-induced turning behaviour in rats indicating that at these doses buspirone does not block postsynaptic striatal D2 and D1 DA receptors. This study determines whether at high doses buspirone blocks postsynaptic striatal D2 and D1 DA receptors and provides behavioural evidence for selective blockade of presynaptic nigrostriatal D2 DA autoreceptors by smaller doses of buspirone. We investigated in rats whether buspirone induces catalepsy and effect of its pretreatment on DA agonist induced oral stereotypies and on cataleptic effect of haloperidol and small doses (0.05, 0.1 mg/kg, ip) of apomorphine. Buspirone at 1.25, 2.5, 5 mg/kg, ip neither induced catalepsy nor antagonised apomorphine stereotypy but did potentiate dexamphetamine stereotypy and antagonised cataleptic effect of haloperidol and small doses of apomorphine. Buspirone at 10, 20, 40 mg/kg, ip induced catalepsy and antagonised apomorphine and dexamphetamine stereotypies. Our results indicate that buspirone at 1.25, 2.5, 5 mg/kg blocks only presynaptic nigrostriatal D2 DA autoreceptors while at 10, 20, 40 mg/kg, it blocks postsynaptic striatal D2 and D1 DA receptors. Furthermore, buspirone at 1.25, 2.5, 5 mg/kg by selectively blocking presynaptic nigrostriatal D2 DA autoreceptors, increases synthesis of DA and makes more DA available for release by dexamphetamine and during haloperidol-induced compensatory 'feedback' increase of nigrostriatal DAergic neuronal activity and thus potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

  17. Cell-attached single-channel recordings in intact prefrontal cortex pyramidal neurons reveal compartmentalized D1/D5 receptor modulation of the persistent sodium current.

    Directory of Open Access Journals (Sweden)

    Natalia eGorelova

    2015-02-01

    Full Text Available The persistent Na current (INap is believed to be an important target of dopamine modulation in prefrontal cortex (PFC neurons. While past studies have tested the effects of dopamine on INap, the results have been contradictory largely because of difficulties in measuring INap using somatic whole-cell recordings. To circumvent these confounds we used the cell-attached patch-clamp technique to record single Na channels from the soma, proximal dendrite or proximal axon of intact prefrontal layer V pyramidal neurons. Under baseline conditions, numerous well resolved Na channel openings were recorded that exhibited an extrapolated reversal potential of 73 mV, a slope conductance of 14-19pS and were blocked by TTX. While similar in most respects, the propensity to exhibit prolonged bursts lasting >40ms was many fold greater in the axon than the soma or dendrite. Bath application of the D1 agonist SKF81297 shifted the ensemble current activation curve leftward and increased the number of late events recorded from the proximal dendrite but not the soma or axon. However, the greatest effect was on prolonged bursting where the D1 agonist increased their occurrence 3 fold in the proximal dendrite and nearly 7 fold in the soma, but not at all in the axon. As a result, D1 activation equalized the probability of prolonged burst occurrence across the proximal axosomatodendritic region. Therefore, D1 modulation appears to be targeted mainly to Na channels in the proximal dendrite/soma and not the proximal axon. By circumventing the pitfalls of previous attempts to study the D1R modulation of INap, we demonstrate conclusively that D1R can increase the INap generated proximally, however questions still remain as to how D1R modulates Na currents in the more distal initial segment where most of the INap is normally generated.

  18. Dopamine receptors - physiological understanding to therapeutic intervention potential

    NARCIS (Netherlands)

    Emilien, G; Maloteaux, JM; Hoogenberg, K; Cragg, S

    1999-01-01

    There are two families of dopamine (DA) receptors, called D(1) and D(2), respectively. The D(1) family consists of D(1)- and D(5)-receptor subtypes and the D(2) family consists of D(2)-, D(3)-, and D(4)-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a lar

  19. NEUROTRANSMITTERS AND IMMUNITY: 1. DOPAMINE

    Directory of Open Access Journals (Sweden)

    Lucian Hritcu

    2007-08-01

    Full Text Available Dopamine is one of the principal neurotransmitters in the central nervous system (CNC, and its neuronal pathways are involved in several key functions such as behavior (Hefco et al., 2003a,b, control of movement, endocrine regulation, immune response (Fiserova et al., 2002; Levite et al., 2001, Hritcu et al., 2006a,b,c, and cardiovascular function. Dopamine has at least five G-protein, coupled receptor subtypes, D1-D5, each arising from a different gene (Sibley et al., 1993. Traditionally, these receptors have been classified into D1-like (the D1 and D5 and D2-like (D2, D3 and D4 receptors subtypes, primarily according to their ability to stimulate or inhibit adenylate cyclase, respectively, and to their pharmacological characteristics (Seeman et al., 1993. Receptors for dopamine (particularly of D2 subclass are the primary therapeutic target in a number of neuropathological disorders including schizophrenia, Parkinson’s disease and Huntington’s chorea (Seeman et al., 1987. Neither dopamine by itself, nor dopaminergic agonists by themselves, has been shown to activate T cell function. Nevertheless, lymphocytes are most probably exposed to dopamine since the primary and secondary lymphoid organs of various mammals are markedly innervated, and contain nerve fibers which stain for tyrosine hydroxylase (Weihe et al., 1991, the enzyme responsible for dopamine synthesis. Moreover, cathecolamines and their metabolites are present in single lymphocytes and in extracts of T and B cell clones, and pharmacological inhibition of tyrosine hydroxylase reduces catecholamine levels, suggesting catecholamine synthesis by lymphocytes (Bergquist et al., 1994. The existence of putative dopamine receptors of D2, D3, D4 and D5 subtypes on immune cells has been proposed of several authors, primarily on the basis of dopaminergic ligand binding assays and specific mRNA expression as monitored by reverse transcription-PCR. Several experiments evoked the idea of a

  20. Effects of dextromethorphan on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Gaikwad, R V; Gaonkar, R K; Jadhav, S A; Thorat, V M; Jadhav, J H; Balsara, J J

    2007-08-01

    Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.

  1. Characterization of pre- and postsynaptic dopamine receptors in Lymnaea.

    Science.gov (United States)

    Audesirk, T E

    1989-01-01

    1. The effects of dopamine and several synthetic agonists and antagonists were studied using two identified neurons of the snail Lymnaea stagnalis. 2. In both the buccal-2 (B-2) neurons and the pedal giant (RPeD1) neuron dopamine elicited a hyperpolarizing response at least partly due to potassium efflux. RPeD1 is itself dopaminergic, implicating autoreceptors in its response to dopamine. 3. The following agents were tested: agonists--LY171555, pergolide, SKF38393, (-)-3-PPP, R(-)NPA and dopamine; antagonists--SCH23390, sulpiride, and metaclopramide. Dibutyryl cAMP was applied to determine whether the response is cAMP-mediated. 4. Results indicate that the pharmacological profiles of dopamine receptors on these neurons are inconsistent with those of either D-1, D-2 or autoreceptors in mammals.

  2. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

    Energy Technology Data Exchange (ETDEWEB)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R. [Department of Molecular Genetics, Weizmann Institute of Science Rehovot 76100 (Israel)

    1996-09-01

    Human neuroblastoma NMB cells take up [{sup 3}H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [{sup 3}H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [{sup 3}H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996

  3. Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice.

    Science.gov (United States)

    Zeng, Chunyu; Armando, Ines; Luo, Yingjin; Eisner, Gilbert M; Felder, Robin A; Jose, Pedro A

    2008-02-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D(1)-like (D(1) and D(5)) and D(2)-like (D(2), D(3), and D(4)) subtypes based on their structure and pharmacology. In recent years, mice deficient in one or more of the five dopamine receptor subtypes have been generated, leading to a better understanding of the physiological role of each of the dopamine receptor subtypes. This review summarizes the results from studies of various dopamine receptor mutant mice on the role of individual dopamine receptor subtypes and their interactions with other G protein-coupled receptors in the regulation of blood pressure.

  4. The Effects of Dopamine and Estrogen upon Cortical Parvalbumin Expression

    Science.gov (United States)

    2001-10-01

    positive interneurons because studies indicate that the parvalbumin containing subclass of GABAergic neurons are contacted by mesocortical dopamine fibers...that both dopamine and estrogen enhance the maturation of cortical interneurons that express the calcium binding protein, parvalbumin , in the developing... parvalbumin expression in the deep cortical layers in the in vivo model. Dopamine D1 and D2 receptors are located on parvalbumin containing interneurons

  5. Renal Dopamine Receptors, Oxidative Stress, and Hypertension

    OpenAIRE

    Ines Armando; Van Anthony Villar; Pedro A. Jose; Santiago Cuevas

    2013-01-01

    Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxi...

  6. Nucleus accumbens dopamine receptors in the consolidation of spatial memory.

    NARCIS (Netherlands)

    Mele, A.; Avena, M.; Roullet, P.; Leonibus, E. de; Mandillo, S.; Sargolini, F.; Coccurello, R.; Oliverio, A.

    2004-01-01

    Nucleus accumbens dopamine is known to play an important role in motor activity and in behaviours governed by drugs and natural reinforcers, as well as in non-associative forms of learning. At the same time, activation of D1 and D2 dopamine receptors has been suggested to promote intracellular event

  7. Regulation of synaptic strength at mixed synapses: effects of dopamine receptor blockade and protein kinase C activation.

    Science.gov (United States)

    Silva, A; Kumar, S; Pereda, A; Faber, D S

    1995-11-01

    Previous studies of the mixed excitatory synapses between eighth nerve afferents and the lateral dendrite of the goldfish Mauthner (M-) cell have shown that synaptic strength is enhanced for an hour or longer following either repeated brief tetanizations or local extracellular applications of dopamine. Both the initial electrotonic coupling potential, mediated via current flow through gap junctions, and the subsequent chemically mediated excitatory postsynaptic potentials (EPSPs) are potentiated. Different second messenger pathways are implicated in the postsynaptic induction of these potentiations, with a Ca2+ influx presumably triggering the activity dependent long-term potentiations (LTP) and dopamine acting via a cAMP dependent pathway. Experiments performed to determine whether the LTP involves a stimulus-induced release of dopamine or requires a background level of dopamine receptor activation suggest neither is the case, as tetanization in the presence of a D1 receptor antagonist, which blocks the dopamine effects, produced an LTP comparable to that in the absence of the blocker. The effects of Ca2+ are presumably not due to protein kinase C (PKC) activation, since phorbol esters had no effect on the mixed excitatory synaptic responses, although they did enhance the frequency of spontaneously occurring inhibitory PSPs.

  8. [Peculiarities of dopamine receptors on the membrane of spinal cord multipolar neurons of the brook lamprey Lampetra planeri].

    Science.gov (United States)

    Bukinich, A a; Tsvetkov, E A; Veselkin, N P

    2007-01-01

    On isolated multiporal neurons of spinal cord of amniocoete larva of the brook lamprey Lampetra planeri, by the patch-clamp method in configuration "the whole cell", a modulating effect of dopamine on potential-activated Na+ currents was studied. Application of dopamine (10 microM) was shown to produce a complex action on the sodium current amplitude. In some cases a decrease of the amplitude, on average, by 13.5 +/- 2.2% was found, while in others--an increase, on average, by 8.6 +/- 6.1%. The modulation dopamine effect was not accompanied by any changes either of the threshold of the current appearance or of resistance of neuronal cell membranes. Pharmacological analysis with use of dopamine agonist has shown that the agonist of D1-receptors (-)-SKF-38393 (10 microM) decreases the Na+ current amplitude, whereas the agonist of D2-receptors (-)-quinpirole (10 microM) can produce in different cells both an increase, by 30.7 +/- 17.0 %, and a decrease, by 13.2 +/- 3.1%, of the Na+ current amplitude. The obtained data indicate the existence of D1- and D2-receptors on the membrane of multipolar spinal neurons of the amniocoete larva of the brook lamprey. Study of action of antagonists has shown that the antagonist of D1-receptors (+)-SCH-23390 (10 microM) does not affect action of the agonist of D1-receptors (-)-SKF-38393 (10 microM); the antagonist of D2-receptors (-)-sulpiride (10 microM) blocks completely effects both of the agonist of D1-receptors (-)-SKF-38393 (10 microM) and of the agonist of D2-receptors (-)-quinpirole (10 microM). The antagonist of D1-receptors (+)-SCH-23390 (10 microM) produced no effect on action of the agonist of D1-receptors (-)-SKF-38393 (10 microM). The obtained data indicate peculiarities of dopamine receptors of Cyclostomata as compared with those in mammals.

  9. Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice

    OpenAIRE

    ZENG, Chunyu; Armando, Ines; Luo, Yingjin; Eisner, Gilbert M.; Felder, Robin A.; Pedro A. Jose

    2007-01-01

    Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and by interacting with vasoactive hormones/humoral factors, such as aldosterone, angiotensin, catecholamines, endothelin, oxytocin, prolactin pro-opiomelancortin, reactive oxygen species, renin, and vasopressin. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3, and D4) subtypes based on their structure and pharmacology. In recent years, mice deficient i...

  10. EFFECTS OF VERAPAMIL ON DOPAMINE DEPENDENT BEHAVIOURS IN RATS.

    Science.gov (United States)

    Malekar, A R; Balsara, J J; Gaonkar, R K

    1999-01-01

    Abstract : Verapamil at 5, 10 and 20 mg/kg ip did not inhibit the conditioned avoidance response, neither induced catalepsy nor antagonised apomorphine stereotypy in rats indicating that these doses do not block the postsynaptic striatal D 2 and D 1 dopamine (DA) receptors. However, pretreatment with 10 and 20 mg/kg ip verapamil potentiated methamphetamine stereotypy and antagonised catalepsy induced by small doses (0.05 and 0.1 mg/kg ip) of apomorphine. Antagonism of small dose apomorphine-induced catalepsy suggests that at these doses verapamil blocks the presynaptic D2 DA autoreceptors. Further, pretreatment with 10 mg/kg verapamil antagonised, while pretreatment with 20 mg/kg potentiated haloperidol catalepsy. Potentiation of methamphetamine stereotypy by 10 and 20 mg/kg verapamil is explained on the basis of blockade of presynaptic D2 DA autoreceptors by these doses of verapamil and its reported DA neuronal uptake blocking activity. Antagonism of haloperidol catalepsy by 10 mg/kg verapamil is also explained on the basis of presynaptic D2 DA autoreceptor induced blockade by 10 mg/kg verapamil whereas potentiation of haloperidol catalepsy by 20 mg/kg verapamil is explained on the basis of its calcium channel blocking activity.

  11. Dopamine, vesicular transporters, and dopamine receptor expression in rat major salivary glands.

    Science.gov (United States)

    Tomassoni, Daniele; Traini, Enea; Mancini, Manuele; Bramanti, Vincenzo; Mahdi, Syed Sarosh; Amenta, Francesco

    2015-09-01

    The localization of dopamine stores and the expression and localization of dopamine (DAT) and vesicular monoamine transporters (VMAT) type-1 and -2 and of dopamine D1-like and D2-like receptor subtypes were investigated in rat submandibular, sublingual, and parotid salivary glands by HPLC with electrochemical detection, as well as immunochemical and immunohistochemical techniques. Male Wistar rats of 2 mo of age were used. The highest dopamine levels were measured in the parotid gland, followed by the submandibular and sublingual glands. Western blot analysis revealed DAT, VMAT-1, VMAT-2, and dopamine receptors immunoreactivity in membrane preparations obtained from the three glands investigated. Immunostaining for dopamine and transporters was developed within striated ducts. Salivary glands processed for dopamine receptors immunohistochemistry developed an immunoreaction primarily in striated and excretory ducts. In the submandibular gland, acinar cells displayed strong immunoreactivity for the D2 receptor, while cells of the convoluted granular tubules were negative for both D1-like and D2-like receptors. Parotid glands acinar cells displayed the highest immunoreactivity for both D1 and D2 receptors compared with other salivary glands. The above localization of dopamine and dopaminergic markers investigated did not correspond closely with neuron-specific enolase (NSE) localization. This indicates that at least in part, catecholamine stores and dopaminergic markers are independent from glandular innervation. These findings suggest that rat major salivary glands express a dopaminergic system probably involved in salivary secretion. The stronger immunoreactivity for dopamine transporters and receptors in striated duct cells suggests that the dopaminergic system could regulate not only quality, but also volume and ionic concentration of saliva.

  12. Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling.

    Science.gov (United States)

    Wassum, Kate M; Ostlund, Sean B; Balleine, Bernard W; Maidment, Nigel T

    2011-01-01

    Here we attempted to clarify the role of dopamine signaling in reward seeking. In Experiment 1, we assessed the effects of the dopamine D(1)/D(2) receptor antagonist flupenthixol (0.5 mg/kg i.p.) on Pavlovian incentive motivation and found that flupenthixol blocked the ability of a conditioned stimulus to enhance both goal approach and instrumental performance (Pavlovian-to-instrumental transfer). In Experiment 2 we assessed the effects of flupenthixol on reward palatability during post-training noncontingent re-exposure to the sucrose reward in either a control 3-h or novel 23-h food-deprived state. Flupenthixol, although effective in blocking the Pavlovian goal approach, was without effect on palatability or the increase in reward palatability induced by the upshift in motivational state. This noncontingent re-exposure provided an opportunity for instrumental incentive learning, the process by which rats encode the value of a reward for use in updating reward-seeking actions. Flupenthixol administered prior to the instrumental incentive learning opportunity did not affect the increase in subsequent off-drug reward-seeking actions induced by that experience. These data suggest that although dopamine signaling is necessary for Pavlovian incentive motivation, it is not necessary for changes in reward experience, or for the instrumental incentive learning process that translates this experience into the incentive value used to drive reward-seeking actions, and provide further evidence that Pavlovian and instrumental incentive learning processes are dissociable.

  13. Effects of Anshen Dingzhi Ling on Expression of Dopamine Receptor-1 and 2 in Prefrontal Cortex and Striatum in Rats with Attention Deficit Hyperactivity Disorder%安神定志灵对ADHD模型鼠前额叶皮质和纹状体多巴胺D1,D2受体表达的影响

    Institute of Scientific and Technical Information of China (English)

    刘成全; 韩新民; 徐建亚; 桑锋; 尹东奇; 倪新强; 李亚群

    2011-01-01

    泊发性高血压大鼠(spontaneously hypertensive rat,SHR)前额叶皮质、纹状体多巴胺受体D1,D2(DRDI,DRD2)表达的影响,探讨该药治疗ADHD的作用机制.方法:30只SHR鼠随机分为5组(模型组、利他林组、安神定志灵高、中、低剂量组),每组6只,Wistar大鼠6只作为正常对照组.安神定志灵高、中、低剂量组分别按生药剂量34.1,17.1,8.5 g·kg-1ig;利他林组以2.1 mg·kg-1利他林ig ;模型组和正常对照组以10 mL·g-1生理盐水ig.实验2周后处死大鼠,取脑分别用RT-PCR和Western blot检测各组大鼠前额叶皮质、纹状体内DRDI,DRD2 mRNA和蛋白表达水平.结果:模型组与正常对照组比较,DRD1,DRD2 mRNA和蛋白表达水平显著降低(P<0.01);利他林组与模型组比较,DRDI,DRD2 mRNA和蛋白表达水平显著升高(P<0.01);安神定志灵中剂量组与模型组比较,DRDI,DRD2 znRNA和蛋白表达水平显著升高(P<0.01);安神定志灵低剂量组和高剂量组RDI,DRD2mRNA和蛋白表达水平高于空白模型组,但没有统计学差异.结论:安神定志灵可以上调SHR大鼠额叶皮质和纹状体中DRDI,DRD2 mRNA及蛋白的表达水平,说明安神定志灵在调控前额叶-纹状体通路的功能中发挥着重要的作用,而DRDI,DRD2参与了这一调节的过程,最终起到对ADHD的治疗作用.

  14. Influence of phasic and tonic dopamine release on receptor activation

    DEFF Research Database (Denmark)

    Dreyer, Jakob Kristoffer Kisbye; Herrik, Kjartan F; Berg, Rune W

    2010-01-01

    Tonic and phasic dopamine release is implicated in learning, motivation, and motor functions. However, the relationship between spike patterns in dopaminergic neurons, the extracellular concentration of dopamine, and activation of dopamine receptors remains unresolved. In the present study, we...... develop a computational model of dopamine signaling that give insight into the relationship between the dynamics of release and occupancy of D(1) and D(2) receptors. The model is derived from first principles using experimental data. It has no free parameters and offers unbiased estimation...

  15. Dimensional Reduction for Conformal Blocks

    CERN Document Server

    Hogervorst, Matthijs

    2016-01-01

    We consider the dimensional reduction of a CFT, breaking multiplets of the d-dimensional conformal group SO(d+1,1) up into multiplets of SO(d,1). This leads to an expansion of d-dimensional conformal blocks in terms of blocks in d-1 dimensions. In particular, we obtain a formula for 3d conformal blocks as an infinite sum over 2F1 hypergeometric functions with closed-form coefficients.

  16. Potential dopamine-1 receptor stimulation in hypertension management.

    Science.gov (United States)

    Asghar, Mohammad; Tayebati, Seyed K; Lokhandwala, Mustafa F; Hussain, Tahir

    2011-08-01

    The role of dopamine receptors in blood pressure regulation is well established. Genetic ablation of both dopamine D1-like receptor subtypes (D1, D5) and D2-like receptor subtypes (D2, D3, D4) results in a hypertensive phenotype in mice. This review focuses on the dopamine D1-like receptor subtypes D1 and D5 (especially D1 receptors), as they play a major role in regulating sodium homeostasis and blood pressure. Studies mostly describing the role of renal dopamine D1-like receptors are included, as the kidneys play a pivotal role in the maintenance of sodium homeostasis and the long-term regulation of blood pressure. We also attempt to describe the interaction between D1-like receptors and other proteins, especially angiotensin II type 1 and type 2 receptors, which are involved in the maintenance of sodium homeostasis and blood pressure. Finally, we discuss a new concept of renal D1 receptor regulation in hypertension that involves oxidative stress mechanisms.

  17. Relationship between gene polymorphism of dopamine D1 receptor and angiotensin Ⅱ type Ⅰ receptor and genetic susceptibility to hypertensive disorder complicating pregnancy%多巴胺D1受体及血管紧张素Ⅱ1型受体基因多态性与妊娠期高血压疾病遗传易感性的研究

    Institute of Scientific and Technical Information of China (English)

    廖予妹; 乔福元; 马少平; 卢爱妮

    2007-01-01

    目的: 探讨多巴胺D1受体(DRD1)和血管紧张素Ⅱ1型受体(AT1R)基因多态性与妊娠期高血压疾病的相关性.方法: 应用限制性片段长度多态性聚合酶链反应技术(RFLP-PCR)检测102例患者及108例正常孕妇的DRD1-48A/G和AT1RA1166→C变异多态性,对两组的基因型和等位基因进行分析.结果: DRD1G的分布频率在HDCP组和正常孕妇组分别为27.9%、9.3%,两组间G等位基因频率比较,差异有统计学意义(P<0.01).HDCP组DRD1基因AG/GG型显著高于正常孕妇组(P<0.01).AT1RC等位基因在HDCP组和正常孕妇组的分布频率分别为16.2%和5.6%,两组间C等位基因频率比较,差异有统计学意义(P<0.01).HDCP组AT1R基因AC/CC型较正常孕妇组明显升高(P<0.01).结论: 在中国汉族人群中,多巴胺D1受体基因多态性-48A/G和AT1RA1166位点突变为C多态性与妊娠期高血压疾病发病相关.

  18. Dopamine and vascular dynamics control: present status and future perspectives.

    Science.gov (United States)

    Tayebati, Seyed Khosrow; Lokhandwala, Mustafa F; Amenta, Francesco

    2011-08-01

    The catecholamine dopamine is a precursors in the biosynthesis of norepinephrine and epinephrine as well as a neurotransmitter in the central nervous system. Besides of its well known role of brain neurotransmitter, dopamine exerts specific functions at the periphery, being those at the level of the cardiovascular system and the kidney the most relevant. In fact it plays a role of modulator of blood pressure, sodium balance, and renal and adrenal functions through an independent peripheral dopaminergic system. In vivo administration or in vitro application of dopamine or of dopamine receptor agonists induce vasodilatation in the cerebral, coronary, renal and mesenteric vascular beds and cause hypotension. Moreover, dopamine stimulates cardiac contractility and induces diuresis and natriuresis. Dopamine probably plays a role in the pathogenesis of arterial hypertension by regulating epithelial sodium transport, vascular smooth muscle contractility and production of reactive oxygen species and by interacting with the renin-angiotensin and sympathetic nervous systems. Dopamine exerts its actions via a class of cell surface receptors belonging to the rhodopsin-like family of G-protein coupled receptors. Dopamine receptors are classified into D1-like (D1 and D5) and D2-like (D2, D3 and D4) subtypes based on their structure and pharmacology. Each of the dopamine receptor subtypes can participate in the regulation of blood pressure by specific mechanisms. Some receptors regulate blood pressure by influencing the central and/or autonomic nervous system; others influence epithelial transport and regulate the secretion and receptors of several humeral agents. This paper outlines the biochemistry, anatomical localization and physiology of the different dopamine receptors involved in the regulation of blood pressure, the relationship between dopamine receptor subtypes and hypertension and possibilities of modulating pharmacologically vascular dopamine receptor function.

  19. An indirect action of dopamine on the rat fundus strip mediated by 5-hydroxytryptamine

    NARCIS (Netherlands)

    Sonneville, P.F.

    1968-01-01

    Dopamine in a concentration of 10−7 molar produces a contraction of the rat stomach fundus preparation. This effect is blocked by the 5-HT antagonist methysergide. Repeated exposure to dopamine results in tachyphylaxis, but the sensitivity to dopamine can be restored by incubating the tissue with 5-

  20. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    Science.gov (United States)

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  1. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney

    Directory of Open Access Journals (Sweden)

    N. L. Rukavina Mikusic

    2016-01-01

    Full Text Available Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP and Ang-(1-7 may regulate renal dopamine availability in tubular cells, contributing to Na+, K+-ATPase inhibition. Present results show that CNP did not affect either 3H-dopamine uptake in renal tissue or Na+, K+-ATPase activity; meanwhile, Ang-(1-7 was able to increase 3H-dopamine uptake and decreased Na+, K+-ATPase activity in renal cortex. Ang-(1-7 and dopamine together decreased further Na+, K+-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7 stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide did not modify CNP effects on 3H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7 on 3H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7 was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7 on AT1 receptors on 3H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7 enhances Na+, K+-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  2. Regulation of Dopamine Uptake by Vasoactive Peptides in the Kidney.

    Science.gov (United States)

    Rukavina Mikusic, N L; Kouyoumdzian, N M; Rouvier, E; Gironacci, M M; Toblli, J E; Fernández, B E; Choi, M R

    2016-01-01

    Considering the key role of renal dopamine in tubular sodium handling, we hypothesized that c-type natriuretic peptide (CNP) and Ang-(1-7) may regulate renal dopamine availability in tubular cells, contributing to Na(+), K(+)-ATPase inhibition. Present results show that CNP did not affect either (3)H-dopamine uptake in renal tissue or Na(+), K(+)-ATPase activity; meanwhile, Ang-(1-7) was able to increase (3)H-dopamine uptake and decreased Na(+), K(+)-ATPase activity in renal cortex. Ang-(1-7) and dopamine together decreased further Na(+), K(+)-ATPase activity showing an additive effect on the sodium pump. In addition, hydrocortisone reversed Ang-(1-7)-dopamine overinhibition on the enzyme, suggesting that this inhibition is closely related to Ang-(1-7) stimulation on renal dopamine uptake. Both anantin and cANP (4-23-amide) did not modify CNP effects on (3)H-dopamine uptake by tubular cells. The Mas receptor antagonist, A-779, blocked the increase elicited by Ang-(1-7) on (3)H-dopamine uptake. The stimulatory uptake induced by Ang-(1-7) was even more pronounced in the presence of losartan, suggesting an inhibitory effect of Ang-(1-7) on AT1 receptors on (3)H-dopamine uptake. By increasing dopamine bioavailability in tubular cells, Ang-(1-7) enhances Na(+), K(+)-ATPase activity inhibition, contributing to its natriuretic and diuretic effects.

