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Sample records for apomorphine

  1. Apomorphine and its esters

    DEFF Research Database (Denmark)

    Borkar, Nrupa; Chen, Zhizhong; Saaby, Lasse;

    2016-01-01

    Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson's disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine...

  2. Schizophrenic Symptoms Improve with Apomorphine

    Science.gov (United States)

    Tamminga, Carol A.; And Others

    1978-01-01

    In eighteen chronic schizophrenics, subcutaneous doses of the dopamine reception agonist, apomorphine, improved psychotic symptoms. The results are interpreted as a consequence of presynaptic dopamine receptor activationby apomorphine with a subsequent decrease in dopamine-mediated neural transmission. (Author/BB)

  3. Oxidative behaviour of apomorphine and its metabolites

    OpenAIRE

    Garrido, J. M. P. J.; C. Delerue-Matos; Borges, M. F. M.; Macedo, T. R. A.; Oliveira-Brett, A. M.

    2002-01-01

    The metabolism of apomorphine is quite complex due to interactions with proteins and other tissue components that affect its pharmacokinetic profile. The electrochemical oxidation mechanism of apomorphine and of some synthesised apomorphine derivatives was studied. It was found to be related to the reaction of o-diphenol and tertiary amine groups and strongly dependent on pH.

  4. A study of tolerance to apomorphine.

    OpenAIRE

    Montastruc, J. L.; Llau, M. E.; Senard, J. M.; Tran, M. A.; Rascol, O; Montastruc, P.

    1996-01-01

    1. The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2. Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 micrograms kg-1, i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloralose-anaesthetized dogs. 3. The first administration of apomorphine induced a s...

  5. Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

    OpenAIRE

    Picada J.N.; Roesler R.; Henriques J.A.P.

    2005-01-01

    Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laborator...

  6. Apomorphine

    Science.gov (United States)

    ... action of dopamine, a natural substance in the brain that is lacking in patients with PD. ... depression confusion abnormal behavior change in vision painful erection that does not go away Some laboratory animals ...

  7. Apomorphine

    Science.gov (United States)

    ... not use a cartridge containing a cloudy or green solution or a solution containing particles. If the ... Sorbitrate), isosorbide mononitrate (Imdur, ISMO), or nitroglycerin (Nitro-BID, nitro-Dur, Nitroquick, Nitrostat, others). Nitrates come as ...

  8. Apomorphine induced cognitive changes in Parkinson's disease.

    OpenAIRE

    Růzicka, E; Roth, J.; Spacková, N; Mecír, P; Jech, R.

    1994-01-01

    Auditory event related potentials (ERPs) and visual evoked potentials (VEPs) were recorded from eight patients with Parkinson's disease, before and after a single dose of apomorphine. To assess the treatment effects, the patients' motor state, Benton visual retention test (BVRT), and digit span tests were also examined. After apomorphine, although motor performance improved, the ERP latencies were delayed and the N2-P3 ERP amplitude was significantly diminished by comparison with pretreatment...

  9. The apomorphine test in parkinsonian syndromes.

    OpenAIRE

    D'Costa, D F; Abbott, R J; Pye, I F; Millac, P A

    1991-01-01

    The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and ...

  10. New insights into the oxidation pathways of apomorphine

    OpenAIRE

    Garrido, Jorge; Delerue-Matos, Cristina; Borges, Fernanda; Macedo, Tice R. A.; Oliveira-Brett, A. M.

    2002-01-01

    A detailed study of the oxidative behaviour of apomorphine in aqueous media is reported. Resorting to the synthesis of apomorphine derivatives it was possible to identify all the anodic oxidation peaks of apomorphine, which are related to the oxidation of the catechol and tertiary amine groups. These findings were revealed to be important since they could lead to a better understanding of the biological interactions of apomorphine and gain insight into its metabolic pathways. Duri...

  11. Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

    Directory of Open Access Journals (Sweden)

    Picada J.N.

    2005-01-01

    Full Text Available Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ, were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites.

  12. Au nanoparticle-based sensor for apomorphine detection in plasma

    Directory of Open Access Journals (Sweden)

    Chiara Zanchi

    2015-11-01

    Full Text Available Artificially roughened gold surfaces with controlled nanostructure produced by pulsed laser deposition have been investigated as sensors for apomorphine detection aiming at clinical application. The use of such gold surfaces has been optimized using aqueous solutions of apomorphine in the concentration range between 3.3 × 10−4 M and 3.3 × 10−7 M. The experimental parameters have been investigated and the dynamic concentration range of the sensor has been assessed by the selection of two apomorphine surface enhanced Raman scattering (SERS peaks. The sensor behavior used to detect apomorphine in unfiltered human blood plasma is presented and discussed.

  13. Clinical insights into use of apomorphine in Parkinson's disease

    DEFF Research Database (Denmark)

    Henriksen, Tove

    2014-01-01

    Apomorphine was introduced before the era of levodopa as a treatment for idiopathic Parkinson's disease (iPD). A number of practical obstacles were to be solved before a wider use of the drug was possible. Today, however, the drug is probably still underutilized. Apomorphine is a strong nonergoline...