  3. Topological strings in d < 1

    Science.gov (United States)

    Dijkgraaf, Robbert; Verlinde, Herman; Verlinde, Erik

    1991-03-01

    We calculate correlation functions in minimal topological field theories. These twisted versions of N = 2 minimal models have recently been proposed to describe d < 1 matrix models, once coupled to topological gravity. In our calculation we make use of the Landau-Ginzburg formulation of the N = 2 models, and we find a direct relation between the Landau-Ginzburg superpotential and the KdV differential operator. Using this correspondence we show that the minimal topological models are in perfect agreement with the matrix models as solved in terms of the KdV hierarchy. This proves the equivalence at tree-level of topological and ordinary string thoery in d < 1.

  4. Delusions, superstitious conditioning and chaotic dopamine neurodynamics.

    Science.gov (United States)

    Shaner, A

    1999-02-01

    Excessive mesolimbic dopaminergic neurotransmission is closely related to the psychotic symptoms of schizophrenia. A mathematical model of dopamine neuron firing rates, developed by King and others, suggests a mechanism by which excessive dopaminergic transmission could produce psychotic symptoms, especially delusions. In this model, firing rates varied chaotically when the efficacy of dopaminergic transmission was enhanced. Such non-contingent changes in firing rates in mesolimbic reward pathways could produce delusions by distorting thinking in the same way that non-contingent reinforcement produces superstitious conditioning. Though difficult to test in humans, the hypothesis is testable as an explanation for a common animal model of psychosis--amphetamine stereotypy in rats. The hypothesis predicts that: (1) amphetamine will cause chaotic firing rates in mesolimbic dopamine neurons; (2) non-contingent brain stimulation reward will produce stereotypy; (3) non-contingent microdialysis of dopamine into reward areas will produce stereotypy; and (4) dopamine antagonists will block all three effects.

  5. Regulation of blood pressure by dopamine receptors.

    Science.gov (United States)

    Jose, Pedro A; Eisner, Gilbert M; Felder, Robin A

    2003-01-01

    Dopamine is an important regulator of blood pressure. Its actions on renal hemodynamics, epithelial transport and humoral agents such as aldosterone, catecholamines, endothelin, prolactin, pro-opiomelanocortin, renin and vasopressin place it in central homeostatic position for regulation of extracellular fluid volume and blood pressure. Dopamine also modulates fluid and sodium intake via actions in the central nervous system and gastrointestinal tract, and by regulation of cardiovascular centers that control the functions of the heart, arteries and veins. Abnormalities in dopamine production and receptor function accompany a high percentage of human essential hypertension and several forms of rodent genetic hypertension. Some dopamine receptor genes and their regulators are in loci linked to hypertension in humans and in rodents. Furthermore, single nucleotide polymorphisms (SNPs) of genes that regulate dopamine receptors, alone or via the interaction with SNPs of genes that regulate the renin-angiotensin system, are associated with human essential hypertension. Each of the five dopamine receptor subtypes (D1, D2, D3, D4 and D5) participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors (D2 and D5) influence the central and/or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents (e.g., the D1, D3 and D4 receptors interact with the renin-angiotensin system). Modifications of the usual actions of the receptor can produce blood pressure changes. In addition, abnormal functioning of these dopamine receptor subtypes impairs their antioxidant function.

  6. Dopamine, T cells and multiple sclerosis (MS).

    Science.gov (United States)

    Levite, Mia; Marino, Franca; Cosentino, Marco

    2017-03-10

    Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R-D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient's Teffs to dopamine. DR agonists and antagonists confer some benefits in

  7. In adult female hamsters hypothyroidism stimulates D1 receptor-mediated breathing without altering D1 receptor expression.

    Science.gov (United States)

    Schlenker, Evelyn H; Del Rio, Rodrigo; Schultz, Harold D

    2015-11-01

    Hypothyroidism affects cardiopulmonary regulation and function of dopaminergic receptors. Here we evaluated effects of 5 months of hypothyroidism on dopamine D1 receptor modulation of breathing in female hamsters using a D1 receptor antagonist SCH 23390. Euthyroid hamsters (EH) served as controls. Results indicated that hypothyroid female hamsters (HH) exhibited decreased body weights and minute ventilation (VE) following hypoxia due to decreased frequency of breathing (F). Moreover, SCH 23390 administration in HH increased VE by increasing tidal volume during exposure to air, hypoxia and following hypoxia. Relative to vehicle, SCH 23390 treatment decreased body temperature and hypoxic VE responsiveness in both groups. In EH, SCH 23390 decreased F in air, hypoxia and post hypoxia, and VE during hypoxia trended to decrease (P=0.053). Finally, expression of D1 receptor protein was not different between the two groups in any region evaluated. Thus, hypothyroidism in older female hamsters affected D1 receptor modulation of ventilation differently relative to euthyroid animals, but not expression of D1 receptors.

  8. Topological strings in d < 1

    Energy Technology Data Exchange (ETDEWEB)

    Dijkgraaf, R.; Verlinde, H. (Princeton Univ., NJ (USA). Joseph Henry Labs.); Verlinde, E. (California Univ., Santa Barbara (USA). Inst. for Theoretical Physics)

    1991-03-18

    We calculate correlation functions in minimal topological field theories. These twisted versions of N = 2 minimal models have recently been proposed to describe d < 1 matrix models, once coupled to topological gravity. In our calculation we make use of the Landau-Ginzburg formulation of the N = 2 models, and we find a direct relation between the Landau-Ginzburg superpotential and the KdV differential operator. Using this correspondence we show that the minimal topological models are in perfect agreement with the matrix models as solved in terms of the KdV hierarchy. This proves the equivalence at tree-level of topological and ordinary string theory in d < 1. (orig.).

  9. Acute Cocaine Induces Fast Activation of D1 Receptor and Progressive Deactivation of D2 Receptor Strial Neurons: In Vivo Optical Microprobe [Ca(superscript)2+]subscript)i Imaging

    Energy Technology Data Exchange (ETDEWEB)

    Du, C.; Luo, Z.; Volkow, N.D.; Heintz, N.; Pan, Y.; Du, C.

    2011-09-14

    Cocaine induces fast dopamine increases in brain striatal regions, which are recognized to underlie its rewarding effects. Both dopamine D1 and D2 receptors are involved in cocaine's reward but the dynamic downstream consequences of cocaine effects in striatum are not fully understood. Here we used transgenic mice expressing EGFP under the control of either the D1 receptor (D1R) or the D2 receptor (D2R) gene and microprobe optical imaging to assess the dynamic changes in intracellular calcium ([Ca{sup 2+}]{sub i} ) responses (used as marker of neuronal activation) to acute cocaine in vivo separately for D1R- versus D2R-expressing neurons in striatum. Acute cocaine (8 mg/kg, i.p.) rapidly increased [Ca{sup 2+}]{sub i} in D1R-expressing neurons (10.6 {+-} 3.2%) in striatum within 8.3 {+-} 2.3 min after cocaine administration after which the increases plateaued; these fast [Ca{sup 2+}]{sub i} increases were blocked by pretreatment with a D1R antagonist (SCH23390). In contrast, cocaine induced progressive decreases in [Ca{sup 2+}]{sub i} in D2R-expressing neurons (10.4 {+-} 5.8%) continuously throughout the 30 min that followed cocaine administration; these slower [Ca{sup 2+}]{sub i} decreases were blocked by pretreatment with a D2R antagonist (raclopride). Since activation of striatal D1R-expressing neurons (direct-pathway) enhances cocaine reward, whereas activation of D2R expressing neurons suppresses it (indirect-pathway) (Lobo et al., 2010), this suggests that cocaine's rewarding effects entail both its fast stimulation ofD1R (resulting in abrupt activation of direct-pathway neurons) and a slower stimulation of D2R (resulting in longer-lasting deactivation of indirect-pathway neurons). We also provide direct in vivo evidence of D2R and D1R interactions in the striatal responses to acute cocaine administration.

  10. Dissociable hippocampal and amygdalar D1-like receptor contribution to discriminated Pavlovian conditioned approach learning.

    Science.gov (United States)

    Andrzejewski, Matthew E; Ryals, Curtis

    2016-02-15

    Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 μL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward-related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses.

  11. Dopamine receptor activation increases HIV entry into primary human macrophages.

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    Peter J Gaskill

    Full Text Available Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.

  12. Dopamine inhibits somatolactin gene expression in tilapia pituitary cells through the dopamine D2 receptors.

    Science.gov (United States)

    Jiang, Quan; Lian, Anji; He, Qi

    2016-07-01

    Dopamine (DA) is an important neurotransmitter in the central nervous system of vertebrates and possesses key hypophysiotropic functions. Early studies have shown that DA has a potent inhibitory effect on somatolactin (SL) release in fish. However, the mechanisms responsible for DA inhibition of SL gene expression are largely unknown. To this end, tilapia DA type-1 (D1) and type-2 (D2) receptor transcripts were examined in the neurointermediate lobe (NIL) of the tilapia pituitary by real-time PCR. In tilapia, DA not only was effective in inhibiting SL mRNA levels in vivo and in vitro, but also could abolish pituitary adenylate cyclase-activating polypeptide (PACAP)- and salmon gonadotropin-releasing hormone (sGnRH)-stimulated SL gene expression at the pituitary level. In parallel studies, the specific D2 receptor agonists quinpirole and bromocriptine could mimic the DA-inhibited SL gene expression. Furthermore, the D2 receptor antagonists domperidone and (-)-sulpiride could abolish the SL response to DA or the D2 agonist quinpirole, whereas D1 receptor antagonists SCH23390 and SKF83566 were not effective in this respect. In primary cultures of tilapia NIL cells, D2 agonist quinpirole-inhibited cAMP production could be blocked by co-treatment with the D2 antagonist domperidone and the ability of forskolin to increase cAMP production was also inhibited by quinpirole. Using a pharmacological approach, the AC/cAMP pathway was shown to be involved in quinpirole-inhibited SL mRNA expression. These results provide evidence that DA can directly inhibit SL gene expression at the tilapia pituitary level via D2 receptor through the AC/cAMP-dependent mechanism.

  13. Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats

    DEFF Research Database (Denmark)

    Hankir, Mohammed K; Seyfried, Florian; Hintschich, Constantin A

    2017-01-01

    intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions...

  14. Dopamine and renal function and blood pressure regulation.

    Science.gov (United States)

    Armando, Ines; Villar, Van Anthony M; Jose, Pedro A

    2011-07-01

    Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein-coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1-like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification.

  15. Renal Dopamine Receptors, Oxidative Stress, and Hypertension

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    Ines Armando

    2013-08-01

    Full Text Available Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1, paraoxonase 2 (PON2, and heme oxygenase 2 (HO-2, all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.

  16. Renal dopamine receptors, oxidative stress, and hypertension.

    Science.gov (United States)

    Cuevas, Santiago; Villar, Van Anthony; Jose, Pedro A; Armando, Ines

    2013-08-27

    Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti-oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice.

  17. Geodesics in (Rn, d1

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    Mehmet KILIÇ

    2016-09-01

    Full Text Available The notion of geodesic, which may be regarded as an extension of the line segment in Euclidean geometry to the space we study in, has an important place in many branches of geometry, such as Riemannian geometry, Metric geometry, to name but a few. In this article, the concept of geodesic in a metric space will be introduced, then geodesics in the space (Rn, d1 will be characterized. Furthermore, some examples will be presented to demonstrate the effectiveness of the main result.

  18. Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release.

    Science.gov (United States)

    Nimitvilai, Sudarat; Herman, Melissa; You, Chang; Arora, Devinder S; McElvain, Maureen A; Roberto, Marisa; Brodie, Mark S

    2014-07-01

    Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent decrease in DA-induced inhibition, a complex desensitization called DA inhibition reversal (DIR). DIR is mediated by conventional protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of some Gq-linked receptors. Corticotropin releasing factor (CRF) acts via Gq, and can modulate glutamater neurotransmission in the VTA. In the present study, we used brain slice electrophysiology to characterize the interaction of DA, glutamate antagonists, and CRF agonists in the induction and maintenance of DIR in the VTA. Glutamate receptor antagonists blocked induction but not maintenance of DIR. Putative blockers of neurotransmitter release and store-operated calcium channels blocked and reversed DIR. CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole, consistent with our earlier work indicating that Gq activation reverses quinpirole-mediated inhibition. In whole cell recordings, the combination of urocortin and quinpirole, but not either agent alone, increased spontaneous excitatory postsynaptic currents (sEPSCs) in VTA neurons. Likewise, the combination of a D1-like receptor agonist and quinpirole, but not either agent alone, increased sEPSCs in VTA neurons. In summary, desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA.

  19. Effects of dopamine receptor agonist and antagonists on cholestasis-induced anxiolytic-like behaviors in rats.

    Science.gov (United States)

    Reza Zarrindast, Mohammad; Eslimi Esfahani, Delaram; Oryan, Shahrbano; Nasehi, Mohammad; Torabi Nami, Mohammad

    2013-02-28

    Dysfunctions in the dopamine transmission system have been suggested to contribute to the pathogenesis of hepatic encephalopathy. In an experimental animal model, cholestasis induction through bile duct ligation may present several main pathological features of hepatic encephalopathy. Dopaminergic systems are shown to play pivotal roles in regulation of anxiety-like behaviors. The main bile duct in male Wistar rats, weighing 220-240 g, was ligated using two ligatures plus duct transection in between. Anxiety-like behaviors were measured using the elevated plus maze task. Cholestasis increased the open arm time percentage (%OAT), 13 but not 10 days after bile duct ligation, indicating an anxiolytic-like effect. Sole intraperitoneal injection of apomorphine (dopamine D1/D2 receptor agonist, 0.25 mg/kg), SCH23390 (dopamine D1 receptor antagonist, 0.005, 0.01 and 0.02 mg/kg) or sulpiride (dopamine D2 receptor antagonist, 0.125, 0.25 and 0.5 mg/kg) did not alter %OAT, open arm entries percentage (%OAE) and locomotor activity in the sham-operated rats. Meanwhile, the higher dose apomorphine (0.5 mg/kg) induced anxiolytic-like behaviors in this group. The subthreshold dose injection of SCH23390 or sulpiride, partially reversed the anxiolytic-like behaviors induced by cholestasis (13 days after bile duct ligation). On the other hand, subthreshold dose of apomorphine in cholestatic rats (10 days post bile duct ligation) induced anxiolytic-like effects which could be blocked by SCH23390 or sulpiride. The effective doses of above drugs did not alter locomotor activity, number of rearings, groomings and defections. These findings suggested that the dopaminergic system may potentially be involved in the modulation of cholestasis-induced anxiolytic-like behaviors in rats.

  20. Salsolinol facilitates glutamatergic transmission to dopamine neurons in the posterior ventral tegmental area of rats.

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    Guiqin Xie

    Full Text Available Although in vivo evidence indicates that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse, the underlying mechanisms have not been fully elucidated. We have reported previously that salsolinol stimulates dopamine neurons in the posterior ventral tegmental area (p-VTA partly by reducing inhibitory GABAergic transmission, and that ethanol increases glutamatergic transmission to VTA-dopamine neurons via the activation of dopamine D(1 receptors (D(1Rs. In this study, we tested the hypothesis that salsolinol stimulates dopamine neurons involving activation of D(1Rs. By using whole-cell recordings on p-VTA-dopamine neurons in acute brain slices of rats, we found that salsolinol-induced increase in spike frequency of dopamine neurons was substantially attenuated by DL-2-amino-5-phosphono-valeric acid and 6, 7-dinitroquinoxaline-2, 3-dione, the antagonists of glutamatergic N-Methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, salsolinol increased the amplitude of evoked excitatory postsynaptic currents (EPSCs and the frequency but not the amplitude of spontaneous EPSCs. Additionally, SKF83566, a D(1R antagonist attenuated the salsolinol-induced facilitation of EPSCs and of spontaneous firing of dopamine neurons. Our data reveal that salsolinol enhances glutamatergic transmission onto dopamine neurons via activation of D(1Rs at the glutamatergic afferents in dopamine neurons, which contributes to salsolinol's stimulating effect on p-VTA dopamine neurons. This appears to be a novel mechanism which contributes toward rewarding properties of salsolinol.

  1. Salsolinol facilitates glutamatergic transmission to dopamine neurons in the posterior ventral tegmental area of rats.

    Science.gov (United States)

    Xie, Guiqin; Ye, Jiang-Hong

    2012-01-01

    Although in vivo evidence indicates that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse, the underlying mechanisms have not been fully elucidated. We have reported previously that salsolinol stimulates dopamine neurons in the posterior ventral tegmental area (p-VTA) partly by reducing inhibitory GABAergic transmission, and that ethanol increases glutamatergic transmission to VTA-dopamine neurons via the activation of dopamine D(1) receptors (D(1)Rs). In this study, we tested the hypothesis that salsolinol stimulates dopamine neurons involving activation of D(1)Rs. By using whole-cell recordings on p-VTA-dopamine neurons in acute brain slices of rats, we found that salsolinol-induced increase in spike frequency of dopamine neurons was substantially attenuated by DL-2-amino-5-phosphono-valeric acid and 6, 7-dinitroquinoxaline-2, 3-dione, the antagonists of glutamatergic N-Methyl-D-aspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Moreover, salsolinol increased the amplitude of evoked excitatory postsynaptic currents (EPSCs) and the frequency but not the amplitude of spontaneous EPSCs. Additionally, SKF83566, a D(1)R antagonist attenuated the salsolinol-induced facilitation of EPSCs and of spontaneous firing of dopamine neurons. Our data reveal that salsolinol enhances glutamatergic transmission onto dopamine neurons via activation of D(1)Rs at the glutamatergic afferents in dopamine neurons, which contributes to salsolinol's stimulating effect on p-VTA dopamine neurons. This appears to be a novel mechanism which contributes toward rewarding properties of salsolinol.

  2. Dopamine-induced cyclic AMP increase in canine myocardium, kidney and superior mesenteric artery.

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    Kazuno,Hiroshi

    1982-04-01

    Full Text Available The effect of dopamine on cyclic AMP levels in tissue slices of canine myocardium and kidney, and in chopped superior mesenteric arterial wall was investigated to identify dopamine receptors. Tissues were incubated in modified Krebs-Henseleit Ringer bicarbonate solution at 37 degrees C for 20 min with test drugs, after 20-min preincubation. In the presence of 3-isobutyl-1-methylxanthine (IBMX, dopamine and apomorphine caused dose-dependent increases in cyclic AMP levels in the myocardium, kidney and superior mesenteric artery. Phentolamine significantly intensified the cyclic AMP-increasing effect of dopamine in the superior mesenteric artery, but it did not influence the cyclic AMP increase caused by dopamine or apomorphine in the myocardium and kidney. Propranolol markedly blocked the effect of dopamine on cyclic AMP levels in all tissues studied. Haloperidol slightly inhibited the effect of dopamine and completely blocked the effect of apomorphine in the myocardium and kidney. These data suggest that dopamine increases cyclic AMP levels by activating predominantly beta-adrenergic receptors and partly dopamine receptors in the canine myocardium, kidney and superior mesenteric artery. The present results also suggest that dopamine acts not only on beta-adrenergic and dopamine receptors but also on alpha-adrenergic receptors in the superior mesenteric artery. Contrary to the activation of beta-adrenergic and dopamine receptors, the activation of alpha-adrenergic receptors resulted in a decrease in cyclic AMP levels in this tissue.

  3. Interaction of environmental contaminants with zebrafish organic anion transporting polypeptide, Oatp1d1 (Slco1d1)

    Energy Technology Data Exchange (ETDEWEB)

    Popovic, Marta; Zaja, Roko [Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Rudjer Boskovic Institute, Bijenicka 54, 10 000 Zagreb (Croatia); Fent, Karl [University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Gründenstrasse 40, CH-4132 Muttenz (Switzerland); Swiss Federal Institute of Technology (ETH Zürich), Department of Environmental System Sciences, Institute of Biogeochemistry and Pollution Dynamics, CH-8092 Zürich (Switzerland); Smital, Tvrtko, E-mail: smital@irb.hr [Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Rudjer Boskovic Institute, Bijenicka 54, 10 000 Zagreb (Croatia)

    2014-10-01

    -methyl, E1, E2 are strong inhibitors of Oatp1d1 • PFOA and diclofenac can block Oatp1d1 binding of DHEAS, E3S and E17ß-glucuronide.

  4. Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

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    Rothmond Debora A

    2012-02-01

    Full Text Available Abstract Background Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5, catechol-O-methyltransferase, and monoamine oxidase (A and B in the developing human DLPFC (6 weeks -50 years. Results Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p O-methyltransferase (p = 0.024 were significantly higher in neonates and infants as was catechol-O-methyltransferase protein (32 kDa, p = 0.027. In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002 and dopamine D1 receptor protein expression increased throughout development (p Conclusions We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.

  5. Modulation of memory fields by dopamine Dl receptors in prefrontal cortex

    Science.gov (United States)

    Williams, Graham V.; Goldman-Rakic, Patricia S.

    1995-08-01

    Dopamine has been implicated in the cognitive process of working memory but the cellular basis of its action has yet to be revealed. By combining iontophoretic analysis of dopamine receptors with single-cell recording during behaviour, we found that D1 antagonists can selectively potentiate the 'memory fields' of prefrontal neurons which subserve working memory. The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.

  6. Presence and function of dopamine transporter (DAT in stallion sperm: dopamine modulates sperm motility and acrosomal integrity.

    Directory of Open Access Journals (Sweden)

    Javier A Urra

    Full Text Available Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT, serotonin (SERT and norepinephrine (NET transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylaminostyryl]-N-methylpyridinium iodide (ASP(+, as substrate. In addition, we also showed that dopamine (1 mM treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909 and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility.

  7. PET neuroimaging of extrastriatal dopamine receptors and prefrontal cortex functions.

    Science.gov (United States)

    Takahashi, Hidehiko

    2013-12-01

    The role of prefrontal dopamine D1 receptors in prefrontal cortex (PFC) functions, including working memory, is widely investigated. However, human (healthy volunteers and schizophrenia patients) positron emission tomography (PET) studies about the relationship between prefrontal D1 receptors and PFC functions are somewhat inconsistent. We argued that several factors including an inverted U-shaped relationship between prefrontal D1 receptors and PFC functions might be responsible for these inconsistencies. In contrast to D1 receptors, relatively less attention has been paid to the role of D2 receptors in PFC functions. Several animal and human pharmacological studies have reported that the systemic administration of D2 receptor agonist/antagonist modulates PFC functions, although those studies do not tell us which region(s) is responsible for the effect. Furthermore, while prefrontal D1 receptors are primarily involved in working memory, other PFC functions such as set-shifting seem to be differentially modulated by dopamine. PET studies of extrastriatal D2 receptors including ours suggested that orchestration of prefrontal dopamine transmission and hippocampal dopamine transmission might be necessary for a broad range of normal PFC functions. In order to understand the complex effects of dopamine signaling on PFC functions, measuring a single index related to basic dopamine tone is not sufficient. For a better understanding of the meanings of PET indices related to neurotransmitters, comprehensive information (presynaptic, postsynaptic, and beyond receptor signaling) will be required. Still, an interdisciplinary approach combining molecular imaging techniques with cognitive neuroscience and clinical psychiatry will provide new perspectives for understanding the neurobiology of neuropsychiatric disorders and their innovative drug developments.

  8. A causal link between prediction errors, dopamine neurons and learning.

    Science.gov (United States)

    Steinberg, Elizabeth E; Keiflin, Ronald; Boivin, Josiah R; Witten, Ilana B; Deisseroth, Karl; Janak, Patricia H

    2013-07-01

    Situations in which rewards are unexpectedly obtained or withheld represent opportunities for new learning. Often, this learning includes identifying cues that predict reward availability. Unexpected rewards strongly activate midbrain dopamine neurons. This phasic signal is proposed to support learning about antecedent cues by signaling discrepancies between actual and expected outcomes, termed a reward prediction error. However, it is unknown whether dopamine neuron prediction error signaling and cue-reward learning are causally linked. To test this hypothesis, we manipulated dopamine neuron activity in rats in two behavioral procedures, associative blocking and extinction, that illustrate the essential function of prediction errors in learning. We observed that optogenetic activation of dopamine neurons concurrent with reward delivery, mimicking a prediction error, was sufficient to cause long-lasting increases in cue-elicited reward-seeking behavior. Our findings establish a causal role for temporally precise dopamine neuron signaling in cue-reward learning, bridging a critical gap between experimental evidence and influential theoretical frameworks.

  9. Impaired renal vascular response to a D-1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats

    NARCIS (Netherlands)

    de Vries, P.A.M.; Navis, Ger Jan; De Jong, P.E.; de Zeeuw, Dick

    1999-01-01

    The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D-1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D-1-like recepto

  10. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.

    Science.gov (United States)

    Kupchik, Yonatan M; Brown, Robyn M; Heinsbroek, Jasper A; Lobo, Mary Kay; Schwartz, Danielle J; Kalivas, Peter W

    2015-09-01

    It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

  11. Main: D1GMAUX28 [PLACE

    Lifescience Database Archive (English)

    Full Text Available D1GMAUX28 S000328 20-Feb-2002 (last modified) uchi D1; DNase I protected sequence f...ound in the soybean (G.m.) auxin responsive gene, Aux28, promoter; D1 and D4 share a very similar core seque...nce TAGTXXCTGT and TAGTXCTGT, respectively; D1/D4-like sequence were identified in several other auxin-respo...tors; GmGT-2 are down-regulated by light in a phytochrome-dependent manner; See 000331; Auxin; Aux28; GT-2; phytochrome; D1; hypocotyl; soybean (Glycine max) ACAGTTACTA ...

  12. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    Science.gov (United States)

    Levite, M

    2016-01-01

    Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs

  13. Dcc haploinsufficiency regulates dopamine receptor expression across postnatal lifespan.

    Science.gov (United States)

    Pokinko, Matthew; Grant, Alanna; Shahabi, Florence; Dumont, Yvan; Manitt, Colleen; Flores, Cecilia

    2017-03-27

    Adolescence is a period during which the medial prefrontal cortex (mPFC) undergoes significant remodeling. The netrin-1 receptor, deleted in colorectal cancer (DCC), controls the extent and organization of mPFC dopamine connectivity during adolescence and in turn directs mPFC functional and structural maturation. Dcc haploinsufficiency leads to increased mPFC dopamine input, which causes improved cognitive processing and resilience to behavioral effects of stimulant drugs of abuse. Here we examine the effects of Dcc haploinsufficiency on the dynamic expression of dopamine receptors in forebrain targets of C57BL6 mice. We conducted quantitative receptor autoradiography experiments with [(3)H]SCH-23390 or [(3)H]raclopride to characterize D1 and D2 receptor expression in mPFC and striatal regions in male Dcc haploinsufficient and wild-type mice. We generated autoradiograms at early adolescence (PND21±1), mid-adolescence (PND35±2), and adulthood (PND75±15). C57BL6 mice exhibit overexpression and pruning of D1, but not D2, receptors in striatal regions, and a lack of dopamine receptor pruning in the mPFC. We observed age- and region-specific differences in D1 and D2 receptor density between Dcc haploinsufficient and wild-type mice. Notably, neither group shows the typical pattern of mPFC dopamine receptor pruning in adolescence, but adult haploinsufficient mice show increased D2 receptor density in the mPFC. These results show that DCC receptors contribute to the dynamic refinement of D1 and D2 receptor expression in striatal regions across adolescence. The age-dependent expression of dopamine receptor in C57BL6 mice shows marked differences from previous characterizations in rats.

  14. Mechanisms for Antagonistic Regulation of AMPA and NMDA-D1 Receptor Complexes at Postsynaptic Sites

    Science.gov (United States)

    Schumann, Johann; Scheler, Gabriele

    2004-01-01

    From the analysis of these pathways we conclude that postsynaptic processes that regulate synaptic transmission undergo significant cross-talk with respect to glutamatergic and neuromodulatory (dopamine) signals. The main hypothesis is that of a compensatory regulation, a competitive switch between the induction of increased AMPA conductance by CaMKII-dependent phosphorylation and reduced expression of PP2A, and increased D1 receptor sensitivity and expression by increased PKA, PP2A and decreased PP-1/calcineurin expression. Both types of plasticity are induced by NMDA receptor activation and increased internal calcium, they require different internal conditions to become expressed. Specifically we propose that AMPA regulation and D1 regulation are inversely coupled;The net result may be a bifurcation of synaptic state into predominantly AMPA or NMDA-D1 synapses. This could have functional consequences: stable connections for AMPA and conditional gating for NMDA-D1 synapses.

  15. 多巴胺受体D1基因多态性与原发性高血压的相关性研究%Association of Gene Polymorphism of Dopamine Receptor Gene ( DRD1 ) With Essential Hypertension in Han Nationality Patients

    Institute of Scientific and Technical Information of China (English)

    许骥; 华琦; 李东宝; 陈海翎; 郭金成; 刘荣坤; 杨峥

    2006-01-01

    目的:探讨多巴胺受体D1(DRD1)基因(-48A/G)多态性与原发性高血压的相关性.方法:采用多聚酶链式反应结合限制性内切酶片段长度多态性分析方法检测330例原发性高血压患者(高血压组)和195例健康人(对照组)DRD1基因(-48A/G)多态性,并对两组人群的血压及各项临床指标进行测定.结果:高血压患者中,DRD1基因(-48A/G)多态性各基因型之间的收缩压、舒张压及平均动脉压有显著差异.其中,AG基因型的诊室舒张压、24 h舒张压及24 h平均动脉压显著高于AA基因型(P<0.05);GG基因型的诊室收缩压、诊室舒张压、诊室平均动脉压及24 h舒张压、24 h平均动脉压均显著高于AA基因型(P<0.05);AG基因型与GG基因型之间的收缩压、舒张压及平均动脉压均无显著差异(P>0.05).结论:北京地区汉族人群中DRD1基因(-48A/G)多态性与原发性高血压明显相关.

  16. The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.

    Directory of Open Access Journals (Sweden)

    Xiaoliang Jiang

    Full Text Available Renal dopamine D1-like receptors (D1R and D5R and the gastrin receptor (CCKBR are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.

  17. The Synergistic Roles of Cholecystokinin B and Dopamine D5 Receptors on the Regulation of Renal Sodium Excretion.

    Science.gov (United States)

    Jiang, Xiaoliang; Chen, Wei; Liu, Xing; Wang, Zihao; Liu, Yunpeng; Felder, Robin A; Gildea, John J; Jose, Pedro A; Qin, Chuan; Yang, Zhiwei

    2016-01-01

    Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was verified in HEK293 cells heterologously expressing both human D5R and CCKBR and in RPT cells from a male normotensive human. The specificity of D5R in the D5R and CCKBR interaction was verified further using a selective D5R antagonist, LE-PM436. Also, D5R and CCKBR colocalize and co-immunoprecipitate in BALB/c mouse RPTs and human RPT cells. CCKBR protein expression in plasma membrane-enriched fractions of renal cortex (PMFs) is greater in D5R-/- mice than D5R+/+ littermates and D5R protein expression in PMFs is also greater in CCKBR-/- mice than CCKBR+/+ littermates. High salt diet, relative to normal salt diet, increased the expression of CCKBR and D5R proteins in PMFs. Disruption of CCKBR in mice caused hypertension and decreased sodium excretion. The natriuresis in salt-loaded BALB/c mice was decreased by YF476, a CCKBR antagonist and Sch23390, a D1R/D5R antagonist. Furthermore, the natriuresis caused by gastrin was blocked by Sch23390 while the natriuresis caused by fenoldopam, a D1R/D5R agonist, was blocked by YF476. Taken together, our findings indicate that CCKBR and D5R synergistically interact in the kidney, which may contribute to the maintenance of normal sodium balance following an increase in sodium intake.

  18. Immunomodulatory Effects Mediated by Dopamine

    Science.gov (United States)

    Alvarez-Herrera, Samantha; Pérez-Sánchez, Gilberto; Becerril-Villanueva, Enrique; Cruz-Fuentes, Carlos; Flores-Gutierrez, Enrique Octavio; Quintero-Fabián, Saray

    2016-01-01

    Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers. PMID:27795960

  19. Immunomodulatory Effects Mediated by Dopamine

    Directory of Open Access Journals (Sweden)

    Rodrigo Arreola

    2016-01-01

    Full Text Available Dopamine (DA, a neurotransmitter in the central nervous system (CNS, has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R and D2-like receptors (D2R, D3R, and D4R. The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS, there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.

  20. Effects of dexfenfluramine on dopamine dependent behaviours in rats.

    Science.gov (United States)

    Thorat, V M; Gaonkar, R K; Bhosale, K B; Balsara, J J

    2005-01-01

    5-hydroxytryptamine (5-HT) inhibits the synthesis and release of dopamine (DA) from rat nigrostriatal DAergic neurons. Dexfenfluramine releases 5-HT from brain 5-HTergic neurons. The present study was undertaken to determine whether dexfenfluramine, through the released 5-HT, modulates the intensity of the behaviours dependent on the functional status of the nigrostriatal DAergic system. The effect of pretreatment with dexfenfluramine on dexamphetamine and apomorphine stereotypies of the oral movement variety and on catalepsy induced by haloperidol and small doses (0.05 and 0.1 mg/kg ip) of apomorphine was studied in rats. We also investigated whether dexfenfluramine induces catalepsy in rats. Dexfenfluramine at 2.5, 5 and 10 mg/kg ip did not induce catalepsy and did not antagonise apomorphine stereotypy. However, 1 h pretreatment with 5-HT releasing doses of dexfenfluramine ie 5 and 10 mg/kg ip, antagonized dexamphetamine stereotypy and potentiated catalepsy induced by haloperidol and small doses of apomorphine. Our results, that dexfenfluramine at 2.5, 5 and 10 mg/kg ip neither induced catalepsy nor antagonised apomorphine stereotypy, indicate that dexfenfluramine at these doses does not block the postsynaptic striatal D2 and D1 DA receptors. They also indicate that the 5-HT released by 5 and 10 mg/kg dexfenfluramine does not exert an inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptor sites. However, 5 and 10 mg/kg doses of dexfenfluramine, through the released 5-HT, inhibit the synthesis and release of DA from the nigrostriatal DAergic neurons and thus antagonise dexamphetamine stereotypy and potentiate catalepsy induced by haloperidol and small doses of apomorphine.

  1. Design and discovery of 1,3-benzodiazepines as novel dopamine antagonists.

    Science.gov (United States)

    Zhu, Zhaoning; Sun, Zhong-Yue; Ye, Yuanzan; McKittrick, Brian; Greenlee, William; Czarniecki, Michael; Fawzi, Ahmad; Zhang, Hongtao; Lachowicz, Jean E

    2009-09-01

    A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.

  2. Dopamins renale virkninger

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    1990-01-01

    Dopamine is an endogenic catecholamine which, in addition to being the direct precursor of noradrenaline, has also an effect on peripheral dopaminergic receptors. These are localized mainly in the heart, splanchnic nerves and the kidneys. Dopamine is produced in the kidneys and the renal metaboli...... dialysis unnecessary in a number of patients on account of increased diuresis and natriuresis. The effect of GFR and the significance for the prognosis are not known....

  3. Dysregulation of Striatal Dopamine Receptor Binding in Suicide.

    Science.gov (United States)

    Fitzgerald, Megan L; Kassir, Suham A; Underwood, Mark D; Bakalian, Mihran J; Mann, J John; Arango, Victoria

    2017-03-01

    Inconsistent evidence implicates disruptions of striatal dopaminergic indices in suicide and major depression. To determine whether there are alterations in the striatal dopamine system in suicide, we conducted a quantitative autoradiographic survey of dopamine transporter (DAT; [(3)H]mazindol), D1 receptor ([(3)H]SCH23390), and D2 receptor ([(3)H]sulpiride) binding in the dorsal striatum postmortem from matched suicides and controls. Axis I and axis II psychiatric diagnosis, recent treatment history, and early life adversity (ELA) were determined by psychological autopsy. Mean DAT, D2, and D1 receptor binding did not differ in suicide. However, there was a positive correlation between D1 and D2 receptor binding in the dorsal striatum of control subjects (R(2)=0.31, pELA, there was no correlation between striatal DAT and D1 receptor binding (R(2)=0.07, p=0.33), although DAT and D1 receptor binding was positively correlated in subjects with no report of ELA (R(2)=0.32, pELA-related mean differences. Binding of D1 receptors and DAT throughout the striatum correlated negatively with age (D1 receptor: R(2)=0.12, pELA or age.

  4. A Physical Interaction between the Dopamine Transporter and DJ-1 Facilitates Increased Dopamine Reuptake.

    Directory of Open Access Journals (Sweden)

    Beryl Luk

    Full Text Available The regulation of the dopamine transporter (DAT impacts extracellular dopamine levels after release from dopaminergic neurons. Furthermore, a variety of protein partners have been identified that can interact with and modulate DAT function. In this study we show that DJ-1 can potentially modulate DAT function. Co-expression of DAT and DJ-1 in HEK-293T cells leads to an increase in [3H] dopamine uptake that does not appear to be mediated by increased total DAT expression but rather through an increase in DAT cell surface localization. In addition, through a series of GST affinity purifications and co-immunoprecipitations, we provide evidence that the DAT can be found in a complex with DJ-1, which involve distinct regions within both DAT and DJ-1. Using in vitro binding experiments we also show that this complex can be formed in part by a direct interaction between DAT and DJ-1. Co-expression of a mini-gene that can disrupt the DAT/DJ-1 complex appears to block the increase in [3H] dopamine uptake by DJ-1. Mutations in DJ-1 have been linked to familial forms of Parkinson's disease, yet the normal physiological function of DJ-1 remains unclear. Our study suggests that DJ-1 may also play a role in regulating dopamine levels by modifying DAT activity.

  5. Enhanced striatal dopamine release during food stimulation in binge eating disorder

    Energy Technology Data Exchange (ETDEWEB)

    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.

  6. Enhanced striatal dopamine release during food stimulation in binge eating disorder.

    Science.gov (United States)

    Wang, Gene-Jack; Geliebter, Allan; Volkow, Nora D; Telang, Frank W; Logan, Jean; Jayne, Millard C; Galanti, Kochavi; Selig, Peter A; Han, Hao; Zhu, Wei; Wong, Christopher T; Fowler, Joanna S

    2011-08-01

    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.

  7. Cyclin D1 expression in prostate carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, R.A.; Ravinal, R.C.; Costa, R.S.; Lima, M.S. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Patologia, Ribeirão Preto, SP, Brasil, Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Tucci, S. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Cirurgia e Anatomia, Divisão de Urologia, Ribeirão Preto, SP, Brasil, Divisão de Urologia, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Muglia, V.F. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Medicina Interna (Centro de Ciência da Imagem), Ribeirão Preto, SP, Brasil, Departamento de Medicina Interna (Centro de Ciência da Imagem), Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Reis, R.B. Dos [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Cirurgia e Anatomia, Divisão de Urologia, Ribeirão Preto, SP, Brasil, Divisão de Urologia, Departamento de Cirurgia e Anatomia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Silva, G.E.B. [Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Patologia, Ribeirão Preto, SP, Brasil, Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil)

    2014-05-09

    The purpose of this study was to investigate the relationship between cyclin D1 expression and clinicopathological parameters in patients with prostate carcinoma. We assessed cyclin D1 expression by conventional immunohistochemistry in 85 patients who underwent radical prostatectomy for prostate carcinoma and 10 normal prostate tissue samples retrieved from autopsies. We measured nuclear immunostaining in the entire tumor area and based the results on the percentage of positive tumor cells. The preoperative prostate-specific antigen (PSA) level was 8.68±5.16 ng/mL (mean±SD). Cyclin D1 staining was positive (cyclin D1 expression in >5% of tumor cells) in 64 cases (75.4%) and negative (cyclin D1 expression in ≤5% of tumor cells) in 21 cases (including 15 cases with no immunostaining). Normal prostate tissues were negative for cyclin D1. Among patients with a high-grade Gleason score (≥7), 86% of patients demonstrated cyclin D1 immunostaining of >5% (P<0.05). In the crude analysis of cyclin D1 expression, the high-grade Gleason score group showed a mean expression of 39.6%, compared to 26.9% in the low-grade Gleason score group (P<0.05). Perineural invasion tended to be associated with cyclin D1 expression (P=0.07), whereas cyclin D1 expression was not associated with PSA levels or other parameters. Our results suggest that high cyclin D1 expression could be a potential marker for tumor aggressiveness.

  8. Effect of desipramine on dopamine receptor binding in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Suhara, Tetsuya (National Institute of Radiological Sciences, Chiba (Japan) Jikei Univ., Tokyo (Japan)); Inoue, Osamu; Kobayasi, Kaoru (National Institute of Radiological Sciences, Chiba (Japan))

    1990-01-01

    Effect of desipramine on the in vivo binding of {sup 3}H-SCH23390 and {sup 3}H-N-methylspiperone ({sup 3}H-NMSP) in mouse striatum was studied. The ratio of radioactivity in the striatum to that in the cerebellum at 15 min after i.v. injection of {sup 3}H-SCH23390 or 45 min after injection of {sup 3}H-NMSP were used as indices of dopamine D1 or D2 receptor binding in vivo, respectively. In vivo binding of D1 and D2 receptors was decreased in a dose-dependent manner by acute treatment with desipramine (DMI). A saturation experiment suggested that the DMI-induced reduction in the binding was mainly due to the decrease in the affinity of both receptors. No direct interactions between the dopamine receptors and DMI were observed in vitro by the addition of 1 mM of DMI into striatal homogenate. Other antidepressants such as imipramine, clomipramine, maprotiline and mianserin also decreased the binding of dopamine D1 and D2 receptors. The results indicated an important role of dopamine receptors in the pharmacological effect of antidepressants.

  9. Blocking Dopaminergic Signaling Soon after Learning Impairs Memory Consolidation in Guinea Pigs.

    Directory of Open Access Journals (Sweden)

    Kiera-Nicole Lee

    Full Text Available Formation of episodic memories (i.e. remembered experiences requires a process called consolidation which involves communication between the neocortex and hippocampus. However, the neuromodulatory mechanisms underlying this neocortico-hippocampal communication are poorly understood. Here, we examined the involvement of dopamine D1 receptors (D1R and D2 receptors (D2R mediated signaling on memory consolidation using the Novel Object Recognition (NOR test. We conducted the tests in male Hartley guinea pigs and cognitive behaviors were assessed in customized Phenotyper home cages utilizing Ethovision XT software from Noldus enabled for the 3-point detection system (nose, center of the body, and rear. We found that acute intraperitoneal injections of either 0.25 mg/kg SCH23390 to block D1Rs or 1.0 mg/kg sulpiride to block D2Rs soon after acquisition (which involved familiarization to two similar objects attenuated subsequent discrimination for novel objects when tested after 5-hours in the NOR test. By contrast guinea pigs treated with saline showed robust discrimination for novel objects indicating normal operational processes undergirding memory consolidation. The data suggests that involvement of dopaminergic signaling is a key post-acquisition factor in modulating memory consolidation in guinea pigs.

  10. Dopamine receptor ligands. Part 18: (1) modification of the structural skeleton of indolobenzazecine-type dopamine receptor antagonists.

    Science.gov (United States)

    Robaa, Dina; Enzensperger, Christoph; Abul Azm, Shams El Din; El Khawass, El Sayeda; El Sayed, Ola; Lehmann, Jochen

    2010-03-25

    On the basis of the D(1/5)-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca(2+) assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.

  11. Activation of ventral tegmental area dopamine neurons produces wakefulness through dopamine D2-like receptors in mice.

    Science.gov (United States)

    Oishi, Yo; Suzuki, Yoshiaki; Takahashi, Koji; Yonezawa, Toshiya; Kanda, Takeshi; Takata, Yohko; Cherasse, Yoan; Lazarus, Michael

    2017-01-25

    A growing body of evidence suggests that dopamine plays a role in sleep-wake regulation, but the dopamine-producing brain areas that control sleep-wake states are unclear. In this study, we chemogenetically activated dopamine neurons in the ventral midbrain of mice to examine the role of these neurons in sleep-wake regulation. We found that activation of dopamine neurons in the ventral tegmental area (VTA), but not in the substantia nigra, strongly induced wakefulness, although both cell populations expressed the neuronal activity marker c-Fos after chemogenetic stimulation. Analysis of the pattern of behavioral states revealed that VTA activation increased the duration of wakefulness and decreased the number of wakefulness episodes, indicating that wakefulness was consolidated by VTA activation. The increased wakefulness evoked by VTA activation was completely abolished by pretreatment with the dopamine D2/D3 receptor antagonist raclopride, but not by the D1 receptor antagonist SCH23390. These findings indicate that the activation of VTA dopamine neurons promotes wakefulness via D2/D3 receptors.

  12. Adenosine transiently modulates stimulated dopamine release in the caudate-putamen via A1 receptors.

    Science.gov (United States)

    Ross, Ashley E; Venton, B Jill

    2015-01-01

    Adenosine modulates dopamine in the brain via A1 and A2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of adenosine that suggests a possible rapid modulatory role. Here, fast-scan cyclic voltammetry was used to characterize the extent to which transient adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate-putamen brain slices. Exogenous adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 μM adenosine did not decrease dopamine release. Mechanical stimulation of endogenous adenosine 2 s before dopamine stimulation also decreased stimulated dopamine release by 41 ± 7%, similar to the 54 ± 6% decrease in dopamine after exogenous adenosine application. Dopamine inhibition by transient adenosine was recovered within 10 min. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A2A receptor antagonist SCH 442416. Thus, transient adenosine changes can transiently modulate phasic dopamine release via A1 receptors. These data demonstrate that adenosine has a rapid, but transient, modulatory role in the brain. Here, transient adenosine was shown to modulate phasic dopamine release on the order of seconds by acting at the A1 receptor. However, sustained increases in adenosine did not regulate phasic dopamine release. This study demonstrates for the first time a transient, neuromodulatory function of rapid adenosine to regulate rapid neurotransmitter release.

  13. Could dopamine agonists aid in drug development for anorexia nervosa?

    Science.gov (United States)

    Frank, Guido K W

    2014-01-01

    Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage-years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight, and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological, and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction, and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction, and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  14. Could Dopamine Agonists Aid in Drug Development for Anorexia Nervosa?

    Directory of Open Access Journals (Sweden)

    Guido eFrank

    2014-11-01

    Full Text Available Anorexia nervosa is a severe psychiatric disorder most commonly starting during the teenage years and associated with food refusal and low body weight. Typically there is a loss of menses, intense fear of gaining weight and an often delusional quality of altered body perception. Anorexia nervosa is also associated with a pattern of high cognitive rigidity, which may contribute to treatment resistance and relapse. The complex interplay of state and trait biological, psychological and social factors has complicated identifying neurobiological mechanisms that contribute to the illness. The dopamine D1 and D2 neurotransmitter receptors are involved in motivational aspects of food approach, fear extinction and cognitive flexibility. They could therefore be important targets to improve core and associated behaviors in anorexia nervosa. Treatment with dopamine antagonists has shown little benefit, and it is possible that antagonists over time increase an already hypersensitive dopamine pathway activity in anorexia nervosa. On the contrary, application of dopamine receptor agonists could reduce circuit responsiveness, facilitate fear extinction and improve cognitive flexibility in anorexia nervosa, as they may be particularly effective during underweight and low gonadal hormone states. This article provides evidence that the dopamine receptor system could be a key factor in the pathophysiology of anorexia nervosa and dopamine agonists could be helpful in reducing core symptoms of the disorder. This review is a theoretical approach that primarily focuses on dopamine receptor function as this system has been mechanistically better described than other neurotransmitters that are altered in anorexia nervosa. However, those proposed dopamine mechanisms in anorexia nervosa also warrant further study with respect to their interaction with other neurotransmitter systems, such as serotonin pathways.

  15. Dopamine receptors modulate cytotoxicity of natural killer cells via cAMP-PKA-CREB signaling pathway.

    Directory of Open Access Journals (Sweden)

    Wei Zhao

    Full Text Available Dopamine (DA, a neurotransmitter in the nervous system, has been shown to modulate immune function. We have previously reported that five subtypes of DA receptors, including D1R, D2R, D3R, D4R and D5R, are expressed in T lymphocytes and they are involved in regulation of T cells. However, roles of these DA receptor subtypes and their coupled signal-transduction pathway in modulation of natural killer (NK cells still remain to be clarified. The spleen of mice was harvested and NK cells were isolated and purified by negative selection using magnetic activated cell sorting. After NK cells were incubated with various drugs for 4 h, flow cytometry measured cytotoxicity of NK cells against YAC-1 lymphoma cells. NK cells expressed the five subtypes of DA receptors at mRNA and protein levels. Activation of D1-like receptors (including D1R and D5R with agonist SKF38393 enhanced NK cell cytotoxicity, but activation of D2-like receptors (including D2R, D3R and D4R with agonist quinpirole attenuated NK cells. Simultaneously, SKF38393 elevated D1R and D5R expression, cAMP content, and phosphorylated cAMP-response element-binding (CREB level in NK cells, while quinpirole reduced D3R and D4R expression, cAMP content, and phosphorylated CREB level in NK cells. These effects of SKF38393 were blocked by SCH23390, an antagonist of D1-like receptors, and quinpirole effects were abolished by haloperidol, an antagonist of D2-like receptors. In support these results, H89, an inhibitor of phosphokinase A (PKA, prevented the SKF38393-dependent enhancement of NK cells and forskolin, an activator of adenylyl cyclase (AC, counteracted the quinpirole-dependent suppression of NK cells. These findings show that DA receptor subtypes are involved in modulation of NK cells and suggest that D1-like receptors facilitate NK cells by stimulating D1R/D5R-cAMP-PKA-CREB signaling pathway and D2-like receptors suppress NK cells by inhibiting D3R/D4R-cAMP-PKA-CREB signaling pathway. The

  16. Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex.

    Science.gov (United States)

    Puig, M Victoria; Miller, Earl K

    2015-09-01

    Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia.

  17. Dopamine Activation Preserves Visual Motion Perception Despite Noise Interference of Human V5/MT

    Science.gov (United States)

    Yousif, Nada; Fu, Richard Z.; Abou-El-Ela Bourquin, Bilal; Bhrugubanda, Vamsee; Schultz, Simon R.

    2016-01-01

    When processing sensory signals, the brain must account for noise, both noise in the stimulus and that arising from within its own neuronal circuitry. Dopamine receptor activation is known to enhance both visual cortical signal-to-noise-ratio (SNR) and visual perceptual performance; however, it is unknown whether these two dopamine-mediated phenomena are linked. To assess this, we used single-pulse transcranial magnetic stimulation (TMS) applied to visual cortical area V5/MT to reduce the SNR focally and thus disrupt visual motion discrimination performance to visual targets located in the same retinotopic space. The hypothesis that dopamine receptor activation enhances perceptual performance by improving cortical SNR predicts that dopamine activation should antagonize TMS disruption of visual perception. We assessed this hypothesis via a double-blinded, placebo-controlled study with the dopamine receptor agonists cabergoline (a D2 agonist) and pergolide (a D1/D2 agonist) administered in separate sessions (separated by 2 weeks) in 12 healthy volunteers in a William's balance-order design. TMS degraded visual motion perception when the evoked phosphene and the visual stimulus overlapped in time and space in the placebo and cabergoline conditions, but not in the pergolide condition. This suggests that dopamine D1 or combined D1 and D2 receptor activation enhances cortical SNR to boost perceptual performance. That local visual cortical excitability was unchanged across drug conditions suggests the involvement of long-range intracortical interactions in this D1 effect. Because increased internal noise (and thus lower SNR) can impair visual perceptual learning, improving visual cortical SNR via D1/D2 agonist therapy may be useful in boosting rehabilitation programs involving visual perceptual training. SIGNIFICANCE STATEMENT In this study, we address the issue of whether dopamine activation improves visual perception despite increasing sensory noise in the visual cortex

  18. Rock blocks

    OpenAIRE

    Turner, W.

    2007-01-01

    Consider representation theory associated to symmetric groups, or to Hecke algebras in type A, or to q-Schur algebras, or to finite general linear groups in non-describing characteristic. Rock blocks are certain combinatorially defined blocks appearing in such a representation theory, first observed by R. Rouquier. Rock blocks are much more symmetric than general blocks, and every block is derived equivalent to a Rock block. Motivated by a theorem of J. Chuang and R. Kessar in the case of sym...

  19. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity.

    Science.gov (United States)

    Izumi, Yasuhiko; Sawada, Hideyuki; Yamamoto, Noriyuki; Kume, Toshiaki; Katsuki, Hiroshi; Shimohama, Shun; Akaike, Akinori

    2007-02-28

    Parkinson disease is characterized by selective degeneration of mesencephalic dopaminergic neurons, and endogenous dopamine may play a pivotal role in the degenerative processes. Using primary cultured mesencephalic neurons, we found that glutamate, an excitotoxin, caused selective dopaminergic neuronal death depending on endogenous dopamine content. Pramipexole, a dopamine D2/D3 receptor agonist used clinically in the treatment of Parkinson disease, did not affect glutamate-induced calcium influx but blocked dopaminergic neuronal death induced by glutamate. Pramipexole reduced dopamine content but did not change the levels of total or phosphorylated tyrosine hydroxylase, a rate-limiting enzyme in dopamine synthesis. The neuroprotective effect of pramipexole was independent of dopamine receptor stimulation because it was not abrogated by domperidone, a dopamine D2-type receptor antagonist. Moreover, both active S(-)- and inactive R(+)-enantiomers of pramipexole as a dopamine D2-like receptor agonist equally suppressed dopaminergic neuronal death. These results suggest that pramipexole protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D2-like receptor activation.

  20. (TH)205-501, a non-catechol dopaminergic agonist, labels selectively and with high affinity dopamine D2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Closse, A.; Frick, W.; Markstein, R.; Maurer, R.; Nordmann, R.

    1985-01-01

    (TH)205-501, a non dopaminergic agonist, is presented as a ligand with high affinity (Ksub(D) approx= 1 nM) and high selectivity for dopamine receptors. pKsubi values of dopaminergic agonists derived from competition isotherms in the (TH)205-501 binding assay correlate very well with their potency in the acetylcholine release assay, which is controlled by dopamine D2 receptors. There is however no correlation with their potency stimulating aldenylate cyclase, a process controlled by dopamine D1 receptors. Thus (TH)205-501 is the first agonist ligand selective for dopamine D2 receptors. (Author).

  1. Design, synthesis and biological evaluation of bivalent ligands against A1-D1 receptor heteromers

    Institute of Scientific and Technical Information of China (English)

    Jian SHEN; Lei ZHANG; Wan-ling SONG; Tao MENG; Xin WANG; Lin CHEN; Lin-yin FENG

    2013-01-01

    Aim:To design and synthesize bivalent ligands for adenosine A1-dopamine D1 receptor heteromers (A1-D1R),and evaluate their pharmacological activities.Methods:Bivalent ligands and their corresponding A1R monovalent ligands were designed and synthesized.The affinities of the bivalent ligands for A1R and D1R in rat brain membrane preparation were examined using radiolabeled binding assays.To demonstrate the formation of A1-D1R,fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D1-CFP and A1-YFP.Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions.Results:Two bivalent ligands for A1R and D1R (20a,20b),as well as the corresponding A1R monovalent ligands (21a,21b) were synthesized.In radiolabeled binding assays,the bivalent ligands showed affinities for A1R 10-100 times higher than those of the corresponding monovalent ligands.In FRET experiments,the bivalent ligands significantly increased the heterodimerization of A1R and D1R compared with the corresponding monovalent ligands.A heterodimer model with the interface of helixes 3,4,5 of A1R and helixes 1,6,7 from D1R was established with molecular modeling.The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 (A),which was shorter than the length of the bivalent ligands.Conclusion:This study demonstrates the existence of A1-D1R in situ and a simultaneous interaction of bivalent ligands with both the receptors.

  2. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory.

    Science.gov (United States)

    Kempadoo, Kimberly A; Mosharov, Eugene V; Choi, Se Joon; Sulzer, David; Kandel, Eric R

    2016-12-20

    Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attention-deficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory.

  3. The association between dopamine D1 receptor gene polymorphisms and schizophrenia:a meta-analysis

    Institute of Scientific and Technical Information of China (English)

    潘雨晴

    2014-01-01

    Objective This study was carried out to examine the association between DRD1 gene polymorphism and the risk of schizophrenia.Methods Relevant case-control studies were retrieved by Chinese and English database(CNKI,WANFANG,VIP,PubMed and Web of Science)and selected according to the established inclusion criteria.The meta-analysis was performed using Stata version 10.0.The strength of the association was meas-

  4. Interactions between Histamine H3 and Dopamine D2 Receptors and the Implications for Striatal Function

    OpenAIRE

    Ferrada, Carla; Ferré, Sergi; Casadó, Vicent; Cortés, Antonio; Justinova, Zuzana; Barnes, Chanel; Canela, Enric I.; Goldberg, Steven R.; Leurs, Rob; Lluis, Carme; Franco, Rafael

    2008-01-01

    The striatum contains a high density of histamine H3 receptors, but their role in striatal function is poorly understood. Previous studies have demonstrated antagonistic interactions between striatal H3 and dopamine D1 receptors at the biochemical level, while contradictory results have been reported about interactions between striatal H3 and dopamine D2 receptors. In the present study, by using reserpinized mice, we demonstrate the existence of behaviorally significant antagonistic postsynap...

  5. Dopamine regulation of gonadotropin-releasing hormone neuron excitability in male and female mice.

    Science.gov (United States)

    Liu, Xinhuai; Herbison, Allan E

    2013-01-01

    Numerous in vivo studies have shown that dopamine is involved in the regulation of LH secretion in mammals. However, the mechanisms through which this occurs are not known. In this study, we used green fluorescent protein-tagged GnRH neurons to examine whether and how dopamine may modulate the activity of adult GnRH neurons in the mouse. Bath-applied dopamine (10-80 μm) potently inhibited the firing of approximately 50% of GnRH neurons. This resulted from direct postsynaptic inhibitory actions through D1-like, D2-like, or both receptors. Further, one third of GnRH neurons exhibited an increase in their basal firing rate after administration of SCH23390 (D1-like antagonist) and/or raclopride (D2-like antagonist) indicating tonic inhibition by endogenous dopamine in the brain slice. The role of dopamine in presynaptic modulation of the anteroventral periventricular nucleus (AVPV) γ-aminobutyric acid/glutamate input to GnRH neurons was examined. Exogenous dopamine was found to presynaptically inhibit AVPV-evoked γ-aminobutyric acid /glutamate postsynaptic currents in about 50% of GnRH neurons. These effects were, again, mediated by both D1- and D2-like receptors. Neither postsynaptic nor presynaptic actions of dopamine were found to be different between diestrous, proestrous, and estrous females, or males. Approximately 20% of GnRH neurons were shown to receive a dopaminergic input from AVPV neurons in male and female mice. Together, these observations show that dopamine is one of the most potent inhibitors of GnRH neuron excitability and that this is achieved through complex pre- and postsynaptic actions that each involve D1- and D2-like receptor activation.

  6. Medial prefrontal cortex dopamine controls the persistent storage of aversive memories

    OpenAIRE

    María Carolina Gonzalez; Cecilia Paula Kramar; Micol eTomaiuolo; Cynthia eKatche; Noelia eWeisstaub; Martín eCammarota; Jorge Horacio Medina

    2014-01-01

    Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC imme...

  7. Altered dopamine signaling in naturally occurring maternal neglect.

    Directory of Open Access Journals (Sweden)

    Stephen C Gammie

    Full Text Available BACKGROUND: Child neglect is the most common form of child maltreatment, yet the biological basis of maternal neglect is poorly understood and a rodent model is lacking. METHODOLOGY/PRINCIPAL FINDINGS: The current study characterizes a population of mice (MaD1 which naturally exhibit maternal neglect (little or no care of offspring at an average rate of 17% per generation. We identified a set of risk factors that can predict future neglect of offspring, including decreased self-grooming and elevated activity. At the time of neglect, neglectful mothers swam significantly more in a forced swim test relative to nurturing mothers. Cross-fostered offspring raised by neglectful mothers in turn exhibit increased expression of risk factors for maternal neglect and decreased maternal care as adults, suggestive of possible epigenetic contributions to neglect. Unexpectedly, offspring from neglectful mothers elicited maternal neglect from cross-fostered nurturing mothers, suggesting that factors regulating neglect are not solely within the mother. To identify a neurological pathway underlying maternal neglect, we examined brain activity in neglectful and nurturing mice. c-Fos expression was significantly elevated in neglectful relative to nurturing mothers in the CNS, particularly within dopamine associated areas, such as the zona incerta (ZI, ventral tegmental area (VTA, and nucleus accumbens. Phosphorylated tyrosine hydroxylase (a marker for dopamine production was significantly elevated in ZI and higher in VTA (although not significantly in neglectful mice. Tyrosine hydroxylase levels were unaltered, suggesting a dysregulation of dopamine activity rather than cell number. Phosphorylation of DARPP-32, a marker for dopamine D1-like receptor activation, was elevated within nucleus accumbens and caudate-putamen in neglectful versus nurturing dams. CONCLUSIONS/SIGNIFICANCE: These findings suggest that atypical dopamine activity within the maternal brain

  8. Dopamine and anorexia nervosa.

    Science.gov (United States)

    Södersten, P; Bergh, C; Leon, M; Zandian, M

    2016-01-01

    We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes.

  9. Regulation of striatal dopamine responsiveness by Notch/RBP-J signaling.

    Science.gov (United States)

    Toritsuka, M; Kimoto, S; Muraki, K; Kitagawa, M; Kishimoto, T; Sawa, A; Tanigaki, K

    2017-03-07

    Dopamine signaling is essential for reward learning and fear-related learning, and thought to be involved in neuropsychiatric diseases. However, the molecular mechanisms underlying the regulation of dopamine responsiveness is unclear. Here we show the critical roles of Notch/RBP-J signaling in the regulation of dopamine responsiveness in the striatum. Notch/RBP-J signaling regulates various neural cell fate specification, and neuronal functions in the adult central nervous system. Conditional deletion of RBP-J specifically in neuronal cells causes enhanced response to apomorphine, a non-selective dopamine agonist, and SKF38393, a D1 agonist, and impaired dopamine-dependent instrumental avoidance learning, which is corrected by SCH23390, a D1 antagonist. RBP-J deficiency drastically reduced dopamine release in the striatum and caused a subtle decrease in the number of dopaminergic neurons. Lentivirus-mediated gene transfer experiments showed that RBP-J deficiency in the striatum was sufficient for these deficits. These findings demonstrated that Notch/RBP-J signaling regulates dopamine responsiveness in the striatum, which may explain the mechanism whereby Notch/RBP-J signaling affects an individual's susceptibility to neuropsychiatric disease.

  10. Dissociable effects of dopamine on neuronal firing rate and synchrony in the dorsal striatum

    Directory of Open Access Journals (Sweden)

    John M Burkhardt

    2009-10-01

    Full Text Available Previous studies showed that dopamine depletion leads to both changes in firing rate and in neuronal synchrony in the basal ganglia. Since dopamine D1 and D2 receptors are preferentially expressed in striatonigral and striatopallidal medium spiny neurons, respectively, we investigated the relative contribution of lack of D1 and/or D2-type receptor activation to the changes in striatal firing rate and synchrony observed after dopamine depletion. Similar to what was observed after dopamine depletion, co-administration of D1 and D2 antagonists to mice chronically implanted with multielectrode arrays in the striatum caused significant changes in firing rate, power of the local field potential (LFP oscillations, and synchrony measured by the entrainment of neurons to striatal local field potentials. However, although blockade of either D1 or D2 type receptors produced similarly severe akinesia, the effects on neural activity differed. Blockade of D2 receptors affected the firing rate of medium spiny neurons and the power of the LFP oscillations substantially, but it did not affect synchrony to the same extent. In contrast, D1 blockade affected synchrony dramatically, but had less substantial effects on firing rate and LFP power. Furthermore, there was no consistent relation between neurons changing firing rate and changing LFP entrainment after dopamine blockade. Our results suggest that the changes in rate and entrainment to the LFP observed in medium spiny neurons after dopamine depletion are somewhat dissociable, and that lack of D1- or D2-type receptor activation can exert independent yet interactive pathological effects during the progression of Parkinson’s disease.

  11. D=1 supergravity and spinning particles

    Energy Technology Data Exchange (ETDEWEB)

    Holten, J.W. van

    1995-10-06

    In this paper I review the multiplet calculus of N-1, D=1 local supersymmetry with applications to the construction of models for spinning particles in background fields, and models with space-time supersymmetry. New features include a non-linear realization of the local supersymmetry algebra and the coupling to anti-symmetric tensor fields of both odd and even rank. The non-linear realization allows the construction of a D=1 cosmological-constant term, which provides a mass term in the equations of motion. (orig.).

  12. Berberine Suppresses Cyclin D1 Expression through Proteasomal Degradation in Human Hepatoma Cells

    Directory of Open Access Journals (Sweden)

    Ning Wang

    2016-11-01

    Full Text Available The aim of this study is to explore the underlying mechanism on berberine-induced Cyclin D1 degradation in human hepatic carcinoma. We observed that berberine could suppress both in vitro and in vivo expression of Cyclin D1 in hepatoma cells. Berberine exhibits dose- and time-dependent inhibition on Cyclin D1 expression in human hepatoma cell HepG2. Berberine increases the phosphorylation of Cyclin D1 at Thr286 site and potentiates Cyclin D1 nuclear export to cytoplasm for proteasomal degradation. In addition, berberine recruits the Skp, Cullin, F-box containing complex-β-Transducin Repeat Containing Protein (SCFβ-TrCP complex to facilitate Cyclin D1 ubiquitin-proteasome dependent proteolysis. Knockdown of β-TrCP blocks Cyclin D1 turnover induced by berberine; blocking the protein degradation induced by berberine in HepG2 cells increases tumor cell resistance to berberine. Our results shed light on berberine′s potential as an anti-tumor agent for clinical cancer therapy.

  13. D5 dopamine receptor knockout mice and hypertension.

    Science.gov (United States)

    Yang, Zhiwei; Sibley, David R; Jose, Pedro A

    2004-08-01

    Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.

  14. NEW DOPAMINE AGONISTS IN CARDIOVASCULAR THERAPY

    NARCIS (Netherlands)

    GIRBES, ARJ; VANVELDHUISEN, DJ; SMIT, AJ

    1992-01-01

    Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1) stim

  15. 42 CFR 52d.1 - Applicability.

    Science.gov (United States)

    2010-10-01

    ... CANCER EDUCATION PROGRAM § 52d.1 Applicability. The regulations in this part apply to grants under the Clinical Cancer Education Program authorized by section 404(a)(4) of the Public Health Service Act, to... neoplastic disease and the preventive measures and diagnostic and therapeutic skills necessary to...

  16. Growth of dopamine crystals

    Science.gov (United States)

    Patil, Vidya; Patki, Mugdha

    2016-05-01

    Many nonlinear optical (NLO) crystals have been identified as potential candidates in optical and electro-optical devices. Use of NLO organic crystals is expected in photonic applications. Hence organic nonlinear optical materials have been intensely investigated due to their potentially high nonlinearities, and rapid response in electro-optic effect compared to inorganic NLO materials. There are many methods to grow organic crystals such as vapor growth method, melt growth method and solution growth method. Out of these methods, solution growth method is useful in providing constraint free crystal. Single crystals of Dopamine have been grown by evaporating the solvents from aqueous solution. Crystals obtained were of the size of orders of mm. The crystal structure of dopamine was determined using XRD technique. Images of crystals were obtained using FEG SEM Quanta Series under high vacuum and low KV.

  17. Reward-based hypertension control by a synthetic brain-dopamine interface.

    Science.gov (United States)

    Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

    2013-11-05

    Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

  18. Glutamate stimulation of (/sup 3/H)dopamine release from dissociated cell cultures of rat ventral mesencephalon

    Energy Technology Data Exchange (ETDEWEB)

    Mount, H.; Welner, S.; Quirion, R.; Boksa, P.

    1989-04-01

    In dissociated cell cultures of fetal rat ventral mesencephalon preloaded with (3H)dopamine, glutamate (10(-5)-10(-3) M) stimulated the release of (3H)dopamine. Glutamate stimulation of (3H)dopamine release was Ca2+ dependent and was blocked by the glutamate antagonist, cis-2,3-piperidine dicarboxylic acid. Glutamate stimulation of (3H)dopamine release was not due to glutamate neurotoxicity because (1) glutamate did not cause release of a cytosolic marker, lactate dehydrogenase, and (2) preincubation of cultures with glutamate did not impair subsequent ability of the cells to take up or release (3H)dopamine. Thus, these dissociated cell cultures appear to provide a good model system to characterize glutamate stimulation of dopamine release. Release of (3H)dopamine from these cultures was stimulated by veratridine, an activator of voltage-sensitive Na+ channels, and this stimulation was blocked by tetrodotoxin. However, glutamate-stimulated (3H)dopamine release was not blocked by tetrodotoxin or Zn2+. Substitution of NaCl in the extracellular medium by sucrose, LiCl, or Na2SO4 had no effect on glutamate stimulation of (3H)dopamine release; however, release was inhibited when NaCl was replaced by choline chloride or N-methyl-D-glucamine HCl. Glutamate-stimulated (3H)-dopamine release was well maintained (60-82% of control) in the presence of Co2+, which blocks Ca2+ action potentials, and was unaffected by the local anesthetic, lidocaine. These results are discussed in terms of the receptor and ionic mechanisms involved in the stimulation of dopamine release by excitatory amino acids.

  19. Intrinsic vascular dopamine - a key modulator of hypoxia-induced vasodilatation in splanchnic vessels.

    Science.gov (United States)

    Pfeil, Uwe; Kuncova, Jitka; Brüggmann, Doerthe; Paddenberg, Renate; Rafiq, Amir; Henrich, Michael; Weigand, Markus A; Schlüter, Klaus-Dieter; Mewe, Marco; Middendorff, Ralf; Slavikova, Jana; Kummer, Wolfgang

    2014-04-15

    Dopamine not only is a precursor of the catecholamines noradrenaline and adrenaline but also serves as an independent neurotransmitter and paracrine hormone. It plays an important role in the pathogenesis of hypertension and is a potent vasodilator in many mammalian systemic arteries, strongly suggesting an endogenous source of dopamine in the vascular wall. Here we demonstrated dopamine, noradrenaline and adrenaline in rat aorta and superior mesenteric arteries (SMA) by radioimmunoassay. Chemical sympathectomy with 6-hydroxydopamine showed a significant reduction of noradrenaline and adrenaline, while dopamine levels remained unaffected. Isolated endothelial cells were able to synthesize and release dopamine upon cAMP stimulation. Consistent with these data, mRNAs coding for catecholamine synthesizing enzymes, i.e. tyrosine hydroxylase (TH), aromatic l-amino acid decarboxylase, and dopamine-β-hydroxylase were detected by RT-PCR in cultured endothelial cells from SMA. TH protein was detected by immunohistochemisty and Western blot. Exposure of endothelial cells to hypoxia (1% O2) increased TH mRNA. Vascular smooth muscle cells partially expressed catecholaminergic traits. A physiological role of endogenous vascular dopamine was shown in SMA, where D1 dopamine receptor blockade abrogated hypoxic vasodilatation. Experiments on SMA with endothelial denudation revealed a significant contribution of the endothelium, although subendothelial dopamine release dominated. From these results we conclude that endothelial cells and cells of the underlying vascular wall synthesize and release dopamine in an oxygen-regulated manner. In the splanchnic vasculature, this intrinsic non-neuronal dopamine is the dominating vasodilator released upon lowering of oxygen tension.

  20. Identification of human dopamine receptors agonists from Chinese herbs

    Institute of Scientific and Technical Information of China (English)

    Yi-lin ZHANG; Hai-qing ZHANG; Xiao-yu LIU; Shi-neng HUA; Lu-bing ZHOU; Jun YU; Xue-hai TAN

    2007-01-01

    Aim: To find human dopamine receptors, especially D1-like receptor specific ago-nists from Chinese herbs as potential antihypertension drug leads. Methods: Two D1-like receptor cell lines carrying a β-lactamase reporter gene, and a D2 receptor cell line coexpressing a promiscuous G protein G15 were constructed using HEK293 cells. A natural compound library made from fractionated samples of herbal ex-tracts was used for high-throughput screening (HTS) against one of the cell lines,HEK/D5R/CRE-blax. The interested hits were evaluated for their activities against various dopamine receptors. Results: Fourteen hits were identified from primary screening, of which 2 of the better hit samples, HD0522 and HD0059, were selected for further material and activity analysis, and to obtain 2 compounds that ap-peared as 2 single peaks in HPLC, HD0522H01 and HD0059H01. HD0059H01 could activate D1, D2, and D5 receptors, with EC50 values of 2.28 μg/mL, 0.85 μg/mL, and 1.41 μg/mL, respectively. HD0522H01 could only activate D1R and D5R with EC50 values of 2.95 μg/mL and 8.38 μg/mL. Conclusion: We established cell-based assays for 3 different human dopamine receptors and identified specific agonists HD0522H01 and HD0059H01 through HTS. The specific agonist to D1-like receptors, HD0522H01, may become a new natural product-based drug lead for antihypertension treatment.

  1. Population Blocks.

    Science.gov (United States)

    Smith, Martin H.

    1992-01-01

    Describes an educational game called "Population Blocks" that is designed to illustrate the concept of exponential growth of the human population and some potential effects of overpopulation. The game material consists of wooden blocks; 18 blocks are painted green (representing land), 7 are painted blue (representing water); and the remaining…

  2. Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

    Energy Technology Data Exchange (ETDEWEB)

    Kujirai, K.; Przedborski, S.; Kostic, V.; Jackson-Lewis, V.; Fahn, S.; Cadet, J.L. (Columbia Univ., New York, NY (USA))

    1990-11-01

    We examined the status of dopamine (DA) D1 and D2 receptors by using (3H)SCH 23390 and (3H)spiperone binding, respectively, and DA uptake sites by using (3H)mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher (3H)SCH 23390 and (3H)spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in (3H)mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal (3H)spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

  3. Three dopamine pathways induce aversive odor memories with different stability.

    Directory of Open Access Journals (Sweden)

    Yoshinori Aso

    Full Text Available Animals acquire predictive values of sensory stimuli through reinforcement. In the brain of Drosophila melanogaster, activation of two types of dopamine neurons in the PAM and PPL1 clusters has been shown to induce aversive odor memory. Here, we identified the third cell type and characterized aversive memories induced by these dopamine neurons. These three dopamine pathways all project to the mushroom body but terminate in the spatially segregated subdomains. To understand the functional difference of these dopamine pathways in electric shock reinforcement, we blocked each one of them during memory acquisition. We found that all three pathways partially contribute to electric shock memory. Notably, the memories mediated by these neurons differed in temporal stability. Furthermore, combinatorial activation of two of these pathways revealed significant interaction of individual memory components rather than their simple summation. These results cast light on a cellular mechanism by which a noxious event induces different dopamine signals to a single brain structure to synthesize an aversive memory.

  4. Cocaine and amphetamine elicit differential effects in rats with a unilateral injection of dopamine transporter antisense oligodeoxynucleotides.

    Science.gov (United States)

    Silvia, C P; Jaber, M; King, G R; Ellinwood, E H; Caron, M G

    1997-02-01

    We have developed an antisense oligodeoxynucleotide to the dopamine transporter and used it to discriminate the behavioral properties of amphetamine and cocaine. In SK-N-MC cells permanently transfected with the dopamine transporter complementary DNA, treatment with 5 mM antisense oligodeoxynucleotide reduced dopamine uptake by 25% when compared to sense control. Unilateral intranigral administration of dopamine transporter antisense (50 microM) twice daily in freely moving rats for 2.5 days was sufficient to reduce dopamine transporter messenger RNA by 70% as measured by in situ hybridization, but not protein levels as measured by [3H]mazindol binding. However, intranigral treatment via implanted osmotic minipump over a period of seven days produced reductions in both dopamine transporter messenger RNA and protein levels (32%) at a dose of 500 pmol/day. These results indicate a longer half-life for the dopamine transporter than expected. Potassium chloride depolarization of ipsilateral striatal slices showed a greater than 200% increase in dopamine overflow on the antisense-treated side compared to the control side. Since imbalance of dopamine tone is known to induce rotational activity, we tested this behavioral paradigm in rats treated with various oligodeoxynucleotides at different doses and time-points. We have found that antisense-treated animals did not rotate spontaneously under any experimental conditions. Using various psychostimulants that target the dopamine transporter and increase dopamine levels, we found that the antisense-treated animals consistently rotated contralaterally in response to amphetamine (2 mg/kg), but not to cocaine (10 mg/kg) or nomifensine (10 mg/kg). These results bring in vivo evidence for a different mode of action of amphetamine and cocaine on the dopamine transporter and lend direct support to the view that amphetamine acts as a dopamine releaser, whereas cocaine acts by blocking dopamine transport.

  5. Methamphetamine Increases Locomotion and Dopamine Transporter Activity in Dopamine D5 Receptor-Deficient Mice

    OpenAIRE

    Seiji Hayashizaki; Shinobu Hirai; Yumi Ito; Yoshiko Honda; Yosefu Arime; Ichiro Sora; Haruo Okado; Tohru Kodama; Masahiko Takada

    2013-01-01

    Dopamine regulates the psychomotor stimulant activities of amphetamine-like substances in the brain. The effects of dopamine are mediated through five known dopamine receptor subtypes in mammals. The functional relevance of D5 dopamine receptors in the central nervous system is not well understood. To determine the functional relevance of D5 dopamine receptors, we created D5 dopamine receptor-deficient mice and then used these mice to assess the roles of D5 dopamine receptors in the behaviora...

  6. Breathing is affected by dopamine D2-like receptors in the basolateral amygdala.

    Science.gov (United States)

    Sugita, Toshihisa; Kanamaru, Mitsuko; Iizuka, Makito; Sato, Kanako; Tsukada, Setsuro; Kawamura, Mitsuru; Homma, Ikuo; Izumizaki, Masahiko

    2015-04-01

    The precise mechanisms underlying how emotions change breathing patterns remain unclear, but dopamine is a candidate neurotransmitter in the process of emotion-associated breathing. We investigated whether basal dopamine release occurs in the basolateral amygdala (BLA), where sensory-related inputs are received and lead to fear or anxiety responses, and whether D1- and D2-like receptor antagonists affect breathing patterns and dopamine release in the BLA. Adult male mice (C57BL/6N) were perfused with artificial cerebrospinal fluid, a D1-like receptor antagonist (SCH 23390), or a D2-like receptor antagonist ((S)-(-)-sulpiride) through a microdialysis probe in the BLA. Respiratory variables were measured using a double-chamber plethysmograph. Dopamine release was measured by an HPLC. Perfusion of (S)-(-)-sulpiride in the BLA, not SCH 23390, specifically decreased respiratory rate without changes in local release of dopamine. These results suggest that basal dopamine release in the BLA, at least partially, increases respiratory rates only through post-synaptic D2-like receptors, not autoreceptors, which might be associated with emotional responses.

  7. Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice.

    Science.gov (United States)

    Ukai, Makoto; Lin, Hui Ping

    2002-06-20

    The involvement of dopamine receptors in the amnesic effects of the endogenous micro-opioid receptor agonists endomorphins 1 and 2 was investigated by observing step-down type passive avoidance learning in mice. Although the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol hydrochloride (R(+)-SKF38393) (0.05 and 0.1 mg/kg), the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (R(+)-SCH23390) (2.5 and 5 microg/kg) or the dopamine D2 receptor agonist N-n-phenethyl-N-propylethyl-p-(3-hydroxyphenyl)-ethylamine (RU24213) (0.3 and 1 mg/kg) had no significant effects on the endomorphin-1 (10 microg)- or endomorphin-2 (10 microg)-induced decrease in step-down latency of passive avoidance learning, (-)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, significantly reversed the decrease in step-down latency evoked by endomorphin-2 (10 microg), but not by endomorphin-1 (10 microg). Taken together, it is likely that stimulation of dopamine D2 receptors results in the endomorphin-2-but not endomorphin-1-induced impairment of passive avoidance learning.

  8. Dopamine Signaling in reward-related behaviors

    Directory of Open Access Journals (Sweden)

    Ja-Hyun eBaik

    2013-10-01

    Full Text Available Dopamine (DA regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DAmesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural rewards such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  9. Dopamine signaling in reward-related behaviors.

    Science.gov (United States)

    Baik, Ja-Hyun

    2013-01-01

    Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

  10. Effect of dopamine on pentagastrin-stimulated gastric acid secretion and mucosal blood flow in dogs with gastric fistula

    DEFF Research Database (Denmark)

    Hovendal, C P; Bech, K; Gottrup, F;

    1982-01-01

    The purpose of this study was to elucidate the effect of intravenously administered dopamine on dopamine receptors and adrenergic receptors in terms of its effect on gastric acid secretion, the kinetic mechanism, blood flow, and antral motility. Dopamine was used alone and in conjunction...... with selective blockade of alpha-, beta-, and dopaminergic receptors. A significant inhibition of gastric acid secretion was found with the highest dose of dopamine used (40 micrograms/kg/min). The kinetic study showed characteristics of a non-competitive type. The anti-secretory effect dopamine...... was significantly blocked by non-selective beta-blockade or by selective beta-blockade but not by alpha- or dopaminergic receptor blockade. This suggests that the inhibitory effect of dopamine on gastric secretion is mediated by beta-receptors. There was no significant effect on gastric mucosal blood flow...

  11. Salsolinol modulation of dopamine neurons

    Directory of Open Access Journals (Sweden)

    Guiqin eXie

    2013-05-01

    Full Text Available Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. However, the underlying neuronal mechanisms are unclear. Here we present an overview of some of the recent research on this topic. Electrophysiological studies reveal that dopaminergic neurons in the posterior ventral tegmental area (pVTA are a target of salsolinol. In acute brain slices from rats, salsolinol increases the excitability and accelerates the ongoing firing of dopamine neurons in the pVTA. Intriguingly, this action of salsolinol involves multiple pre- and post-synaptic mechanisms, including: (a depolarizing the membrane potential of dopamine neurons; (b activating mu opioid receptors on the GABAergic inputs to dopamine neurons, which decreases GABAergic activity and dopamine neurons are disinhibited; and (c enhancing presynaptic glutamatergic transmission onto dopamine neurons via activation of dopamine type 1 receptors, probably situated on the glutamatergic terminals. These novel mechanisms may contribute to the rewarding/reinforcing properties of salsolinol observed in vivo.

  12. Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine- mediated regulation of Tiam1

    Directory of Open Access Journals (Sweden)

    Ramesh eChandra

    2013-05-01

    Full Text Available Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs. These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin cytoskeleton, such as Tiam1. Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2 expressing MSNs. We find that repeated ChR2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0, we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant mediated behavior and function.

  13. Zitongdong Block

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    @@ The Zitongdong Block (Eastern Zitong Block) is located in the northwest of the Sichuan Basin. Tectonically, it is situated in the east part of Zitong Depression, southeast of mid-Longmenshan folded and faulted belt( as shown on Fig. 8 ), covering an area of 1 730 km2. The traffic is very convenient, the No. 108 national highway passes through the north of the block. Topographically, the area belongs to low hilly land at the elevation of 500-700 m.

  14. Repeated stressful experiences differently affect brain dopamine receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Puglisi-Allegra, S.; Cabib, S. (Istituto di Psicobiologia e Psicofarmacologia (CNR), Roma (Italy)); Kempf, E.; Schleef, C. (Centre de Neurochimi, Strasbourg (Italy))

    1991-01-01

    The binding of tritiated spiperone (D2 antagonist) and tritiated SCH 23390 (D1 antagonist), in vivo, was investigated in the caudatus putamen (CP) and nucleus accumbens septi (NAS) of mice submitted to ten daily restraint stress sessions. Mice sacrificed 24 hr after the last stressful experience presented a 64% decrease of D2 receptor density (Bmax) but no changes in D1 receptor density in the NAS. In the CP a much smaller (11%) reduction of D2 receptor density was accompanied by a 10% increase of D1 receptors. These results show that the two types of dopamine (DA) receptors adapt in different or even opposite ways to environmental pressure, leading to imbalance between them.

  15. Dopamine inhibits proliferation, induces differentiation and apoptosis of K562 leukaemia cells

    Institute of Scientific and Technical Information of China (English)

    HE Qun; YUAN Lin-bo

    2007-01-01

    Background Dopamine exerts its effects mainly in nervous system through D1, D2 or D3 receptors. There are few reports dealing with the effects of dopamine on leukaemia cells. However, some dopamine agonists or antagonists do show biological effects on some types of leukaemia cells. Here, we report the effects of dopamine on the proliferation,differentiation and apoptosis of K562 leukaemia cells.Methods Proliferation was determined by MTT assay and cell counting both in liquid and semisolid cultures.Differentiation was verified by morphology, benzidine staining and flow cytometry. Apoptosis was checked by Hoechst 33258 staining and flow cytometry. The two groups were untreated group and treated group (dopamine 10-9 mol/L-10-4mol/L).Results In liquid culture, MTT assay and colony assay, dopamine inhibited proliferation of K562 cells. Inhibition rate was 29.28% at 10-6 mol/L and 36.10% at 10-5 mol/L after culture for 5 days in MTT assay. In benzidine staining and CD71 expression, dopamine induced K562 cells toward erythroid differentiation by increased 155% at 10-6 mol/L and by 171% at 10-5 mol/L after culture for 5 days in benzidine staining. In Hoechst 33258 staining and flow cytometry,dopamine induced K562 cells toward apoptosis. The sub G1 peak stained by PI was 14.23% at 10-4 mol/L dopamine after culture for 3 days compared with the control (0.81%) in flow cytometry.Conclusion Dopamine inhibites proliferation and induces both differentiation and apoptosis of K562 leukaemia cells.

  16. Pharmacological characterization of dopamine receptors in the rice striped stem borer, Chilo suppressalis.

    Science.gov (United States)

    Xu, Gang; Wu, Shun-Fan; Gu, Gui-Xiang; Teng, Zi-Wen; Ye, Gong-Yin; Huang, Jia

    2017-04-01

    Dopamine is an important neurotransmitter and neuromodulator in both vertebrates and invertebrates and is the most abundant monoamine present in the central nervous system of insects. A complement of functionally distinct dopamine receptors mediate the signal transduction of dopamine by modifying intracellular Ca(2+) and cAMP levels. In the present study, we pharmacologically characterized three types of dopamine receptors, CsDOP1, CsDOP2 and CsDOP3, from the rice striped stem borer, Chilo suppressalis. All three receptors show considerable sequence identity with orthologous dopamine receptors. The phylogenetic analysis also clusters the receptors within their respective groups. Transcript levels of CsDOP1, CsDOP2 and CsDOP3 were all expressed at high levels in the central nervous system, indicating their important roles in neural processes. After heterologous expression in HEK 293 cells, CsDOP1, CsDOP2 and CsDOP3 were dose-dependently activated by dopamine and synthetic dopamine receptor agonists. They can also be blocked by different series of antagonists. This study offers important information on three dopamine receptors from C. suppressalis that will provide the basis for forthcoming studies investigating their roles in behaviors and physiology, and facilitate the development of new insecticides for pest control.

  17. Dopamine receptor agonists modulate voluntary alcohol intake independently of individual levels of alcohol intake in rats

    NARCIS (Netherlands)

    Spoelder, Marcia; Baars, Annemarie M; Rotte, Marthe D; Vanderschuren, Louk J M J; Lesscher, Heidi M B

    2016-01-01

    RATIONALE: Individual susceptibility to alcohol use disorder has been related to functional changes in dopaminergic neurotransmission. OBJECTIVES: The aim of the current work was to assess the effects of selective dopamine D1 and D2 receptor agonists and antagonists on alcohol consumption in rats th

  18. Electrophysiological effects of dopamine receptor stimulation in the hippocampus of Acomys cahirinus.

    Science.gov (United States)

    Bijak, M; Danek, L; Smiałowski, A

    1988-01-01

    The effect of dopamine receptor agonists on the spontaneous bioelectrical activity of CA1 layer neurons in the hippocampal slice preparation from the Acomys and rat has been studied. The selective D1 receptor agonist SKF 38393 diminished the neuronal firing rate while the selective D2 receptor agonist LY 171555 (quinpirole) evoked an excitatory reaction, however, a great proportion of hippocampal neurons remained unresponsive to SKF 38393 and LY 171555. Both dopamine and apomorphine elicited mainly an increase in the neuronal discharge rate, the effect of the former having been antagonized by sulpiride. The present data reveal that the action of dopamine agonists on the hippocampal neurons of the Acomys generally resembles their activity on the rat hippocampal cells, however, the potency of dopamine and apomorphine in evoking the excitatory reaction is higher in the Acomys.

  19. Dopamine Oxidation and Autophagy

    Directory of Open Access Journals (Sweden)

    Patricia Muñoz

    2012-01-01

    Full Text Available The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic α-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i the formation of α-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii the formation of adducts with α- and β-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

  20. Synthesis and characterization of a series of chiral alkoxymethyl morpholine analogs as dopamine receptor 4 (D4R) antagonists

    Science.gov (United States)

    Witt, Jonathan O.; McCollum, Andrea L.; Hurtado, Miguel A.; Huseman, Eric D.; Jeffries, Daniel E.; Temple, Kayla J.; Plumley, Hyekyung C.; Blobaum, Anna L.; Lindsley, Craig W.; Hopkins, Corey R.

    2017-01-01

    Herein, we report the synthesis and structure–activity relationship of a series of chiral alkoxymethyl morpholine analogs. Our efforts have culminated in the identification of (S)-2-(((6-chloropyridin-2-yl) oxy)methyl)-4-((6-fluoro-1H-indol-3-yl)methyl)morpholine as a novel potent and selective dopamine D4 receptor antagonist with selectivity against the other dopamine receptors tested (D1, D2L, D2S, D3, and D5). PMID:27080176

  1. Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the neonatal mouse.

    Science.gov (United States)

    Humphreys, Jennifer M; Whelan, Patrick J

    2012-12-01

    Monoamines can modulate the output of a variety of invertebrate and vertebrate networks, including the spinal cord networks that control walking. Here we examined the multiple changes in the output of locomotor networks induced by dopamine (DA). We found that DA can depress the activation of locomotor networks in the neonatal mouse spinal cord following ventral root stimulation. By examining disinhibited rhythms, where the Renshaw cell pathway was blocked, we found that DA depresses a putative recurrent excitatory pathway that projects onto rhythm-generating circuitry of the spinal cord. This depression was D(2) but not D(1) receptor dependent and was not due exclusively to depression of excitatory drive to motoneurons. Furthermore, the depression in excitation was not dependent on network activity. We next compared the modulatory effects of DA on network function by focusing on a serotonin and a N-methyl-dl-aspartate-evoked rhythm. In contrast to the depressive effects on a ventral root-evoked rhythm, we found that DA stabilized a drug-evoked rhythm, reduced the frequency of bursting, and increased amplitude. Overall, these data demonstrate that DA can potentiate network activity while at the same time reducing the gain of recurrent excitatory feedback loops from motoneurons onto the network.

  2. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion.

    Science.gov (United States)

    Rubí, Blanca; Ljubicic, Sanda; Pournourmohammadi, Shirin; Carobbio, Stefania; Armanet, Mathieu; Bartley, Clarissa; Maechler, Pierre

    2005-11-04

    Dopamine signaling is mediated by five cloned receptors, grouped into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families. We identified by reverse transcription-PCR the presence of dopamine receptors from both families in INS-1E insulin-secreting cells as well as in rodent and human isolated islets. D2 receptor expression was confirmed by immunodetection revealing localization on insulin secretory granules of INS-1E and primary rodent and human beta cells. We then tested potential effects mediated by the identified receptors on beta cell function. Dopamine (10 microM) and the D2-like receptor agonist quinpirole (5 microM) inhibited glucose-stimulated insulin secretion tested in several models, i.e. INS-1E beta cells, fluorescence-activated cell-sorted primary rat beta cells, and pancreatic islets of rat, mouse, and human origin. Insulin exocytosis is controlled by metabolism coupled to cytosolic calcium changes. Measurements of glucose-induced mitochondrial hyperpolarization and ATP generation showed that dopamine and D2-like agonists did not inhibit glucose metabolism. On the other hand, dopamine decreased cell membrane depolarization as well as cytosolic calcium increases evoked by glucose stimulation in INS-1E beta cells. These results show for the first time that dopamine receptors are expressed in pancreatic beta cells. Dopamine inhibited glucose-stimulated insulin secretion, an effect that could be ascribed to D2-like receptors. Regarding the molecular mechanisms implicated in dopamine-mediated inhibition of insulin release, our results point to distal steps in metabolism-secretion coupling. Thus, the role played by dopamine in glucose homeostasis might involve dopamine receptors, expressed in pancreatic beta cells, modulating insulin release.

  3. Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment.

    Science.gov (United States)

    Anitha, M; Abraham, Pretty Mary; Paulose, C S

    2012-12-05

    The incidence of type 2 diabetes mellitus is rising at alarming proportions. Central nervous system plays an important part in orchestrating glucose metabolism, with accumulating evidence linking dysregulated central nervous system circuits to the failure of normal glucoregulatory mechanisms. Pyridoxine is a water soluble vitamin and it has important role in brain function. This study aims to evaluate the role of pyridoxine in striatal glucose regulation through dopaminergic receptor expressions in streptozotocin induced diabetic rats. Radio receptor binding assays for dopamine D(1), D(2) receptors were done using [(3)H] 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol and [(3)H] 5-chloro-2-methoxy-4-methylamino-N-[-2-methyl-1-(phenylmethyl)pyrrolidin-3-yl]benzamide. Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). Bmax of dopamine D(1) receptor is decreased and B(max) of dopamine D(2) was increased in diabetic rats compared to control. Gene expression of dopamine D(1) receptor was down regulated and dopamine D(2) receptor was up regulated in diabetic rats. Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. Our results suggest the potential role of pyridoxine supplementation in ameliorating diabetes mediated dysfunctions in striatal dopaminergic receptor expressions and insulin signaling. Thus pyridoxine has therapeutic significance in diabetes management.

  4. Zitongxi Block

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    @@ Zitongxi Block (Western Zitong Block), is located in Zitong County, northwest of Sichuan Province (as shown on Fig. 8 ). Geologically. it is situated in the Zitong Depression, southwest of the middle Longmenshan faulted and folded belt, covering an area of 1 830 km2. Transportation is very convenient. A crisscross network of highways run through the block and the Baocheng railway is nearby. The climate is moderate. Most area belongs to hilly land with the elevation of 500-600 m.The Tongjiang River runs across the area.

  5. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    Science.gov (United States)

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  6. Chengzikou Block

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    @@ Chengzikou Block is located in the north of Hekou district, Dongying City, Shandong Province, adjacent to Bohai Bay. It can be geographically divided into three units: onshore, transitional zone and offshore ultrashallow zone, totally covering an area of 470 km2. The southern onshore area is low and gentle in topography;the northern shallow sea is at water depths of 2-8 m below sea level, and the transitional zone occupies more than 60% of the whole block. The climate belongs to temperate zone with seasonal wind. Highways are welldeveloped here, and the traffic is very convenient. The Chengzikou Block is about 80 km away from Dongying City and 290 km from Jinan City in the south. The northern offshore area of the block is 160 km away from Longkou port in the east and only 38 km away in the west from Zhuangxi port.

  7. Activity of D1/2 Receptor Expressing Neurons in the Nucleus Accumbens Regulates Running, Locomotion, and Food Intake

    Directory of Open Access Journals (Sweden)

    Xianglong eZhu

    2016-04-01

    Full Text Available While weight gain is clearly promoted by excessive energy intake and reduced expenditure, the underlying neural mechanisms of energy balance remain unclear. The NAc is one brain region that has received attention for its role in the regulation of energy balance; its D1 and D2 receptor containing neurons have distinct functions in regulating reward behavior and require further examination. The goal of the present study is to investigate how activation and inhibition of D1 and D2 neurons in the NAc influences behaviors related to energy intake and expenditure. Specific manipulation of D1 vs D2 neurons was done in both low expenditure and high expenditure (wheel running conditions to assess behavioral effects in these different states. Direct control of neural activity was achieved using a DREADD (Designer Receptors Exclusively Activated by Designer Drugs strategy. Activation of NAc D1 neurons increased food intake, wheel running and locomotor activity. In contrast, activation of D2 neurons in the NAc reduced running and locomotion while D2 neuron inhibition had opposite effects. These results highlight the importance of considering both intake and expenditure in the analysis of D1 and D2 neuronal manipulations. Moreover, the behavioral outcomes from D1 NAc neuronal manipulations depend upon the activity state of the animals (wheel running vs non-running. The data support and complement the hypothesis of specific NAc dopamine pathways facilitating energy expenditure and suggest a potential strategy for human weight control.

  8. Longmenshan Block

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    @@ Longmenshan Block is located in Jiange County of Jiangyou City in the northwest of Sichuan Basin. covering an area of 2 628 km2. Geologically, it is situated in the Mid-Longmenshan fault and fold belt, neighbouring Zitong Depression in its southeast. There are mountains surrounding its northwest , the rest area being hilly land,with the elevation of 500-700 m. The BaoCheng railway and the No. 108 highway run through the block, the traffic is very convenient.

  9. Dopamine, the kidney, and hypertension.

    Science.gov (United States)

    Harris, Raymond C; Zhang, Ming-Zhi

    2012-04-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.

  10. Cyclin D1 Expression and Its Correlation with Histopathological Differentiation in Oral Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Swati Saawarn

    2012-01-01

    Full Text Available Background. Cyclin D1 regulates the G1 to S transition of cell cycle. Its deregulation or overexpression may lead to disturbance in the normal cell cycle control and tumour formation. Overexpression of cyclin D1 has been reported in various tumors of diverse histogenesis. This case control retrospective study was carried out to study the immunohistochemical reactivity and expression of cyclin D1 and its association with site, clinical staging, and histopathological differentiation of oral squamous cell carcinoma (OSCC. Methods. Forty formalin-fixed paraffin-embedded tissue blocks of biopsy specimens of oral squamous cell carcinoma were immunohistochemically evaluated for expression of cyclin D1. Results. Cyclin D1 expression was seen in 45% cases of OSCC. It did not correlate with site and clinical staging. Highest expression was seen in well-differentiated, followed by moderately differentiated, and poorly differentiated squamous cell carcinomas, with a statistically significant correlation. Conclusion. Cyclin D1 expression significantly increases with increase in differentiation.

  11. Dopamine, the Kidney, and Hypertension

    OpenAIRE

    Raymond C. Harris; Zhang, Ming-Zhi

    2012-01-01

    There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal mo...

  12. Interval timing, dopamine, and motivation

    OpenAIRE

    Balcı, Fuat

    2014-01-01

    The dopamine clock hypothesis suggests that the dopamine level determines the speed of the hypothetical internal clock. However, dopaminergic function has also been implicated for motivation and thus the effect of dopaminergic manipulations on timing behavior might also be independently mediated by altered motivational state. Studies that investigated the effect of motivational manipulations on peak responding are reviewed in this paper. The majority of these studies show that a higher reward...

  13. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Guiqin eXie; Kresimir eKrnjevic; Jiang Hong Ye

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens. ...

  14. Salsolinol modulation of dopamine neurons

    OpenAIRE

    Xie, Guiqin; Krnjević, Krešimir; Ye, Jiang-Hong

    2013-01-01

    Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic (DA) system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumb...

  15. Dopamine, affordance and active inference.

    Directory of Open Access Journals (Sweden)

    Karl J Friston

    2012-01-01

    Full Text Available The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order in which cues are presented. These simulations provide a (Bayes-optimal model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

  16. Dopamine is involved in food-anticipatory activity in mice.

    Science.gov (United States)

    Liu, Yuan-Yuan; Liu, Tian-Ya; Qu, Wei-Min; Hong, Zong-Yuan; Urade, Yoshihiro; Huang, Zhi-Li

    2012-10-01

    When food is available during a restricted and predictable time of the day, mammals exhibit food-anticipatory activity (FAA), an increase in locomotor activity preceding the presentation of food. Although many studies have attempted to locate the food-entrainable circadian oscillator in the central nervous system, the pathways that mediate food entrainment are a matter of controversy. The present study was designed to determine the role of dopaminergic and histaminergic systems on FAA. Mice were given access to food for 2 h (ZT12-ZT14), and FAA was defined as the locomotor activity that occurred 2 h before the availability of food. Dopamine D(1) receptor (R), D(2)R, and histamine H(1)R-specific antagonists were used to clarify the role of dopamine and histamine receptors in FAA induced by food restriction (FR). FAA was monitored by infrared locomotor activity sensors. Mice were sacrificed at ZT12 on the 14th day of FR, and monoamine concentrations were determined by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ECD). The results showed that pretreatment with the D(1)R antagonist SCH23390 at 1, 3, or 10 µg/kg significantly reduced FAA by 19% (p antagonist raclopride at 22, 67, or 200 µg/kg significantly reduced FAA by 16% (p dopamine and its metabolites in the striatum and midbrain were significantly increased during FAA, even with the pretreatment of D(1)R and D(2)R antagonists. However, pretreatment with pyrilamine at 2.5, 5, or 10 mg/kg did not significantly reduce FAA, although it reduced the locomotor activity during the dark period in ad libitum mice. These results strongly indicate that the dopaminergic system plays an essential role in the FAA in mice.

  17. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens.

    Science.gov (United States)

    Danjo, Teruko; Yoshimi, Kenji; Funabiki, Kazuo; Yawata, Satoshi; Nakanishi, Shigetada

    2014-04-29

    Dopamine (DA) transmission from the ventral tegmental area (VTA) is critical for controlling both rewarding and aversive behaviors. The transient silencing of DA neurons is one of the responses to aversive stimuli, but its consequences and neural mechanisms regarding aversive responses and learning have largely remained elusive. Here, we report that optogenetic inactivation of VTA DA neurons promptly down-regulated DA levels and induced up-regulation of the neural activity in the nucleus accumbens (NAc) as evaluated by Fos expression. This optogenetic suppression of DA neuron firing immediately evoked aversive responses to the previously preferred dark room and led to aversive learning toward the optogenetically conditioned place. Importantly, this place aversion was abolished by knockdown of dopamine D2 receptors but not by that of D1 receptors in the NAc. Silencing of DA neurons in the VTA was thus indispensable for inducing aversive responses and learning through dopamine D2 receptors in the NAc.

  18. Chadong Block

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    @@ The Chadong Block, located in the east of Qaidam Basin, Qinghai Province, covers an area of 12 452 km2. It is bounded by Kunlum Mountains in the south and the northwest is closely adjacent to Aimunike Mountain.Rivers are widely distributed, which always run in NWSE direction, including the Sulunguole, Qaidam and Haluwusu Rivers. The traffic condition is good, the Qinghai-Tibet highway stretching through the whole area and the Lan-Qing railway, 20-50 km away from the block, passing from north to west. A lot of Mongolia minority people have settled there, of which herdsmen always live nearby the Qaidam River drainage area.

  19. Effects of the NMDA receptor antagonists on deltamethrin-induced striatal dopamine release in conscious unrestrained rats.

    Science.gov (United States)

    Morikawa, Takuya; Furuhama, Kazuhisa

    2009-08-01

    To better understand the neurotoxicity caused by the pyrethroid pesticide, we examined the effects of the N-methyl-D-aspartate (NMDA) receptor antagonists MK-801, a non-competitive cation channel blocker, and 2-amino-5-phosphonovaleric acid (APV), a competitive Na(+) channel blocker, on extracellular dopamine levels in male Sprague-Dawley rats receiving the type II pyrethroid deltamethrin using an in vivo microdialysis system. Deltamethrin (60 mg/kg, i.p.) evidently increased striatal dopamine levels with a peak time of 120 min, and the local infusion (i.c.) of either MK-801(650 muM) or APV (500 muM) completely blocked these actions. The fluctuation in the dopamine metabolite 3-MT also resembled that in dopamine. Our results suggest that dopamine-releasing neurons would be modulated via the NMDA receptor by the excitatory glutamatergic neurons after deltamethrin treatment.

  20. Dopamine systems adaptation during acquisition and consolidation of a skill

    Directory of Open Access Journals (Sweden)

    Wolfgang H Sommer

    2014-11-01

    Full Text Available The striatum plays a key role in motor learning. Striatal function depends strongly on dopaminergic neurotransmission, but little is known about neuroadaptions of the dopamine system during striatal learning. Using an established task that allows differentiation between acquisition and consolidation of motor learning, we here investigate D1 and D2-like receptor binding and transcriptional levels after initial and long-term training of mice. We found profound reduction in D1 binding within the dorsomedial striatum (DMS after the first training session on the accelerated rotarod and a progressive reduction in D2-like binding within the dorsolateral striatum (DLS after extended training. Given that similar phase- and region-specific striatal neuroadaptations have been found also during learning of complex procedural tasks including habit formation and automatic responding, the here observed neurochemical alterations are important for our understanding of neuropsychiatric disorders that show a dysbalance in the function of striatal circuits, such as in addictive behaviours.

  1. Dopamine Transporters in Striatum Correlated with Deactivation in the Default Mode Network during Visuospatial Attention

    Energy Technology Data Exchange (ETDEWEB)

    Tomasi, D.; Fowler, J.; Tomasi, D.; Volkow, N.D.; Wang, R.L.; Telang, F.; Wang, Chang, L.; Ernst, T.; /Fowler, J.S.

    2009-06-01

    Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [{sup 11}C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN.

  2. Dopamine transporters in striatum correlate with deactivation in the default mode network during visuospatial attention.

    Directory of Open Access Journals (Sweden)

    Dardo Tomasi

    Full Text Available BACKGROUND: Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN. Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. METHODOLOGY/PRINCIPAL FINDINGS: For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11C]cocaine used as DAT radiotracer and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7 and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32. With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. CONCLUSIONS/SIGNIFICANCE: These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness and cingulate gyrus (region deactivated in proportion to emotional interference. These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT in inattention reflect in part their ability to facilitate the deactivation of the DMN.

  3. Evidence That Sleep Deprivation Downregulates Dopamine D2R in Ventral Striatum in the Human Brain

    Energy Technology Data Exchange (ETDEWEB)

    Volkow N. D.; Fowler J.; Volkow, N.D.; Tomasi, D.; Wang, G.-J.; Fowler, J.S.; Logan, J.; Benveniste, H.; Kin, R.; Thanos, P.K.; Sergi F.

    2012-03-23

    Dopamine D2 receptors are involved with wakefulness, but their role in the decreased alertness associated with sleep deprivation is unclear. We had shown that sleep deprivation reduced dopamine D2/D3 receptor availability (measured with PET and [{sup 11}C]raclopride in controls) in striatum, but could not determine whether this reflected dopamine increases ([{sup 11}C]raclopride competes with dopamine for D2/D3 receptor binding) or receptor downregulation. To clarify this, we compared the dopamine increases induced by methylphenidate (a drug that increases dopamine by blocking dopamine transporters) during sleep deprivation versus rested sleep, with the assumption that methylphenidate's effects would be greater if, indeed, dopamine release was increased during sleep deprivation. We scanned 20 controls with [{sup 11}C]raclopride after rested sleep and after 1 night of sleep deprivation; both after placebo and after methylphenidate. We corroborated a decrease in D2/D3 receptor availability in the ventral striatum with sleep deprivation (compared with rested sleep) that was associated with reduced alertness and increased sleepiness. However, the dopamine increases induced by methylphenidate (measured as decreases in D2/D3 receptor availability compared with placebo) did not differ between rested sleep and sleep deprivation, and were associated with the increased alertness and reduced sleepiness when methylphenidate was administered after sleep deprivation. Similar findings were obtained by microdialysis in rodents subjected to 1 night of paradoxical sleep deprivation. These findings are consistent with a downregulation of D2/D3 receptors in ventral striatum with sleep deprivation that may contribute to the associated decreased wakefulness and also corroborate an enhancement of D2 receptor signaling in the arousing effects of methylphenidate in humans.

  4. Ischemic-LTP in striatal spiny neurons of both direct and indirect pathway requires the activation of D1-like receptors and NO/soluble guanylate cyclase/cGMP transmission

    OpenAIRE

    Arcangeli, Sara; Amoroso, Salvatore; Calabresi, Paolo; Costa, Cinzia; Fusco, Francesca Romana; Di Filippo, Massimiliano; Spaccatini, Cristiano; de Iure, Antonio; Picconi, Barbara; Giampa, Carmen; Tantucci, Michela; Tozzi, Alessandro

    2013-01-01

    Striatal medium-sized spiny neurons (MSNs) are highly vulnerable to ischemia. A brief ischemic insult, produced by oxygen and glucose deprivation (OGD), can induce ischemic long-term potentiation (i-LTP) of corticostriatal excitatory postsynaptic response. Since nitric oxide (NO) is involved in the pathophysiology of brain ischemia and the dopamine D1/D5-receptors (D1-like-R) are expressed in striatal NOS-positive interneurons, we hypothesized a relation between NOS-positive interneurons and ...

  5. L-DOPA Oppositely Regulates Synaptic Strength and Spine Morphology in D1 and D2 Striatal Projection Neurons in Dyskinesia

    Science.gov (United States)

    Suarez, Luz M; Solis, Oscar; Aguado, Carolina; Lujan, Rafael; Moratalla, Rosario

    2016-01-01

    Dopamine depletion in Parkinson's disease (PD) produces dendritic spine loss in striatal medium spiny neurons (MSNs) and increases their excitability. However, the synaptic changes that occur in MSNs in PD, in particular those induced by chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, are still poorly understood. We exposed BAC-transgenic D1-tomato and D2-eGFP mice to PD and dyskinesia model paradigms, enabling cell type-specific assessment of changes in synaptic physiology and morphology. The distinct fluorescence markers allowed us to identify D1 and D2 MSNs for analysis using intracellular sharp electrode recordings, electron microscopy, and 3D reconstructions with single-cell Lucifer Yellow injections. Dopamine depletion induced spine pruning in both types of MSNs, affecting mushroom and thin spines equally. Dopamine depletion also increased firing rate in both D1- and D2-MSNs, but reduced evoked-EPSP amplitude selectively in D2-MSNs. L-DOPA treatment that produced dyskinesia differentially affected synaptic properties in D1- and D2-MSNs. In D1-MSNs, spine density remained reduced but the remaining spines were enlarged, with bigger heads and larger postsynaptic densities. These morphological changes were accompanied by facilitation of action potential firing triggered by synaptic inputs. In contrast, although L-DOPA restored the number of spines in D2-MSNs, it resulted in shortened postsynaptic densities. These changes in D2-MSNs correlated with a decrease in synaptic transmission. Our findings indicate that L-DOPA-induced dyskinesia is associated with abnormal spine morphology, modified synaptic transmission, and altered EPSP-spike coupling, with distinct effects in D1- and D2-MSNs. PMID:27613437

  6. Dopamine, reward learning, and active inference

    Directory of Open Access Journals (Sweden)

    Thomas eFitzgerald

    2015-11-01

    Full Text Available Temporal difference learning models propose phasic dopamine signalling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behaviour. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings.

  7. NOVEL FLUORESCENT PROBES FOR THE DOPAMINE TRANSPORTER

    DEFF Research Database (Denmark)

    Cha, J; Vægter, Christian Bjerggaard; Adkins, Erica

    To enable visualization of the dopamine transporter (DAT) through fluorescence technologies we have synthesized a novel series of fluorescently tagged analogs of cocaine. Previous structure-activity relationship (SAR) studies have demonstrated that the dopamine transporter (DAT) can tolerate...

  8. Behavioural effects of chemogenetic dopamine neuron activation

    NARCIS (Netherlands)

    Boekhoudt, L

    2016-01-01

    Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific p

  9. Dopamine regulates body size in Caenorhabditis elegans.

    Science.gov (United States)

    Nagashima, Takashi; Oami, Eitaro; Kutsuna, Natsumaro; Ishiura, Shoichi; Suo, Satoshi

    2016-04-01

    The nervous system plays a critical role in the regulation of animal body sizes. In Caenorhabditis elegans, an amine neurotransmitter, dopamine, is required for the tactile perception of food and food-dependent behavioral changes, while its role in development is unknown. In this study, we show that dopamine negatively regulates body size through a D2-like dopamine receptor, DOP-3, in C. elegans. Dopamine alters body size without affecting food intake or developmental rate. We also found that dopamine promotes egg-laying, although the regulation of body size by dopamine was not solely caused by this effect. Furthermore, dopamine negatively regulates body size through the suppression of signaling by octopamine and Gq-coupled octopamine receptors, SER-3 and SER-6. Our results demonstrate that dopamine and octopamine regulate the body size of C. elegans and suggest a potential role for perception in addition to ingestion of food for growth.

  10. Dopamine-mediated learning and switching in cortico-striatal circuit explain behavioral changes in reinforcement learning.

    Directory of Open Access Journals (Sweden)

    Simon eHong

    2011-03-01

    Full Text Available The basal ganglia (BG are thought to play a crucial role in reinforcement learning. Central to the learning mechanism are dopamine D1 and D2 receptors located in the cortico-striatal synapses. However, it is still unclear how this dopamine-mediated synaptic plasticity is deployed and coordinated during reward-contingent behavioral changes. Here we propose a computational model of reinforcement learning that uses different thresholds of D1- and D2-mediated synaptic plasticity which are antagonized by dopamine-independent synaptic plasticity. A phasic increase in dopamine release caused by a larger-than-expected reward induces long-term potentiation (LTP in the direct pathway, whereas a phasic decrease in dopamine release caused by a smaller-than-expected reward induces a cessation of long-term depression (LTD, leading to LTP in the indirect pathway. This learning mechanism can explain the robust behavioral adaptation observed in a location-reward-value-association task where the animal makes shorter latency saccades to rewarding locations. The changes in saccade latency become quicker as the monkey becomes more experienced. This behavior can be explained by a switching mechanism which activates the cortico-striatal circuit selectively. Our model can also simulate the effects of D1 and D2 receptor blockade, and behavioral changes in Parkinson’s disease.

  11. Dopamine neuron stimulating actions of a GDNF propeptide.

    Directory of Open Access Journals (Sweden)

    Luke H Bradley

    Full Text Available BACKGROUND: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF, have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed. METHODS AND FINDINGS: Here we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11, an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria. CONCLUSIONS: Collectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not

  12. The dopamine D2 antagonist eticlopride accelerates extinction and delays reacquisition of food self-administration in rats

    OpenAIRE

    Koerber, Jonathon; Goodman, David; Barnes, Jesse L.; Grimm, Jeffrey W.

    2013-01-01

    Dopamine receptors are implicated in the reinforcing effects of food and drug reinforcement. The purpose of this study was to evaluate whether blocking D2 dopamine receptors during extinction (secondary reinforcement) would affect reacquisition of responding for food pellets (primary reinforcement). Food-restricted rats self-administered (FR1) food pellets in 1-h daily sessions for seven days. For the next seven days rats responded in extinction conditions. Prior to each extinction session ra...

  13. Analysis list: Nr1d1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Nr1d1 Adipocyte,Cardiovascular,Liver,Neural + mm9 http://dbarchive.biosciencedbc.jp.../kyushu-u/mm9/target/Nr1d1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Nr1d1.5.tsv http://db...archive.biosciencedbc.jp/kyushu-u/mm9/target/Nr1d1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Nr1d1....Adipocyte.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Nr1d1.C...ardiovascular.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Nr1d1.Liver.tsv,http://dbarchive.biosc

  14. Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.

    Science.gov (United States)

    Berg, Daniel A; Kirkham, Matthew; Wang, Heng; Frisén, Jonas; Simon, András

    2011-04-08

    Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

  15. Quantized Faraday effect in 3D+1 and 2D+1 systems

    CERN Document Server

    Rodriguez, L Cruz; Rojas, H Perez; Querts, E Rodriguez

    2013-01-01

    We study Faraday rotation in the quantum relativistic limit. Starting from the photon self-energy in the presence of a constant magnetic field the rotation of the polarization vector of a plane electromagnetic wave which travel along the fermion-antifermion gas is studied. The connection between Faraday Effect and Quantum Hall Effect (QHE) is discussed. The Faraday Effect is also investigated for a massless relativistic 2D+1 fermion system which is derived by using the compactification along the dimension parallel to the magnetic field. Faraday angle shows a quantized behavior as Hall conductivity in two and three dimensions.

  16. Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice

    OpenAIRE

    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark

    2005-01-01

    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear con...

  17. Dopamine agents for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian

    2014-01-01

    BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...... therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS: Trials were identified through the Cochrane...... of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy...

  18. Upregulation of renal D5 dopamine receptor ameliorates the hypertension in D3 dopamine receptor-deficient mice.

    Science.gov (United States)

    Wang, Xiaoyan; Escano, Crisanto S; Asico, Laureano; Jones, John E; Barte, Alan; Lau, Yuen-Sum; Jose, Pedro A; Armando, Ines

    2013-08-01

    D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice.

  19. High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats.

    Science.gov (United States)

    Rui, Gao; Guangjian, Zhang; Yong, Wang; Jie, Feng; Yanchao, Cui; Xi, Jia; Fen, Li

    2013-01-15

    The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.

  20. Chaotic behavior in dopamine neurodynamics.

    Science.gov (United States)

    King, R; Barchas, J D; Huberman, B A

    1984-02-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of mood in some patients with an affective disorder. Moreover our hypothesis offers specific results concerning the appearance or disappearance of erratic solutions as a function of k and the external input to the dopamine neuronal system.

  1. Nucleic acid sequences encoding D1 and D1/D2 domains of human coxsackievirus and adenovirus receptor (CAR)

    Science.gov (United States)

    Freimuth, Paul I.

    2010-04-06

    The invention provides recombinant human CAR (coxsackievirus and adenovirus receptor) polypeptides which bind adenovirus. Specifically, polypeptides corresponding to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2 are provided. In another aspect, the invention provides nucleic acid sequences encoding these domains and expression vectors for producing the domains and bacterial cells containing such vectors. The invention also includes an isolated fusion protein comprised of the D1 polypeptide fused to a polypeptide which facilitates folding of D1 when expressed in bacteria. The functional D1 domain finds application in a therapeutic method for treating a patient infected with a CAR D1-binding virus, and also in a method for identifying an antiviral compound which interferes with viral attachment. The invention also provides a method for specifically targeting a cell for infection by a virus which binds to D1.

  2. Aspirin-triggered resolvin D1 down-regulates inflammatory responses and protects against endotoxin-induced acute kidney injury

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jiao [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Shetty, Sreerama [Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, TX 75708 (United States); Zhang, Ping [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041 (China); Gao, Rong; Hu, Yuxin [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Wang, Shuxia [Graduate Center for Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536 (United States); Li, Zhenyu [Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536 (United States); Fu, Jian, E-mail: jian.fu@uky.edu [Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536 (United States)

    2014-06-01

    The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1 h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.

  3. Over-Expression of Dopamine D2 Receptor and Inwardly Rectifying Potassium Channel Genes in Drug-Naive Schizophrenic Peripheral Blood Lymphocytes as Potential Diagnostic Markers

    OpenAIRE

    Ágnes Zvara; György Szekeres; Zoltán Janka; Kelemen, János Z.; Csongor Cimmer; Miklós Sántha; Puskás, László G.

    2005-01-01

    Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL) express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3) was found to be over-exp...

  4. A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Takashi Nakano

    2010-02-01

    Full Text Available Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD, the combination with dopamine switches LTD to long-term potentiation (LTP, which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32, as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA, protein phosphatase 2A (PP2A, and the phosphorylation site at threonine 75 of DARPP-32 (Thr75 served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B-CK1 (casein kinase 1-Cdk5 (cyclin-dependent kinase 5-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP. The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The

  5. Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro.

    Science.gov (United States)

    Iwakura, Hiroshi; Ariyasu, Hiroyuki; Hosoda, Hiroshi; Yamada, Go; Hosoda, Kiminori; Nakao, Kazuwa; Kangawa, Kenji; Akamizu, Takashi

    2011-07-01

    To understand the physiological role of ghrelin, it is crucial to study both the actions of ghrelin and the regulation of ghrelin secretion. Although ghrelin actions have been extensively revealed, the direct factors regulating ghrelin secretion by ghrelin-producing cells (X/A-like cells), however, is not fully understood. In this study, we examined the effects of peptide hormones and neurotransmitters on in vitro ghrelin secretion by the recently developed ghrelin-producing cell line MGN3-1. Oxytocin and vasopressin significantly stimulated ghrelin secretion by MGN3-1 cells. Because MGN3-1 cells express only oxytocin receptor mRNA, not vasopressin receptor mRNA, oxytocin is the likely regulator, with the effect of vasopressin mediated by a cross-reaction. We also discovered that dopamine stimulates ghrelin secretion from MGN3-1 cells in a similar manner to the previously known ghrelin stimulators, epinephrine and norepinephrine. MGN3-1 cells expressed mRNA encoding dopamine receptors D1a and D2. The dopamine receptor D1 agonist fenoldopam stimulated ghrelin secretion, whereas the D2, D3 agonist bromocriptine did not. Furthermore, the D1 receptor antagonist SKF83566 attenuated the stimulatory effect of dopamine. These results indicate that the stimulatory effect of dopamine on ghrelin secretion is mediated by the D1a receptor. In conclusion, we identified two direct regulators of ghrelin, oxytocin and dopamine. These findings will provide new direction for further studies seeking to further understand the regulation of ghrelin secretion, which will in turn lead to greater understanding of the physiological role of ghrelin.

  6. Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion

    Science.gov (United States)

    Kouyoumdzian, Nicolás M.; Rukavina Mikusic, Natalia L.; Kravetz, María C.; Lee, Brenda M.; Carranza, Andrea; Del Mauro, Julieta S.; Pandolfo, Marcela; Gironacci, Mariela M.; Gorzalczany, Susana; Toblli, Jorge E.; Fernández, Belisario E.

    2016-01-01

    The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP) on organic cation transporters (OCTs) expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T), ANP, dopamine (DA), D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects. PMID:27392042

  7. Atrial Natriuretic Peptide Stimulates Dopamine Tubular Transport by Organic Cation Transporters: A Novel Mechanism to Enhance Renal Sodium Excretion.

    Directory of Open Access Journals (Sweden)

    Nicolás M Kouyoumdzian

    Full Text Available The aim of this study was to demonstrate the effects of atrial natriuretic peptide (ANP on organic cation transporters (OCTs expression and activity, and its consequences on dopamine urinary levels, Na+, K+-ATPase activity and renal function. Male Sprague Dawley rats were infused with isotonic saline solution during 120 minutes and randomized in nine different groups: control, pargyline plus tolcapone (P+T, ANP, dopamine (DA, D-22, DA+D-22, ANP+D-22, ANP+DA and ANP+DA+D-22. Renal functional parameters were determined and urinary dopamine concentration was quantified by HPLC. Expression of OCTs and D1-receptor in membrane preparations from renal cortex tissues were determined by western blot and Na+, K+-ATPase activity was determined using in vitro enzyme assay. 3H-DA renal uptake was determined in vitro. Compared to P+T group, ANP and dopamine infusion increased diuresis, urinary sodium and dopamine excretion significantly. These effects were more pronounced in ANP+DA group and reversed by OCTs blockade by D-22, demonstrating that OCTs are implied in ANP stimulated-DA uptake and transport in renal tissues. The activity of Na+, K+-ATPase exhibited a similar fashion when it was measured in the same experimental groups. Although OCTs and D1-receptor protein expression were not modified by ANP, OCTs-dependent-dopamine tubular uptake was increased by ANP through activation of NPR-A receptor and protein kinase G as signaling pathway. This effect was reflected by an increase in urinary dopamine excretion, natriuresis, diuresis and decreased Na+, K+-ATPase activity. OCTs represent a novel target that links the activity of ANP and dopamine together in a common mechanism to enhance their natriuretic and diuretic effects.

  8. Linking animal models of psychosis to computational models of dopamine function.

    Science.gov (United States)

    Smith, Andrew J; Li, Ming; Becker, Suzanna; Kapur, Shitij

    2007-01-01

    Psychosis is linked to dysregulation of the neuromodulator dopamine and antipsychotic drugs (APDs) work by blocking dopamine receptors. Dopamine-modulated disruption of latent inhibition (LI) and conditioned avoidance response (CAR) have served as standard animal models of psychosis and antipsychotic action, respectively. Meanwhile, the 'temporal difference' algorithm (TD) has emerged as the leading computational model of dopamine neuron firing. In this report TD is extended to include action at the level of dopamine receptors in order to explain a number of behavioral phenomena including the dose-dependent disruption of CAR by APDs, the temporal dissociation of the effects of APDs on receptors vs behavior, the facilitation of LI by APDs, and the disruption of LI by amphetamine. The model also predicts an APD-induced change to the latency profile of CAR--a novel prediction that is verified experimentally. The model's primary contribution is to link dopamine neuron firing, receptor manipulation, and behavior within a common formal framework that may offer insights into clinical observations.

  9. Expression of a novel D4 dopamine receptor in the lamprey brain. Evolutionary considerations about dopamine receptors.

    Directory of Open Access Journals (Sweden)

    Juan ePérez-Fernández

    2016-01-01

    Full Text Available Numerous data reported in lampreys, which belong to the phylogenetically oldest branch of vertebrates, show that the dopaminergic system was already well developed at the dawn of vertebrate evolution. The expression of dopamine in the lamprey brain is well conserved when compared to other vertebrates, and this is also true for the D2 receptor. Additionally, the key role of dopamine in the striatum, modulating the excitability in the direct and indirect pathways through the D1 and D2 receptors, has also been recently reported in these animals. The moment of divergence regarding the two whole genome duplications occurred in vertebrates suggests that additional receptors, apart from the D1 and D2 previously reported, could be present in lampreys. We used in situ hybridization to characterize the expression of a novel dopamine receptor, which we have identified as a D4 receptor according to the phylogenetic analysis. The D4 receptor shows in the sea lamprey a more restricted expression pattern than the D2 subtype, as reported in mammals. Its main expression areas are the striatum, lateral and ventral pallial sectors, several hypothalamic regions, habenula, and mesencephalic and rhombencephalic motoneurons. Some expression areas are well conserved through vertebrate evolution, as is the case of the striatum or the habenula, but the controversies regarding the D4 receptor expression in other vertebrates hampers for a complete comparison, especially in rhombencephalic regions. Our results further support that the dopaminergic system in vertebrates is well conserved and suggest that at least some functions of the D4 receptor were already present before the divergence of lampreys.

  10. Apo-ghrelin receptor (apo-GHSR1a Regulates Dopamine Signaling in the Brain

    Directory of Open Access Journals (Sweden)

    Andras eKern

    2014-08-01

    Full Text Available The orexigenic peptide hormone ghrelin is synthesized in the stomach and its receptor growth hormone secretagogue receptor (GHSR1a is expressed mainly in the central nervous system (CNS. In this review we confine our discussion to the physiological role of GHSR1a in the brain. Paradoxically, despite broad expression of GHSR1a in the CNS, other than trace amounts in the hypothalamus, ghrelin is undetectable in the brain. In our efforts to elucidate the function of the ligand-free ghrelin receptor (apo-GHSR1a we identified subsets of neurons that co-express GHSR1a and dopamine receptors. In this review we focus on interactions between apo-GHSR1a and dopamine-2 receptor (DRD2 and formation of GHSR1a:DRD2 heteromers in hypothalamic neurons that regulate appetite, and discuss implications for the treatment of Prader-Willi syndrome. GHSR1a antagonists of distinct chemical structures, a quinazolinone and a triazole, respectively enhance and inhibit dopamine signaling through GHSR1a:DRD2 heteromers by an allosteric mechanism. This finding illustrates a potential strategy for designing the next generation of drugs for treating eating disorders as well as psychiatric disorders caused by abnormal dopamine signaling. Treatment with a GHSR1a antagonist that enhances dopamine/DRD2 activity in GHSR1a:DRD2 expressing hypothalamic neurons has the potential to inhibit the uncontrollable hyperphagia associated with Prader-Willi syndrome. DRD2 antagonists are prescribed for treating schizophrenia, but these block dopamine signaling in all DRD2 expressing neurons and are associated with adverse side effects, including enhanced appetite and excessive weight gain. A GHSR1a antagonist of structural class that allosterically blocks dopamine/DRD2 action in GHSR1a:DRD2 expressing neurons would have no effect on neurons expressing DRD2 alone; therefore, the side effects of DRD2 antagonists would potentially be reduced thereby enhancing patient compliance.

  11. NK3 receptors mediate an increase in firing rate of midbrain dopamine neurons of the rat and the guinea pig.

    Science.gov (United States)

    Werkman, Taco R; McCreary, Andrew C; Kruse, Chris G; Wadman, Wytse J

    2011-08-01

    This in vitro study investigates and compares the effects of NK3 receptor ligands on the firing rate of rat and guinea pig midbrain dopamine neurons. The findings are discussed in the light of choosing suitable animal models for investigating pharmacological properties of NK3 receptor antagonists, which have been proposed to possess therapeutic activity in neuropsychiatric diseases like e.g. schizophrenia. In vitro midbrain slice preparations of both species were used to record (extracellularly) the firing rates of dopamine neurons located in the substantia nigra (SN) and ventral tegmental area (VTA). Furthermore, the effect of the D2 receptor agonist quinpirole on guinea pig SN and VTA dopamine neurons was investigated. The efficacy of quinpirole in inhibiting guinea pig dopamine neuron firing activity was much less as compared to that of rat dopamine neurons, suggesting a lower dopamine D2 autoreceptor density on the guinea pig neurons. The NK3 receptor agonist senktide induced in subpopulations of rat SN (55%) and VTA (79%) and guinea pig SN (50%) and VTA (21%) dopamine neurons an increase in firing rate. In responsive neurons this effect was concentration-dependent with EC₅₀ values of 3-5 nM (for both species). The selective NK3 receptor antagonist osanetant (100 nM) was able to partly block the senktide-induced increase in firing rates of dopamine neurons and shifted the concentration-response relation curves for senktide to the right (pA₂ values were ~7.5). The fractional block of the senktide responses by osanetant appeared to be larger in guinea pig dopamine neurons, indicating that osanetant is a more potent blocker of NK3 receptor-mediated responses with noncompetitive properties in the guinea pig.

  12. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics

    Science.gov (United States)

    Sokoloff, Pierre; Giros, Bruno; Martres, Marie-Pascale; Bouthenet, Marie-Louise; Schwartz, Jean-Charles

    1990-09-01

    A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions. It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors.

  13. Functional recovery of supersensitive dopamine receptors after intrastriatal grafts of fetal substantia nigra

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, T.M.; Dawson, V.L.; Gage, F.H.; Fisher, L.J.; Hunt, M.A.; Wamsley, J.K. (Univ. of Utah Health Sciences Center, Salt Lake City (USA))

    1991-03-01

    Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with the phencyclidine derivative (3H)BTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of (3H)SCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in the number (Bmax) of (3H)sulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of (3H)BTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat.

  14. Age-related hypertension and salt sensitivity are associated with unique cortico-medullary distribution of D1R, AT1R, and NADPH-oxidase in FBN rats

    OpenAIRE

    Pokkunuri, Indira; Chugh, Gaurav; Rizvi, Imran; Asghar, Mohammad

    2015-01-01

    We examined effects of normal (NS) and high salt (HS) on blood pressure (BP) and cortico-medullary distribution of dopamine D1 receptor (D1R), angiotensin AT1 receptor (AT1R), NADPH oxidase-gp91phox, and sodium transporters (NHE-3, Na, K ATPase) in adult and aged rats. Aged rats fed with NS diet had higher BP, which further increased with HS. HS increased D1R mRNA and protein levels in cortex and medulla of adult rats. NS or HS fed-aged rats had higher AT1R and gp91phox mRNA levels in cortex ...

  15. MicroRNA-132 dysregulation in Toxoplasma gondii infection has implications for dopamine signaling pathway

    Science.gov (United States)

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Karuppagounder, Senthilkumar S.; Talbot, C. Conover; Dawson, Valina L.; Dawson, Ted M.; Yolken, Robert H.

    2014-01-01

    Congenital toxoplasmosis and toxoplasmic encephalitis can be associated with severe neuropsychiatric symptoms. However, which host cell processes are regulated and how Toxoplasma gondii affects these changes remain unclear. MicroRNAs (miRNAs) are small noncoding RNA sequences critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of over 1000 miRNAs in human neuroepithelioma cells in response to infection with Toxoplasma. MiR-132, a cyclic AMP-responsive element binding (CREB)-regulated miRNA, was the only miRNA that was substantially upregulated by all three prototype Toxoplasma strains. The increased expression of miR-132 was also documented in mice following infection with Toxoplasma. To identify cellular pathways regulated by miR-132, we performed target prediction followed by pathway enrichment analysis in the transcriptome of Toxoplasma-infected mice. This led us to identify 20 genes and dopamine receptor signaling was their strongest associated pathway. We then examined myriad aspects of the dopamine pathway in the striatum of Toxoplasma infected mice 5 days after infection. Here we report decreased expression of D1-like dopamine receptors (DRD1, DRD5), metabolizing enzyme (MAOA) and intracellular proteins associated with the transduction of dopamine-mediated signaling (DARPP-32 phosphorylation at Thr34 and Ser97). Increased concentrations of dopamine and its metabolites, serotonin and 5-hydroxyindoleacetic acid were documented by HPLC analysis; however, the metabolism of dopamine was decreased and serotonin metabolism was unchanged. Our data show that miR-132 is upregulated following infection with Toxoplasma and is associated with changes in dopamine receptor signaling. Our findings provide a possible mechanism for how the parasite contributes to the neuropathology of infection. PMID:24657774

  16. Waiting time distribution in M/D/1 queueing systems

    DEFF Research Database (Denmark)

    Iversen, Villy Bæk; Staalhagen, Lars

    1999-01-01

    The well-known formula for the waiting time distribution of M/D/1 queueing systems is numerically unsuitable when the load is close to 1.0 and/or the results for a large waiting time are required. An algorithm for any load and waiting time is presented, based on the state probabilities of M/D/1...

  17. Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice

    Directory of Open Access Journals (Sweden)

    Tanda Koichi

    2009-06-01

    Full Text Available Abstract Background Neuronal nitric oxide synthase (nNOS is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. Results nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. Conclusion These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders.

  18. Fluorescent diazapyrenium films and their response to dopamine.

    Science.gov (United States)

    Cejas, Mabel A; Raymo, Françisco M

    2005-06-21

    Experimental protocols for the preparation of 2,7-diazapyrenium films on glass, quartz, and silica in one or two steps have been developed. The one-step procedures involve the adsorption of preformed 2,7-diazapyrenium dications with trimethoxysilane appendages to the hydroxylated substrates. The two-step procedures consist in the formation of interfacial polysiloxanes with pendent chloromethyl groups and their subsequent coupling to monoalkylated 2,7-diazapyrene derivatives. For the modification of the glass slides, the silane building blocks have been copolymerized with Si(OEt)4. The transmission absorption spectra of the coated glass and quartz slides all reveal the characteristic bands of the 2,7-diazapyrenium chromophores. Combustion analyses confirm the adsorption of the 2,7-diazapyrenium dications on the silica particles. A comparison of the surface coverages of all films indicates that the one-step procedures are significantly more efficient than their two-step counterparts. Furthermore, the copolymerization of the silane building blocks with Si(OEt)4 translates into an increase in 2,7-diazapyrenium surface coverage of approximately 1 order of magnitude. The emission and excitation spectra of all modified substrates reveal the characteristic bands of the 2,7-diazapyrenium fluorophores. The fluorescence quantum yield, however, decreases as the surface coverage increases. Presumably, interactions between adjacent fluorophores encourage nonradiative deactivation pathways. With the exception of the glass slides modified in two steps, all films respond to the presence of dopamine, in aqueous environments at neutral pH, with pronounced decreases in emission intensity. The association of the 2,7-diazapyrenium acceptors and dopamine donors at the solid/liquid interface is responsible for fluorescence quenching. The glass slides and silica particles modified in one step are the most sensitive substrates and respond to sub-millimolar concentrations of dopamine with

  19. Resibufogenin Induces G1-Phase Arrest through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells.

    Directory of Open Access Journals (Sweden)

    Masami Ichikawa

    Full Text Available Huachansu, a traditional Chinese medicine prepared from the dried toad skin, has been used in clinical studies for various cancers in China. Resibufogenin is a component of huachansu and classified as bufadienolides. Resibufogenin has been shown to exhibit the anti-proliferative effect against cancer cells. However, the molecular mechanism of resibufogenin remains unknown. Here we report that resibufogenin induces G1-phase arrest with hypophosphorylation of retinoblastoma (RB protein and down-regulation of cyclin D1 expression in human colon cancer HT-29 cells. Since the down-regulation of cyclin D1 was completely blocked by a proteasome inhibitor MG132, the suppression of cyclin D1 expression by resibufogenin was considered to be in a proteasome-dependent manner. It is known that glycogen synthase kinase-3β (GSK-3β induces the proteasomal degradation of cyclin D1. The addition of GSK-3β inhibitor SB216763 inhibited the reduction of cyclin D1 caused by resibufogenin. These effects on cyclin D1 by resibufogenin were also observed in human lung cancer A549 cells. These findings suggest that the anti-proliferative effect of resibufogenin may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3β.

  20. Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization.

    Science.gov (United States)

    Peng, Qinghua; Sun, Xi; Liu, Ziyong; Yang, Jianghua; Oh, Ki-Wan; Hu, Zhenzhen

    2014-09-01

    Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5'-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55-102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55-102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55-102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55-102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55-102.

  1. Dopamine D1 and D2 Receptors in the Nucleus Accumbens Core and Shell Mediate Pavlovian-Instrumental Transfer

    Science.gov (United States)

    Lex, Anja; Hauber, Wolfgang

    2008-01-01

    Pavlovian stimuli previously paired with food can markedly elevate the rate of food-reinforced instrumental responding. This effect, termed Pavlovian-instrumental transfer (PIT), depends both on general activating and specific cueing properties of Pavlovian stimuli. Recent evidence suggests that the general activating properties of Pavlovian…

  2. Dopamine D1 Sensitivity in the Prefrontal Cortex Predicts General Cognitive Abilities and is Modulated by Working Memory Training

    Science.gov (United States)

    Wass, Christopher; Pizzo, Alessandro; Sauce, Bruno; Kawasumi, Yushi; Sturzoiu, Tudor; Ree, Fred; Otto, Tim; Matzel, Louis D.

    2013-01-01

    A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to…

  3. Semaphorin 4A enhances lung fibrosis through activation of Akt via PlexinD1 receptor

    Indian Academy of Sciences (India)

    Hai-Ying Peng; Wei Gao; Fa-Rong Chong; Hong-Yan Liu; Ji Zhang

    2015-12-01

    Semaphorin 4A plays a regulatory role in immune function and angiogenesis. However, its specific involvement in controlling lung fibrosis, a process that is closely related to angiogenesis and inflammation is still poorly understood. In the present study, we show that treatment of Sema4A on normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including a-smooth muscle actin (-SMA), ezrin, moesin, and paxillin. We confirm that Sema4A enhances the ability of lung fibroblasts to contract collagen gel. Sema4A treatment led to resistance to apoptosis in normal lung fibroblasts. Relative to normal lung fibroblasts, fibroblasts cultured from scars of patients with the flbrotic disease Systemic Sclerosis (SSc) showed elevated Sema4A secretion, enhanced -SMA, ezrin, moesin, and paxillin expression, and high ability to induce collagen gel contraction. Using neutralizing antibody against Sema4A receptor, PlexinD1, we found that endogenous Sema4A signalling in SSc fibroblast was through PlexinD1 receptor. We then identified the signalling mechanism through which Sema4A-PlexinD1 promotes the ability of normal fibroblasts to contract a collagen gel matrix. Western blot analysis showed that Sema4A activated the Akt pathway in lung fibroblasts, and the specific inhibitor of Akt pathway, Akt inhibitor III, blocked the ability of Sema4A to promote the ability of lung fibroblasts to contract a collagen gel matrix. Thus, blocking Sema4A-PlexinD1-Akt cascades might be beneficial in reducing pulmonary fibrosis.

  4. Electrophysiological study on biphasic firing activity elicited by D1 agonistic-D2 antagonistic action of (-)-stepholidine in nucleus accumbens%左旋千金藤啶碱D1激动-D2阻滞作用引起伏核双相放电活动的电生理研究

    Institute of Scientific and Technical Information of China (English)

    朱子涛; 傅雨; 胡国渊; 金国章

    2000-01-01

    Our previous work has demonstrated that (-)-stepholidine (SPD) has dual action, ie D1 agonistic-D2 antagonistic action on DA receptors in the nigra-striatal dopamine (DA) system. The present study attempted to ascertain its dual action on the mesolimbic DA system. The firing activities of the nucleus accumbens (NAc) neurons were extracellularly recorded with intravenous and iontophoretic administration of the drug in 6-hydroxydopamine (6-OHDA)-lesioned and intact rats. The results showed that SPD produced a consistently biphasic firing of NAc neurons during the cumulative doses of 0.02~2 mg/kg, iv. When the rats were pretreated with D2 antagonist spiperone, SPD only exerted an increasing effect, which was subsequently reversed by the D1 antagonist SCH-23390. Moreover, SCH-23390 could prevent the rate of increase elicited by SPD at high doses, presumably due to the D1 agonistic action of SPD on the activity of NAc neuron. On the other hand, the inhibition of NAc firing elicited by either D2 agonist LY171555 or D1/D2 agonists apomorphine was completely reversed by SPD, suggesting an antagonistic action of SPD to D2 receptors. In 6-OHDA-lesioned rats, iontophoresis of SPD also had an inhibitory effect in the majority of NAc neurons (91%) as SKF-38393 did. This inhibition could be completely blocked by the ejection of SCH-23390, but not by spiperone. These results indicate that SPD also has a D1 agonistic-D2 antagonistic dual action on NAc neuron activity, which may be beneficial to the treatment of schizophrenia.%为确定左旋千金藤啶碱(SPD)对中脑边缘DA神经系统的作用特性, 本研究采用细胞外记录的电生理学方法, 观察微电泳和尾静脉给药对6-OHDA损毁及未损毁大鼠的伏核(NAc)单位放电的影响.结果显示: SPD累积给药(0.02~2 mg/kg, iv)可诱发NAc神经元双相放电特征, 即小剂量抑制、大剂量兴奋.预先给予D2受体拮抗剂spiperone, SPD则仅产生兴奋效应, 并被D1拮抗剂SCH-23390

  5. D2 receptor block abolishes θ burst stimulation-induced neuroplasticity in the human motor cortex.

    Science.gov (United States)

    Monte-Silva, Katia; Ruge, Diane; Teo, James T; Paulus, Walter; Rothwell, John C; Nitsche, Michael A

    2011-09-01

    Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced.

  6. Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

    Energy Technology Data Exchange (ETDEWEB)

    Martin, J.R.

    1985-01-01

    The present study was undertaken to determine whether there is an alteration of dopamine receptor sensitivity following opiate administration, and whether this alteration has any influence on the development of opiate tolerance and dependence. Behavioral hypersensitivity to direct-acting dopamine agonists was observed in mice following acute or chronic morphine administration. Acute levorphanol administration also resulted in potentiation of dopamine agonist-induced behaviors. An increase in density of dopamine receptors, as measured by (/sup 3/H)butyrophenone binding accompanied the development of behavioral hypersensitivity. This increase was localized to the striatum, an area important in the mediation of dopamine-agonist induced behaviors. Naloxone or LiCl coadministered with the opiates prevented the development of hypersensitivity and the increase in density of dopamine receptors. Coadministration of lithium enhanced the development of acute and chronic tolerance. Lithium enhanced the development of dependence as determined by naloxone-induced hypothermia in chronically morphine-treated mice. Apomorphine enhanced naloxone-induced withdrawal in acutely dependent mice. This enhancement was blocked by coadministration of lithium with the opiates. These results suggest that dopamine receptor supersensitivity influences the degree of tolerance and dependence.

  7. The possible interaction of dopamine system in nucleus accumbens shell and glutamate system of prelimbic region on locomotor activity in rat

    Directory of Open Access Journals (Sweden)

    Hatam Ahmadi

    2013-06-01

    Full Text Available Background: Nucleus accumbens (NAc and prefrontal cortex (PFC dopaminergic and glutamatergic systems are involved in regulating of locomotor activity behaviors. This study has investigated the interaction of NAc shell dopaminergic system and prelimbic glutamatergic systems in regulating locomotor activity and related parameters. Methods: The aim of this study was the effect the drugs injection interaction in the brain of male Wistar rats on locomotor activity and related parameters, in the order of this purpose, open field apparatus that automatically recorded locomotor activity was employed. Unilateral intra-cerebral injection of drugs was done. Results: Unilateral intra-prelimbic injection of D-AP7 (N-methyl-D-aspartic acid= NMDA receptor antagonist; 0.25, 0.5 and 1μg/μl did not alter locomotor activity behaviors. However, infusion of NMDA (0.9μg/μl in this region increased locomotor activity (P<0.01, whereas decreased rearing (P<0.01 and grooming (P<0.01 which was blocked by D-AP7 (0.25μg/μl (P<0.01. Moreover, unilateral infusion of SCH23390 (dopamine D1 receptor antagonist; 0.25, 0.5 and 1μg/μl into the left NAc shell did not alter locomotor activity. However, injection of SKF38393 (dopamine D1 receptor agonist; 4μg/μl into the left NAc shell increased locomotor activity (P<0.05 which was blocked by SCH23390 (0.25μg/μl (P<0.01. Furthermore, the subthreshold dose infusion of SCH23390 (0.25μg/μl into the left NAc shell reduced the effect of intra- prelimbic NMDA on locomotor activity (P<0.01. In addition, intra-NAc shell administration of the subthreshold dose of SKF38393 (1μg/μl potentiated the middle dose (P<0.05, whereas decreased the higher dose of intra-left prelimbic NMDA response (P<0.05 on locomotor activity. Conclusion: The results suggested a modulatory effect of the NAc shell dopaminergic system on increased locomotor activity by activating glutamate system in prelimbic.

  8. Chaotic behavior in dopamine neurodynamics.

    OpenAIRE

    King, R; Barchas, J.D.; Huberman, B A

    1984-01-01

    We report the results of the dynamics of a model of the central dopaminergic neuronal system. In particular, for certain values of a parameter k, which monitors the efficacy of dopamine at the postsynaptic receptor, chaotic solutions of the dynamical equations appear--a prediction that correlates with the observed increased variability in behavior among schizophrenics, the rapid fluctuations in motor activity among Parkinsonian patients treated chronically with L-dopa, and the lability of moo...

  9. Involvement of dopamine receptors in the antidepressant-like effect of melatonin in the tail suspension test.

    Science.gov (United States)

    Binfaré, Ricardo W; Mantovani, Michela; Budni, Josiane; Santos, Adair Roberto S; Rodrigues, Ana Lúcia S

    2010-07-25

    Melatonin was previously shown to produce an antidepressant-like effect in the tail suspension test. In this work the mechanisms underlying its antidepressant-like effect were further studied by investigating the involvement of the dopaminergic system in its antidepressant-like effect in the tail suspension test. The effect of melatonin (1mg/kg, i.p.) was prevented by the pretreatment of mice with haloperidol (0.2mg/kg, i.p., a nonselective dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a selective dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., a selective dopamine D2 receptor antagonist). The i.p. administration of melatonin (0.01 mg/kg) or fluoxetine (1mg/kg, a serotonin reuptake inhibitor) in combination with SFK38393 (0.1mg/kg, s.c., a dopamine D1 receptor agonist) reduced the immobility time in the tail suspension test as compared with either drug alone. Moreover, the pretreatment with melatonin (0.01 mg/kg, i.p.) produced a synergistic effect with apomorphine (0.5 microg/kg, i.p., a dopamine D2 receptor agonist), but the pretreatment with fluoxetine (1mg/kg, i.p.) was ineffective to potentiate the effect of apomorphine. Dopamine receptor antagonists or agonists alone or in combination with melatonin did not affect locomotor activity. These results indicate that the antidepressant-like effect of melatonin in the tail suspension test is likely mediated by an interaction with the dopaminergic system, through an activation of dopamine D1 and D2 receptors. Our data confirm the previous notion on the role exerted by melatonin in depression, suggesting that it might be further investigated as an alternative for the management of depression associated with anhedonia.

  10. Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke.

    Science.gov (United States)

    Kuric, Enida; Wieloch, Tadeusz; Ruscher, Karsten

    2013-09-01

    Treatment with levodopa enhances functional recovery after experimental stroke but its mechanisms of action are elusive. Reactive astrocytes in the ischemic hemisphere are involved in mechanisms promoting recovery and also express dopamine 1 (D1) and dopamine 2 (D2) receptors. Here we investigated if the activation of astrocytic dopamine receptors (D1 and D2) regulates the expression of glial cell line-derived neurotrophic factor (GDNF) after combined in vitro hypoxia/aglycemia (H/A) and studied the expression of GDNF in the ischemic brain after treatment with levodopa/benserazide following transient occlusion of the middle cerebral artery (tMCAO) in the rat. Twenty-four hours after H/A, GDNF levels were upregulated in exposed astrocytes compared to normoxic control cultures and further elevated by the addition of the selective D1 receptor agonist (R)-(+)-SKF-38393 hydrochloride while D1 receptor antagonism by R(+)-SCH-23390 hydrochloride significantly reduced GDNF. No effect on GDNF levels was observed by the application of the D2 receptor agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide hydrate or S-(-)-eticlopride hydrochloride (D2 receptor antagonist). After tMCAO, GDNF was upregulated in D1 expressing reactive astrocytes in the peri-infarct area. In addition, treatment with levodopa/benserazide significantly increased GDNF levels in the infarct core and peri-infarct area after tMCAO without affecting the expression of glial fibrillar acidic protein (GFAP), an intermediate filament and marker of reactive gliosis. After stroke, GDNF levels increase in the ischemic hemisphere in rats treated with levodopa, implicating GDNF in the mechanisms of tissue reorganization and plasticity and in l-DOPA enhanced recovery of lost brain function. Our results support levodopa treatment as a potential recovery enhancing therapy in stroke patients.

  11. Dopamine receptor modulation of repetitive grooming actions in the rat: potential relevance for Tourette syndrome.

    Science.gov (United States)

    Taylor, Jennifer L; Rajbhandari, Abha K; Berridge, Kent C; Aldridge, J Wayne

    2010-03-31

    Studies of rodent grooming can provide valuable insight for dopamine contributions to the initiation, organization, and repetition of motor patterns. This information is useful for understanding how brain dysfunctions contribute to movement disorders such as Tourette syndrome and obsessive compulsive disorder, in which patients are driven to reiterate particular movement patterns. In rodents, dopamine D1 receptor stimulation causes a complex behavioral super-stereotypy in the form of excessive production and rigid execution of whole sequences of movements known as syntactic grooming chains. Sequential super-stereotypy of grooming chains may be particularly advantageous for modeling movement sequences and treatments in Tourette syndrome and related disorders. Here, we report that co-administration of haloperidol, one available treatment for Tourette syndrome and primarily a D2 receptor antagonist, prevented D1 stimulation with SKF38393 from inducing sequential super-stereotypy, which manifests as an exaggeration of the tendency to complete all four phases of a syntactic chain in rigid serial order once the first phase has begun. In a separate experiment, we showed that in contrast to acute D1 agonist administration, 39h withdrawal from chronic (3weeks) administration of the D1 antagonist SCH23390 (which has been suggested to increase D1 receptor expression in the basal ganglia) did not elicit sequential super-stereotypy after drug cessation. Instead, rats suddenly removed from repeated SCH23390 spent more time performing simple stereotypies that included intense scratching and biting behaviors. Together, these results have implications for understanding how dopamine receptors facilitate particular stereotypies manifest in animal models of Tourette syndrome and obsessive compulsive disorder.

  12. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

    DEFF Research Database (Denmark)

    Decressac, Mickael; Mattsson, Bengt; Weikop, Pia

    2013-01-01

    The aggregation of α-synuclein plays a major role in Parkinson disease (PD) pathogenesis. Recent evidence suggests that defects in the autophagy-mediated clearance of α-synuclein contribute to the progressive loss of nigral dopamine neurons. Using an in vivo model of α-synuclein toxicity, we show...... that the PD-like neurodegenerative changes induced by excess cellular levels of α-synuclein in nigral dopamine neurons are closely linked to a progressive decline in markers of lysosome function, accompanied by cytoplasmic retention of transcription factor EB (TFEB), a major transcriptional regulator...... in both A9 and A10 dopamine neurons. Delayed activation of TFEB function through inhibition of mammalian target of rapamycin blocked α-synuclein induced neurodegeneration and further disease progression. The results provide a mechanistic link between α-synuclein toxicity and impaired TFEB function...

  13. Dopamine receptors in pituitary adenomas: PET visualization with 11C-N-methylspiperone

    Energy Technology Data Exchange (ETDEWEB)

    Muhr, C.; Bergstroem, M.L.; Lundberg, P.O.; Bergstroem, K.H.; Hartvig, P.; Lundqvist, H.; Antoni, G.; Langstroem B2

    1986-03-01

    Two patients with pituitary tumors were examined with positron emission tomography (PET) after intravenous administration of 11C-N-methylspiperone. In repeat studies the patients were given 1 mg of intravenous haloperidol prior to the administration of the radioligand to block the dopamine receptors. High uptakes of the radiolabeled ligand were seen in one of the tumors. With haloperidol pretreatment the uptake was lower, probably mainly showing the remaining unspecific binding. The most marked uptake and the largest effect of haloperidol pretreatment was seen in a patient with a hormonally active prolactinoma. Dopamine receptor binding in pituitary tumors can be demonstrated in vivo with PET, and quantification of this binding is possible using a compartmental model. This technique may be useful in improving our understanding of the variable response to medical treatment of prolactinomas with dopamine agonists as well as in the prediction of the effect of such treatment.

  14. Grafted dopamine neurons: Morphology, neurochemistry, and electrophysiology.

    Science.gov (United States)

    Strömberg, Ingrid; Bickford, Paula; Gerhardt, Greg A

    2010-02-09

    Grafting of dopamine-rich tissue to counteract the symptoms in Parkinson's disease became a promising tool for future treatment. This article discusses how to improve the functional outcome with respect to graft outgrowth and functions of dopamine release and electrophysiological responses to graft implantation in the host brain striatal target. It has been documented that a subpopulation of the dopamine neurons innervates the host brain in a target-specific manner, while some of the grafted dopamine neurons never project to the host striatum. Neurochemical studies have demonstrated that the graft-induced outgrowth synthesize, store, metabolize and release dopamine and possibly other neurotransmitters such as 5-HT. Furthermore, the released dopamine affects the dopamine-depleted brain in areas that are larger than the graft-derived nerve fibers reach. While stem cells will most likely be the future source of cells to be used in grafting, it is important to find the guiding cues for how to reinnervate the dopamine-depleted striatum in a proper way with respect to the dopamine subpopulations of A9 and A10 to efficiently treat the motor abnormalities seen in Parkinson's disease.

  15. The D$_1$ enigma and its physical origin

    CERN Document Server

    Stenflo, J O

    2016-01-01

    The D$_1$ enigma is an anomaly, which was first observed on the Sun as a symmetric polarization peak centered in the core of the sodium D$_1$ line that is expected to be intrinsically unpolarizable. To resolve this problem the underlying physics was later explored in the laboratory for D$_1$ scattering at potassium vapor. The experiment showed that the scattering phase matrix element $P_{21}$ is positive while $P_{22}$ is negative, although standard quantum scattering theory predicts that both should be zero. This experimental contradiction is currently the main manifestation of the D$_1$ enigma. Subsequent theoretical studies showed that such polarization effects may arise if scattering theory is extended to allow for interference effects due to level splittings of the ground state, in contrast to standard scattering theory, which only allows for interferences from level splittings of the intermediate state. Previous attempts to implement this idea had to rely on heuristic arguments to allow modeling of the ...

  16. Activation of dopamine receptors in the nucleus accumbens promotes sucrose-reinforced cued approach behavior

    Directory of Open Access Journals (Sweden)

    Saleem M. Nicola

    2016-07-01

    Full Text Available Dopamine receptor activation in the nucleus accumbens (NAc promotes vigorous environmentally-cued food-seeking in hungry rats. Rats fed ad libitum, however, respond to fewer food-predictive cues, particularly when the value of food reward is low. Here, we investigated whether this difference could be due to differences in the degree of dopamine receptor activation in the NAc. First, we observed that although rats given ad libitum access to chow in their home cages approached a food receptacle in response to reward-predictive cues, the number of such approaches declined as animals accumulated food rewards. Intriguingly, cued approach to food occurred in clusters, with several cued responses followed by successive non-responses. This pattern suggested that behavior was dictated by transitions between two states, responsive and non-responsive. Injection of D1 or D2 dopamine receptor agonists into the NAc dose-dependently increased cue responding by promoting transitions to the responsive state and by preventing transitions to the non-responsive state. In contrast, antagonists of either D1 or D2 receptors promoted long bouts of non-responding by inducing transitions to the non-responsive state and by preventing transitions to the responsive state. Moreover, locomotor behavior during the inter-trial interval was correlated with the responsive state, and was also increased by dopamine receptor agonists. These results suggest that activation of NAc dopamine receptors plays an important role in regulating the probability of approach to food under conditions of normative satiety.

  17. Dopamine and angiotensin type 2 receptors cooperatively inhibit sodium transport in human renal proximal tubule cells.

    Science.gov (United States)

    Gildea, John J; Wang, Xiaoli; Shah, Neema; Tran, Hanh; Spinosa, Michael; Van Sciver, Robert; Sasaki, Midori; Yatabe, Junichi; Carey, Robert M; Jose, Pedro A; Felder, Robin A

    2012-08-01

    Little is known regarding how the kidney shifts from a sodium and water reclaiming state (antinatriuresis) to a state where sodium and water are eliminated (natriuresis). In human renal proximal tubule cells, sodium reabsorption is decreased by the dopamine D(1)-like receptors (D(1)R/D(5)R) and the angiotensin type 2 receptor (AT(2)R), whereas the angiotensin type 1 receptor increases sodium reabsorption. Aberrant control of these opposing systems is thought to lead to sodium retention and, subsequently, hypertension. We show that D(1)R/D(5)R stimulation increased plasma membrane AT(2)R 4-fold via a D(1)R-mediated, cAMP-coupled, and protein phosphatase 2A-dependent specific signaling pathway. D(1)R/D(5)R stimulation also reduced the ability of angiotensin II to stimulate phospho-extracellular signal-regulated kinase, an effect that was partially reversed by an AT(2)R antagonist. Fenoldopam did not increase AT(2)R recruitment in renal proximal tubule cells with D(1)Rs uncoupled from adenylyl cyclase, suggesting a role of cAMP in mediating these events. D(1)Rs and AT(2)Rs heterodimerized and cooperatively increased cAMP and cGMP production, protein phosphatase 2A activation, sodium-potassium-ATPase internalization, and sodium transport inhibition. These studies shed new light on the regulation of renal sodium transport by the dopaminergic and angiotensin systems and potential new therapeutic targets for selectively treating hypertension.

  18. Cocaine inhibits dopamine D2 receptor signaling via sigma-1-D2 receptor heteromers.

    Directory of Open Access Journals (Sweden)

    Gemma Navarro

    Full Text Available Under normal conditions the brain maintains a delicate balance between inputs of reward seeking controlled by neurons containing the D1-like family of dopamine receptors and inputs of aversion coming from neurons containing the D2-like family of dopamine receptors. Cocaine is able to subvert these balanced inputs by altering the cell signaling of these two pathways such that D1 reward seeking pathway dominates. Here, we provide an explanation at the cellular and biochemical level how cocaine may achieve this. Exploring the effect of cocaine on dopamine D2 receptors function, we present evidence of σ1 receptor molecular and functional interaction with dopamine D2 receptors. Using biophysical, biochemical, and cell biology approaches, we discovered that D2 receptors (the long isoform of the D2 receptor can complex with σ1 receptors, a result that is specific to D2 receptors, as D3 and D4 receptors did not form heteromers. We demonstrate that the σ1-D2 receptor heteromers consist of higher order oligomers, are found in mouse striatum and that cocaine, by binding to σ1 -D2 receptor heteromers, inhibits downstream signaling in both cultured cells and in mouse striatum. In contrast, in striatum from σ1 knockout animals these complexes are not found and this inhibition is not seen. Taken together, these data illuminate the mechanism by which the initial exposure to cocaine can inhibit signaling via D2 receptor containing neurons, destabilizing the delicate signaling balance influencing drug seeking that emanates from the D1 and D2 receptor containing neurons in the brain.

  19. Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons.

    Science.gov (United States)

    Salum, Cristiane; Schmidt, Fanny; Michel, Patrick P; Del-Bel, Elaine; Raisman-Vozari, Rita

    2016-01-01

    Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.

  20. Dopamine-dependent behavioural stimulation by non-peptide delta opioids BW373U86 and SNC 80: 1. Locomotion, rearing and stereotypies in intact rats.

    Science.gov (United States)

    Spina, L; Longoni, R; Mulas, A; Chang, K J; Di Chiara, G

    1998-02-01

    The unconditioned behavioural effects of two non-peptide delta-opioid receptor agonists, BW 373U86 and SNC 80, were studied in the intact rat. BW 373U86 (0.1-2.5 mg/kg s.c.) and SNC 80 (2.5-10 mg/kg s.c.) dose-dependently elicited locomotion, rearing, stereotyped sniffing, licking and gnawing. These effects were abolished by pretreatment with the delta-opioid receptor antagonist naltrindole (5.0 mg/kg s.c.). In view of the phenomenological similarities between this syndrome and that elicited by dopamine-receptor agonists, the role played by dopamine receptors was investigated. The specific dopamine D1 receptor antagonist SCH 23390 and the specific dopamine D2/D3 receptor antagonist raclopride reduced or even abolished the behavioural stimulation induced by lower doses of BW 373U86 and SNC 80. When higher doses of BW 373U86 were used (2.5 mg/kg), however, raclopride, even at high cataleptic doses (6.0 mg/kg), only partly prevented the behavioural stimulation induced by the delta-opioid receptor agonist. The behavioural stimulation remaining after high doses of raclopride was abolished by the administration of SCH 23390. These results show that delta-opioid receptor stimulation elicits dopamine-dependent behavioural activation in the rat that depends on dopamine receptors, particularly of the D1 subtype.

  1. Dopamine elevates and lowers astroglial Ca2+ through distinct pathways depending on local synaptic circuitry

    Science.gov (United States)

    Jennings, Alistair; Tyurikova, Olga; Bard, Lucie; Zheng, Kaiyu; Semyanov, Alexey; Henneberger, Christian

    2016-01-01

    Whilst astrocytes in culture invariably respond to dopamine with cytosolic Ca2+ rises, the dopamine sensitivity of astroglia in situ and its physiological roles remain unknown. To minimize effects of experimental manipulations on astroglial physiology, here we monitored Ca2+ in cells connected via gap junctions to astrocytes loaded whole‐cell with cytosolic indicators in area CA1 of acute hippocampal slices. Aiming at high sensitivity of [Ca2+] measurements, we also employed life‐time imaging of the Ca2+ indicator Oregon Green BAPTA‐1. We found that dopamine triggered a dose‐dependent, bidirectional Ca2+ response in stratum radiatum astroglia, a jagged elevation accompanied and followed by below‐baseline decreases. The elevation depended on D1/D2 receptors and engaged intracellular Ca2+ storage and removal whereas the dopamine‐induced [Ca2+] decrease involved D2 receptors only and was sensitive to Ca2+ channel blockade. In contrast, the stratum lacunosum moleculare astroglia generated higher‐threshold dopamine‐induced Ca2+ responses which did not depend on dopamine receptors and were uncoupled from the prominent inhibitory action of dopamine on local perforant path synapses. Our findings thus suggest that a single neurotransmitter—dopamine—could either elevate or decrease astrocyte [Ca2+] depending on the receptors involved, that such actions are specific to the regional neural circuitry and that they may be causally uncoupled from dopamine actions on local synapses. The results also indicate that [Ca2+] elevations commonly detected in astroglia can represent the variety of distinct mechanisms acting on the microscopic scale. GLIA 2017;65:447–459 PMID:27896839

  2. 电针对脑缺血再灌注大鼠纹状体D1R和DAT表达的影响%Effect of Electroacupuncture on Striatal D1R and DAT Expressions in Cerebral Ischemia-reperfusion Rats

    Institute of Scientific and Technical Information of China (English)

    徐鸣曙; 陈春艳; 李昌植; 葛林宝; 张淑静; 赵丹; 李明哲; 韩清; 张英杰

    2015-01-01

    ObjectiveTo investigate the effects of dopamine D1 receptor (D1R) tool drugs and combined acupuncture and medicine on striatal expressions of D1R and dopamine transporters (DAT) in middle cerebral artery occlusion (MCAO)-reperfusion rats.MethodForty-seven male SD rats were randomly grouped, used to make a model and given corresponding interventions. The materials were taken and fixed six hrs later. Striatal D1R and DAT expressions were detectedby an immunohistochemical method in different groups.ResultThe neurological deficit score was significantly higher in the model group than in the blank group. Electroacupuncture treatment decreased the score significantly (P0.05). DAT expression was significantly down-regulated in the other groups compared with the model group (P0.05).ConclusionCerebral ischemia-reperfusion can result in high D1R and DAT expressions in rat striatum on the ischemic side. Electroacupuncture, D1R antagonists and a combination of the two can significantly down-regulate D1R expression and have a protective effect on the brain. The effects of electroacupuncture and D1R antagonists can not be added to each other. D1R signaling pathway may be one of ways by which electroacupuncture produces a protective effecton the brain.%目的:探讨电针、多巴胺D1受体(D1R)工具药及针药结合对大脑中动脉缺血(MCAO)再灌注大鼠纹状体内D1R和多巴胺转运体(DAT)表达的影响。方法将47只SD雄性大鼠随机分组、造模、施予相应干预措施,6 h后取材固定,用免疫组化法检测不同组别纹状体内D1R、DAT的表达。结果模型组神经功能缺血评分明显高于空白组,电针治疗可使评分明显降低(P<0.05)。拮抗剂组、电针组、电针+拮抗剂组D1R表达与模型组比较显著下调(P<0.05);模型组D1R表达与激动剂组、电针+激动剂组比较无显著变化(P>0.05);各组 DAT 表达与模型组比较均显著下调(P<0.05),除模型组外各组间比较有

  3. Computational systems analysis of dopamine metabolism.

    Directory of Open Access Journals (Sweden)

    Zhen Qi

    Full Text Available A prominent feature of Parkinson's disease (PD is the loss of dopamine in the striatum, and many therapeutic interventions for the disease are aimed at restoring dopamine signaling. Dopamine signaling includes the synthesis, storage, release, and recycling of dopamine in the presynaptic terminal and activation of pre- and post-synaptic receptors and various downstream signaling cascades. As an aid that might facilitate our understanding of dopamine dynamics in the pathogenesis and treatment in PD, we have begun to merge currently available information and expert knowledge regarding presynaptic dopamine homeostasis into a computational model, following the guidelines of biochemical systems theory. After subjecting our model to mathematical diagnosis and analysis, we made direct comparisons between model predictions and experimental observations and found that the model exhibited a high degree of predictive capacity with respect to genetic and pharmacological changes in gene expression or function. Our results suggest potential approaches to restoring the dopamine imbalance and the associated generation of oxidative stress. While the proposed model of dopamine metabolism is preliminary, future extensions and refinements may eventually serve as an in silico platform for prescreening potential therapeutics, identifying immediate side effects, screening for biomarkers, and assessing the impact of risk factors of the disease.

  4. Going for broke: dopamine influences risky choice.

    Science.gov (United States)

    Moschak, Travis M; Carelli, Regina M

    2014-10-01

    Dopamine neurons track reward by increasing or decreasing their firing rate when a reward is present or absent. In this issue of Neuron, Stopper et al. (2014) demonstrate that artificially eliminating these dopamine bursts or dips can alter risky decision-making.

  5. Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation.

    Science.gov (United States)

    Soares-Cunha, Carina; Coimbra, Barbara; David-Pereira, Ana; Borges, Sonia; Pinto, Luisa; Costa, Patricio; Sousa, Nuno; Rodrigues, Ana J

    2016-06-23

    Striatal dopamine receptor D1-expressing neurons have been classically associated with positive reinforcement and reward, whereas D2 neurons are associated with negative reinforcement and aversion. Here we demonstrate that the pattern of activation of D1 and D2 neurons in the nucleus accumbens (NAc) predicts motivational drive, and that optogenetic activation of either neuronal population enhances motivation in mice. Using a different approach in rats, we further show that activating NAc D2 neurons increases cue-induced motivational drive in control animals and in a model that presents anhedonia and motivational deficits; conversely, optogenetic inhibition of D2 neurons decreases motivation. Our results suggest that the classic view of D1-D2 functional antagonism does not hold true for all dimensions of reward-related behaviours, and that D2 neurons may play a more prominent pro-motivation role than originally anticipated.

  6. Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

    Science.gov (United States)

    Rioult-Pedotti, Mengia-Seraina; Pekanovic, Ana; Atiemo, Clement Osei; Marshall, John; Luft, Andreas Rüdiger

    2015-01-01

    Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

  7. Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

    Directory of Open Access Journals (Sweden)

    Mengia-Seraina Rioult-Pedotti

    Full Text Available Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA, leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

  8. Identification of dopamine receptors across the extant avian family tree and analysis with other clades uncovers a polyploid expansion among vertebrates

    Directory of Open Access Journals (Sweden)

    Asher eHaug-Baltzell

    2015-10-01

    Full Text Available Dopamine is an important central nervous system transmitter that functions through two classes of receptors (D1 and D2 to influence a diverse range of biological processes in vertebrates. With roles in regulating neural activity, behavior, and gene expression, there has been great interest in understanding the function and evolution dopamine and its receptors. In this study, we use a combination of sequence analyses, microsynteny analyses, and phylogenetic relationships to identify and characterize both the D1 (DRD1A, DRD1B, DRD1C, and DRD1E and D2 (DRD2, DRD3, and DRD4 dopamine receptor gene families in 43 recently sequenced bird genomes representing the major ordinal lineages across the avian family tree. We show that the common ancestor of all birds possessed at least seven D1 and D2 receptors, followed by subsequent independent losses in some lineages of modern birds. Through comparisons with other vertebrate and invertebrate species we show that two of the D1 receptors, DRD1A and DRD1B, and two of the D2 receptors, DRD2 and DRD3, originated from a whole genome duplication event early in the vertebrate lineage, providing the first conclusive evidence of the origin of these highly conserved receptors. Our findings provide insight into the evolutionary development of an important modulatory component of the central nervous system in vertebrates, and will help further unravel the complex evolutionary and functional relationships among dopamine receptors.

  9. Biologic Effects of Dopamine on Tumor Vasculature in Ovarian Carcinoma

    Directory of Open Access Journals (Sweden)

    Myrthala Moreno-Smith

    2013-05-01

    Full Text Available Chronic sympathetic nervous system activation results in increased angiogenesis and tumor growth in orthotopic mouse models of ovarian carcinoma. However, the mechanistic effects of such activation on the tumor vasculature are not well understood. Dopamine (DA, an inhibitory catecholamine, regulates the functions of normal and abnormal blood vessels. Here, we examined whether DA, an inhibitory catecholamine, could block the effects of chronic stress on tumor vasculature and tumor growth. Exogenous administration of DA not only decreased tumor microvessel density but also increased pericyte coverage of tumor vessels following daily restraint stress in mice. Daily restraint stress resulted in significantly increased tumor growth in the SKOV3ip1 and HeyA8 ovarian cancer models. DA treatment blocked stress-mediated increases in tumor growth and increased pericyte coverage of tumor endothelial cells. Whereas the antiangiogenic effect of DA is mediated by dopamine receptor 2 (DR2, our data indicate that DA, through DR1, stimulates vessel stabilization by increasing pericyte recruitment to tumor endothelial cells. DA significantly stimulated migration of mouse 10T1/2 pericyte-like cells in vitro and increased cyclic adenosine mono-phosphate (cAMP levels in these cells. Moreover, DA or the DR1 agonist SKF 82958 increased platinum concentration in SKOV3ip1 tumor xenografts following cisplatin administration. In conclusion, DA stabilizes tumor blood vessels through activation of pericyte cAMP-protein kinase A signaling pathway by DR1. These findings could have implications for blocking the stimulatory effects of chronic stress on tumor growth.

  10. The inhibition of dopamine synthesis in fetuses changes the pattern of T-lymphocyte maturation in the thymus of adult rats.

    Science.gov (United States)

    Lifantseva, N V; Koneeva, Ts O; Voronova, S N; Zakharova, L A; Melnikova, V I

    2016-09-01

    The mRNA for dopamine receptors of type D1, D3, D5, but not type D2, was detected in the thymus of rats starting from day 16 of embryonic development (E16). Dopamine at concentrations of 10(-8)-10(‒6) M inhibited fetus thymocyte response to mitogen, confirming the functionality of the receptors and the possibility of a direct effect of dopamine on the developing thymus. Pharmacological inhibition of catecholamine synthesis in the crucial period of thymus development leads to long-term changes in the T-system immunity due to increased production of natural regulatory T-lymphocytes. The presence and functional activity of dopamine receptors in the fetal thymus indicates its ability to influence the development of the immune system of rats during ontogeny.

  11. Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy.

    Science.gov (United States)

    Rocha, Luisa; Alonso-Vanegas, Mario; Villeda-Hernández, Juana; Mújica, Mario; Cisneros-Franco, José Miguel; López-Gómez, Mario; Zavala-Tecuapetla, Cecilia; Frías-Soria, Christian Lizette; Segovia-Vila, José; Borsodi, Anna

    2012-01-01

    Experiments were designed to evaluate different variables of the dopaminergic system in the temporal cortex of surgically treated patients with temporal lobe epilepsy (TLE) associated with mesial sclerosis (MTLE, n=12) or with cerebral tumor or lesion (n=8). In addition, we sought to identify dopaminergic abnormalities in those patients with epilepsy that had comorbid anxiety and depression. Specifically, we investigated changes in dopamine and its metabolites, D1 and D2 receptors, tyrosine hydroxylase (TH) and dopamine transporter. Results obtained from patients with epilepsy were compared with those found in experiments using autopsy material. The neocortex of patients with MTLE demonstrated high D1 expression (1680%, p<0.05) and binding (layers I-II, 31%, p<0.05; layers V-VI, 28%, p<0.05), and decreased D2 expression (77%, p<0.05). The neocortex of patients with TLE secondary to cerebral tumor or lesion showed high expression of D1 receptors (1100%, p<0.05), and D2-like induced activation of G proteins (layers I-II, 503%; layers III-IV, 557%; layers V-VI, 964%, p<0.05). Both epileptic groups presented elevated binding to the dopamine transporter and low tissue content of dopamine and its metabolites. Analysis revealed the following correlations: a) D1 receptor binding correlated negatively with seizure onset age and seizure frequency, and positively with duration of epilepsy; b) D2 receptor binding correlated positively with age of seizure onset and negatively with duration of epilepsy; c) dopamine transporter binding correlated positively with duration of epilepsy and frequency of seizures; d) D2-like induced activation of G proteins correlated positively with the age of patients. When compared with autopsies and patients with anxiety and depression, patients without neuropsychiatric disorders showed high D2-like induced activation of G proteins, an effect that correlated positively with age of patient and seizure onset age, and negatively with duration of

  12. Design activities on helical DEMO reactor FFHR-d1

    Energy Technology Data Exchange (ETDEWEB)

    Sagara, A., E-mail: sagara.akio@LHD.nifs.ac.jp [National Institute for Fusion Science, Toki, Gifu 509-5292 (Japan); Goto, T.; Miyazawa, J.; Yanagi, N.; Tanaka, T.; Tamura, H.; Sakamoto, R.; Tanaka, M.; Tsumori, K. [National Institute for Fusion Science, Toki, Gifu 509-5292 (Japan); Mitarai, O. [Tokai University, 9-1-1 Toroku, Kumamoto 862-8652 (Japan); Imagawa, S.; Muroga, T. [National Institute for Fusion Science, Toki, Gifu 509-5292 (Japan)

    2012-08-15

    Highlights: Black-Right-Pointing-Pointer Conceptual design studies of the helical DEMO reactor FFHR-d1 have been conducted. Black-Right-Pointing-Pointer Design window analyses with core plasma and engineering designs have been carried out. Black-Right-Pointing-Pointer R and Ds on blanket, magnet, tritium control, fuelling and heating systems are discussed. - Abstract: Based on high-density and high-temperature plasma experiments in the large helical device (LHD), conceptual design studies of the LHD-type helical DEMO reactor FFHR-d1 have been conducted by integrating wide-ranged R and D activities on core plasmas and reactor technologies through cooperative researches under the fusion engineering research project, which has been launched newly in NIFS. Current activities for the FFHR-d1 in this project are presented on design window analyses with designs on core plasma, neutronics for liquid blankets, continuous helical magnets, pellet fueling, tritium systems and plasma heating devices.

  13. Different effects of direct and indirect dopamine receptor agonists on immobility time in reserpine-treated mice.

    Science.gov (United States)

    Zarrindast, M R; Minaian, A

    1991-01-01

    1. The effects of dopamine agonists on the immobility time in mice were examined. 2. Apomorphine (APO), bupropion (BUP), bromocriptine (BRC) and quinpirole but not SKF 38393 elicited anti-immobility effect. The effect of the agonists was decreased by the D-2 antagonist sulpiride but not by the D-1 antagonist SCH 23390. 3. In animals pretreated with reserpine, the anti-immobility effects of APO and quinpirole were potentiated, while the response of BPU was decreased and that of BRC was not changed. 4. It is concluded that D-2 dopamine receptors are involved in the anti-immobility effects of dopaminergic agents, D-2 dopamine receptors may become hypersensitive by reserpine and BUP exerts its response through indirect dopaminergic if mechanism.

  14. (+)-Dinapsoline: an efficient synthesis and pharmacological profile of a novel dopamine agonist.

    Science.gov (United States)

    Sit, Sing-Yuen; Xie, Kai; Jacutin-Porte, Swanee; Taber, Matthew T; Gulwadi, Amit G; Korpinen, Carolyn D; Burris, Kevin D; Molski, Thaddeus F; Ryan, Elaine; Xu, Cen; Wong, Henry; Zhu, Juliang; Krishnananthan, Subramaniam; Gao, Qi; Verdoorn, Todd; Johnson, Graham

    2002-08-15

    A highly convergent synthesis was developed for the novel dopamine agonist dinapsoline (12) (Ghosh, D.; Snyder, S. E.; Watts, V. J.; Mailman, R. B.; Nichols, D. E. 8,9-Dihydroxy-2,3,7, 11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: A Potent Full Dopamine D(1) Agonist Containing a Rigid beta-Phenyldopamine Pharmacophore. J. Med. Chem. 1996, 39 (2), 549-555). The crucial step in the new synthesis was a free radical-initiated cyclization to give the complete dinapsoline framework. The improved synthesis required half as many steps as the original procedure (Nichols, D. E.; Mailman, R.; Ghosh, D. Preparation of novel naphtho[1,2,3-de]isoquinolines as dopamine receptor ligands. PCT Int. Appl. WO 9706799 A1, Feb 27, 1997). One of the late-stage intermediates (11) was resolved into a pair of enantiomers. From there, the (R)-(+)-12 (absolute configuration by X-ray) of dinapsoline was identified as the active enantiomer. In unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats, (+)-dinapsoline showed robust rotational behavior comparable to that of an external benchmark, trans-4,5,5a,6,7,11b-hexahydro-2-propyl-benzo[f]thieno[2,3-c]quinoline-9,10-diol, hydrochloride 18 (Michaelides, M. R.; Hong, Y. Preparation of heterotetracyclic compounds as dopamine agonists. PCT Int. Appl. WO 9422858 A1, Oct 13, 1994).

  15. Dopamine beta-hydroxylase deficiency

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    Senard Jean-Michel

    2006-03-01

    Full Text Available Abstract Dopamine beta-hydroxylase (DβH deficiency is a very rare form of primary autonomic failure characterized by a complete absence of noradrenaline and adrenaline in plasma together with increased dopamine plasma levels. The prevalence of DβH deficiency is unknown. Only a limited number of cases with this disease have been reported. DβH deficiency is mainly characterized by cardiovascular disorders and severe orthostatic hypotension. First symptoms often start during a complicated perinatal period with hypotension, muscle hypotonia, hypothermia and hypoglycemia. Children with DβH deficiency exhibit reduced ability to exercise because of blood pressure inadaptation with exertion and syncope. Symptoms usually worsen progressively during late adolescence and early adulthood with severe orthostatic hypotension, eyelid ptosis, nasal stuffiness and sexual disorders. Limitation in standing tolerance, limited ability to exercise and traumatic morbidity related to falls and syncope may represent later evolution. The syndrome is caused by heterogeneous molecular alterations of the DBH gene and is inherited in an autosomal recessive manner. Restoration of plasma noradrenaline to the normal range can be achieved by therapy with the synthetic precursor of noradrenaline, L-threo-dihydroxyphenylserine (DOPS. Oral administration of 100 to 500 mg DOPS, twice or three times daily, increases blood pressure and reverses the orthostatic intolerance.

  16. Dopamine Agonists and Pathologic Behaviors

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    Brendan J. Kelley

    2012-01-01

    Full Text Available The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

  17. Ultrasound guided supraclavicular block.

    LENUS (Irish Health Repository)

    Hanumanthaiah, Deepak

    2013-09-01

    Ultrasound guided regional anaesthesia is becoming increasingly popular. The supraclavicular block has been transformed by ultrasound guidance into a potentially safe superficial block. We reviewed the techniques of performing supraclavicular block with special focus on ultrasound guidance.

  18. Accelerated habit formation following amphetamine exposure is reversed by D1, but enhanced by D2, receptor antagonists

    Directory of Open Access Journals (Sweden)

    Andrew John Dudley Nelson

    2013-05-01

    Full Text Available Repeated exposure to the psychostimulant amphetamine has been shown to disrupt goal-directed instrumental actions and promote the early and abnormal development of goal-insensitive habitual responding (Nelson and Killcross, 2006. To investigate the neuropharmacological specificity of this effect as well as restore goal-directed responding in animals with pre-training amphetamine exposure, animals were treated with the non-selective dopamine antagonist α-flupenthixol, the selective D1 antagonist SCH 23390 or the selective D2 antagonist eticlopride, prior to instrumental training (3 sessions. Subsequently, the reinforcer was paired with LiCL-induced gastric-malaise and animals were given a test of goal-sensitivity both in extinction and reacquisition. The effect of these dopaminergic antagonists on the sensitivity of lever press performance to outcome devaluation was assessed in animals with pre-training exposure to amphetamine (Experiments 1a-1c or in non-sensitized animals (Experiment 2. Both α-flupenthixol and SCH23390 reversed accelerated habit formation following amphetamine sensitization. However, eticlopride appeared to enhance this effect and render instrumental performance compulsive as these animals were unable to inhibit responding both in extinction and reacquisition, even though a consumption test confirmed they had acquired an aversion to the reinforcer. These findings demonstrate that amphetamine induced-disruption of goal-directed behaviour is mediated by activity at distinct dopamine receptor subtypes and may represent a putative model of the neurochemical processes involved in the loss of voluntary control over behaviour.

  19. Intermittent-access binge consumption of sweet high-fat liquid does not require opioid or dopamine receptors in the nucleus accumbens.

    Science.gov (United States)

    Lardeux, Sylvie; Kim, James J; Nicola, Saleem M

    2015-10-01

    Binge eating disorders are characterized by episodes of intense consumption of high-calorie food. In recently developed animal models of binge eating, rats given intermittent access to such food escalate their consumption over time. Consumption of calorie-dense food is associated with neurochemical changes in the nucleus accumbens, including dopamine release and alterations in dopamine and opioid receptor expression. Therefore, we hypothesized that binge-like consumption on intermittent access schedules is dependent on opioid and/or dopamine neurotransmission in the accumbens. To test this hypothesis, we asked whether injection of dopamine and opioid receptor antagonists into the core and shell of the accumbens reduced consumption of a sweet high-fat liquid in rats with and without a history of intermittent binge access to the liquid. Although injection of a μ opioid agonist increased consumption, none of the antagonists (including μ opioid, δ opioid, κ opioid, D1 dopamine and D2 dopamine receptor antagonists, as well as the broad-spectrum opioid receptor antagonist naltrexone) reduced consumption, and this was the case whether or not the animals had a prior history of intermittent access. These results suggest that consumption of sweet, fatty food does not require opioid or dopamine receptor activation in the accumbens even under intermittent access conditions that resemble human binge episodes.

  20. Alterations in nigral NMDA and GABAA receptor control of the striatal dopamine level after repetitive exposures to nitrogen narcosis.

    Science.gov (United States)

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

    2008-07-01

    Nitrogen pressure exposure in rats results in decreased dopamine (DA) release at the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, demonstrating the narcotic potency of nitrogen. This effect is attributed to decreased excitatory and increased inhibitory inputs to dopaminergic neurons, involving a change in NMDA and GABA(A) receptor function. We investigated whether repetitive exposures to nitrogen modify the excitatory and inhibitory control of the dopaminergic nigro-striatal pathway. We used voltammetry to measure dopamine levels in freely-moving rats, implanted with dopamine-sensitive electrodes in the striatum. NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) were administered through a guide-cannula into the SNc, and their effects on striatal dopamine levels were measured under normobaric conditions, before and after five repetitive exposures to 1 MPa nitrogen. NMDA-mediated dopamine release was greater following repetitive exposures, AP7-mediated inhibition of glutamatergic input was blocked, suggesting that NMDA receptor sensitivity was increased and glutamate release reduced. Muscimol did not modify dopamine levels following repetitive exposures, whereas the effect of gabazine was greater after exposures than before. This suggested that interneuronal GABA(A) receptors were desensitized, leading to an increased GABAergic input at dopaminergic cells. Thus, repetitive nitrogen exposure induced persistent changes in glutamatergic and GABAergic control of dopaminergic neurons, resulting in decreased activity of the nigrostriatal pathway.

  1. The effect of Dopamine receptor agonists on twich response of Guinea-pig ileum longitudinal muscle and its relation to Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Keshavarz M

    1998-09-01

    Full Text Available In this study the effects of bromocriptine and apomorphine (dopamine receptor agonists on electrical field induced twitch response of longitudinal muscle of guinea-pig illeum was investigated. Bromocriptine and apomorphine dose dependently inhibited illeal contraction. IC50 for this inhibitory effects were 6.22±0.645×10^-7 M and 5.48±0.647×10^-6 M, respectively. sulpiride (a specific D2 dopamine receptor antagonist with concentration of 10^-5 M inhibited the effects of these agonists. Yohimbine (an ?2 adrenergic receptor antagonist only blocked the inhibitory effect of bromocriptine but failed to block apomorphine inhibitory effects. L-NAME (nitric oxide synthetase inhibitor with concentration of 10^-3 M blocked the effects of bromocriptine and apomorphine. These data suggest that there is inhibitory presynaptic dopamine receptors in cholinergic terminals of guinea-pig ileum and its function is related to formation of nitric oxide.

  2. Dopamine-Secreting Paraganglioma in the Retroperitoneum.

    Science.gov (United States)

    Matsuda, Yusuke; Kimura, Noriko; Yoshimoto, Takanobu; Sekiguchi, Yoshihiro; Tomoishi, Junzo; Kasahara, Ichiro; Hara, Yoshihito; Ogawa, Yoshihiro

    2017-03-01

    Pheochromocytomas and paragangliomas, which exclusively produce dopamine, are very rare. Herein, we report for the first time a Japanese case of an exclusively dopamine-producing paraganglioma accompanied by detailed immunohistochemical analyses. A 70-year-old Japanese woman was referred to our hospital for functional examination of her left retroperitoneal mass. Her adrenal functions were normal, except for excessive dopamine secretion. After the tumorectomy, her dopamine level normalized. The histopathological diagnosis of the tumor was paraganglioma; this was confirmed by positive immunostaining of chromogranin A (CgA), tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), and succinate dehydrogenase gene subunit B (SDHB). However, the immunostaining of CgA in the tumor cells showed peculiar dot-like staining located corresponding to Golgi complex in the perinuclear area, rather than the diffuse cytoplasmic staining usually observed in epinephrine- or norepinephrine-producing functional pheochromocytomas and paragangliomas. The immunohistochemical results suggested that the tumor cells had sparse neuroendocrine granules in the cytoplasm, resulting in inhibition of catecholamine synthesis from dopamine to norepinephrine in neurosecretory granules. This may be the mechanism responsible for exclusive dopamine secretion in the present case.

  3. 17 CFR 270.35d-1 - Investment company names.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Investment company names. 270... (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.35d-1 Investment company names. (a... words “United States” or “U.S. government.” (2) Names suggesting investment in certain investments...

  4. On the D1-D5 conformal field theory

    Science.gov (United States)

    Dijkgraaf, Robbert

    2000-03-01

    I give a review of some aspects of the D1-D5 conformal field theory that is dual to string theory on AdS 3 . Particular attention is paid to the gravitational interpretation of the elliptic genus as a sum over 3-manifolds.

  5. 26 CFR 31.3231(d)-1 - Service.

    Science.gov (United States)

    2010-04-01

    ... Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Railroad Retirement Tax Act (Chapter 22, Internal Revenue Code of 1954) General Provisions § 31.3231(d)-1 Service....

  6. Rescue of cyclin D1 deficiency by knockin cyclin E

    NARCIS (Netherlands)

    Geng, Y.; Whoriskey, W.; Park, M.Y.; Bronson, R.T.; Medema, R.H.; Li, T.; Weinberg, R.A.; Sicinski, P.

    1999-01-01

    D-type cyclins and cyclin E represent two very distinct classes of mammalian G1 cyclins. We have generated a mouse strain in which the coding sequences of the cyclin D1 gene (Ccnd1) have been deleted and replaced by those of human cyclin E (CCNE). In the tissues and cells of these mice, the expressi

  7. Underground storage tank 511-D1U1 closure plan

    Energy Technology Data Exchange (ETDEWEB)

    Mancieri, S.; Giuntoli, N.

    1993-09-01

    This document contains the closure plan for diesel fuel underground storage tank 511-D1U1 and appendices containing supplemental information such as staff training certification and task summaries. Precision tank test data, a site health and safety plan, and material safety data sheets are also included.

  8. Block Cipher Analysis

    DEFF Research Database (Denmark)

    Miolane, Charlotte Vikkelsø

    Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto en...... on small scale variants of AES. In the final part of the thesis we present a new block cipher proposal Present and examine its security against algebraic and differential cryptanalysis in particular.......Block ciphersarecryptographicprimitivesthatoperateon fixed sizetexts(blocks). Mostdesigns aim towards secure andfastencryption oflarge amounts ofdata. Block ciphers also serve as the building block of a number of hash functions and message authentication codes(MAC).Thetask of cryptanalysisisto...... ensurethat no attack violatesthe securitybounds specifiedbygeneric attack namely exhaustivekey search and table lookup attacks. This thesis contains a general introduction to cryptography with focus on block ciphers and important block cipher designs, in particular the Advanced Encryption Standard...

  9. Electrified Fluctuations in D1$\\bot$D3 and D1$\\bot$D5 Systems

    CERN Document Server

    Douari, Jamila

    2008-01-01

    We present the physical phenomenon of the subject discussed in the paper \\cite{fluc}. In that paper we dealt with the fluctuations of funnel solutions of intersecting D1 and D3 branes and the electric field $E$ was considered as very high value causing the results to be non-physical. In the present work, the variation interval of $E$ is to be $[0,\\frac{1}{\\lambda}[$. Then, we extend the study to discuss the overall transverse fluctuations of electrified funnel solutions of D1$\\bot$D5 system in the flat background. The boundary conditions are found to be Neumann boundary conditions.

  10. Cellular regulation of the dopamine transporter

    DEFF Research Database (Denmark)

    Eriksen, Jacob

    2010-01-01

    The dopamine transporter (DAT) mediates reuptake of dopamine from the synaptic cleft and is a target for widely abused psychostimulants such as cocaine and amphetamine. Nonetheless, little is known about the cellular distribution and trafficking of natively expressed DAT. DAT and its trafficking...... in heterologous cells and in cultured DA neurons. DAT has been shown to be regulated by the dopamine D2 receptor (D2R), the primary target foranti-psychotics, through a direct interaction. D2R is among other places expressed as an autoreceptor in DA neurons. Transient over-expression of DAT with D2R in HEK293...

  11. Medial prefrontal cortex dopamine controls the persistent storage of aversive memories

    Science.gov (United States)

    Gonzalez, María C.; Kramar, Cecilia P.; Tomaiuolo, Micol; Katche, Cynthia; Weisstaub, Noelia; Cammarota, Martín; Medina, Jorge H.

    2014-01-01

    Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus. PMID:25506318

  12. Medial prefrontal cortex dopamine controls the persistent storage of aversive memories

    Directory of Open Access Journals (Sweden)

    María Carolina Gonzalez

    2014-11-01

    Full Text Available Medial prefrontal cortex (mPFC is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-tem aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 hour later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long-lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus.

  13. Evidence for dopamine D-2 receptors on cholinergic interneurons in the rat caudate-putamen

    Energy Technology Data Exchange (ETDEWEB)

    Dawson, V.L.; Dawson, T.M.; Filloux, F.M.; Wamsley, J.K.

    1988-01-01

    The aziridinium ion of ethylcholine (AF64A) is a neurotoxin that has demonstrated selectivity for cholinergic neurons. Unilateral stereotaxic injection of AF64A into the caudate-putamen of rats, resulted in a decrease in dopamine D-2 receptors as evidenced by a decrease in (/sup 3/H)-sulpiride binding. Dopamine D-1 receptors, labeled with (/sup 3/H)-SCH 23390, were unchanged. The efficacy of the lesion was demonstrated by the reduction of Na/sup +/-dependent high affinity choline uptake sites labeled with (/sup 3/H)-hemicholinium-3. These data indicate that a population of D-2 receptors are postsynaptic on cholinergic interneurons within the striatum of rat brain.

  14. Dopamine receptor DOP-4 modulates habituation to repetitive photoactivation of a C. elegans polymodal nociceptor.

    Science.gov (United States)

    Ardiel, Evan L; Giles, Andrew C; Yu, Alex J; Lindsay, Theodore H; Lockery, Shawn R; Rankin, Catharine H

    2016-10-01

    Habituation is a highly conserved phenomenon that remains poorly understood at the molecular level. Invertebrate model systems, like Caenorhabditis elegans, can be a powerful tool for investigating this fundamental process. Here we established a high-throughput learning assay that used real-time computer vision software for behavioral tracking and optogenetics for stimulation of the C. elegans polymodal nociceptor, ASH. Photoactivation of ASH with ChR2 elicited backward locomotion and repetitive stimulation altered aspects of the response in a manner consistent with habituation. Recording photocurrents in ASH, we observed no evidence for light adaptation of ChR2. Furthermore, we ruled out fatigue by demonstrating that sensory input from the touch cells could dishabituate the ASH avoidance circuit. Food and dopamine signaling slowed habituation downstream from ASH excitation via D1-like dopamine receptor, DOP-4. This assay allows for large-scale genetic and drug screens investigating mechanisms of nociception modulation.

  15. Dopamine agonist suppression of rapid-eye-movement sleep is secondary to sleep suppression mediated via limbic structures

    Energy Technology Data Exchange (ETDEWEB)

    Miletich, R.S.

    1985-01-01

    The effects of pergolide, a direct dopamine receptor agonist, on sleep and wakefulness, motor behavior and /sup 3/H-spiperone specific binding in limbic structures and striatum in rats was studied. The results show that pergolide induced a biphasic dose effect, with high doses increasing wakefulness and suppressing sleep while low dose decreased wakefulness, but increased sleep. It was shown that pergolide-induced sleep suppression was blocked by ..cap alpha..-glupenthixol and pimozide, two dopamine receptor antagonists. It was further shown that pergolide merely delayed the rebound resulting from rapid-eye-movement (REM) sleep deprivation, that dopamine receptors stimulation had no direct effect on the period, phase or amplitude of the circadian rhythm of REM sleep propensity and that there was no alteration in the coupling of REM sleep episodes with S/sub 2/ episodes. Rapid-eye-movement sleep deprivation resulted in increased sensitivity to the pergolide-induced wakefulness stimulation and sleep suppression and pergolide-induced motor behaviors of locomotion and head bobbing. /sup 3/H-spiperone specific binding to dopamine receptors was shown to be altered by REM sleep deprivation in the subcortical limbic structures. It is concluded that the REM sleep suppressing action of dopamine receptor stimulation is secondary to sleep suppression per se and not secondary to a unique effect on the REM sleep. Further, it is suggested that the wakefulness stimulating action of dopamine receptor agonists is mediated by activation of the dopamine receptors in the terminal areas of the mesolimbocortical dopamine projection system.

  16. High-Fat-Diet-Induced Deficits in Dopamine Terminal Function Are Reversed by Res