  14. Selective labeling of apomorphine receptors by 3H-LSD

    International Nuclear Information System (INIS)

    There are at least two types of dopamine receptors: the 3H-dopamine or 3H-apomorphine receptor (with high or nM affinity for dopamine), and the 3H-neuroleptic receptor (with low or μm affinity for dopamine). While 3H-LSD can label the 3H-neuroleptic receptor, this study was done in order to label the 3H-apomorphine/dopamine receptor site. In the presence of excess phentolamine, serotonin and spiperone (to preculude binding to α-adrenergic, serotonergic and neuroleptic receptors, respectively) similar concentrations of dopaminergic drugs inhibited the binding (to calf caudate) of 3H-LSD and 3H-apomorphine. This is compatible with the concept that the 3H-apomorphine/dopamine receptor and the 3H-neuroleptic/dopamine receptor are separate. (Auth.)

  15. The motor response to sequential apomorphine in parkinsonian fluctuations.

    OpenAIRE

    Hughes, A J; A. J. Lees; Stern, G M

    1991-01-01

    Fifteen patients with Parkinson's disease and levodopa-induced motor fluctuations, were studied with repeated injections of apomorphine using two protocols to explore possible changes in the duration of motor response. One involved different interdose intervals; in the other, doses were given when the motor effects induced by the previous dose had just worn off. No significant change in the duration of motor response to sequential subcutaneous apomorphine with either protocol was found. The r...

  16. Au nanoparticle-based sensor for apomorphine detection in plasma

    OpenAIRE

    Chiara Zanchi; Andrea Lucotti; Matteo Tommasini; Sebastiano Trusso; Ugo de Grazia; Emilio Ciusani; Paolo M. Ossi

    2015-01-01

    Artificially roughened gold surfaces with controlled nanostructure produced by pulsed laser deposition have been investigated as sensors for apomorphine detection aiming at clinical application. The use of such gold surfaces has been optimized using aqueous solutions of apomorphine in the concentration range between 3.3 × 10−4 M and 3.3 × 10−7 M. The experimental parameters have been investigated and the dynamic concentration range of the sensor has been assessed by the selection of two apomo...

  17. Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?

    OpenAIRE

    Dépatie, L; Lal, S

    2001-01-01

    The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic sy...

  18. Interactions of apomorphine with serum and tissue proteins

    Energy Technology Data Exchange (ETDEWEB)

    Smith, R.V.; Velagapudi, R.B.; McLean, A.M.; Wilcox, R.E.

    1985-05-01

    Physical and covalent interactions of apomorphine with serum and tissue proteins could influence the drug's disposition and pharmacological activities in mammals. Ultrafiltration, equilibrium dialysis, and ultraviolet spectrophotometric methods have been used to study the reversible binding of apomorphine to bovine, human, rat, and swine plasma proteins. The degree of binding was generally greater than 90%, but variations were noted in some instances on the basis of drug concentrations and pH over the range of 6.8-7.8. Incubation of (8,9-/sup 3/H2)apomorphine with bovine serum albumin led to retention of radioactivity and a stoichiometrically controlled released of tritium which arose from the reaction of an electrophilic drug oxidation product and protein, producing drug-protein conjugates. In vitro experiments with mouse striatal brain preparations indicated parallel covalent binding reactions. In vivo experiments in mice indicated accumulation of radioactivity in brain regions and other tissues following daily injections of (8,9-/sup 3/H2)apomorphine for 14 days. The physical and covalent interactions of apomorphine with mammalian tissue proteins could be the cause of longer disposition half-lives in mammals than those previously reported. The covalent interactions, in particular, may be important in elucidating the mechanism of apomorphine-induced behavioral effects in mice.

  19. Pen injected apomorphine against off phenomena in late Parkinson's disease: a double blind, placebo controlled study.

    OpenAIRE

    Ostergaard, L; Werdelin, L.; Odin, P; Lindvall, O; Dupont, E.; Christensen, P. B.; Boisen, E; Jensen, N B; Ingwersen, S H; Schmiegelow, M

    1995-01-01

    The effect, therapeutic dose range, and pharmacokinetics of apomorphine, given as subcutaneous injections by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathic Parkinson's disease. At study entry a placebo controlled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3.4 (range 0.8-6.0) mg) and compared with placebo in a double blind cross over phase. With apomorphine compared with placebo the mean daily d...

  20. Somatosensory Evoked Potentials and Dopaminergic Responsiveness to Apomorphine and Levodopa in Parkinsonian Patients

    OpenAIRE

    Miranda, M.; J. L. Castillo; Araya, F.

    1996-01-01

    Short-latency somatosensory evoked potentials (SSEPs) were recorded from 10 parkinsonian patients in ‘off’ and ‘on’ states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p

  1. Assessment of erectogenic properties of apomorphine and yohimbine in man.

    OpenAIRE

    Danjou, P; Alexandre, L; Warot, D.; Lacomblez, L; Puech, A. J.

    1988-01-01

    1. In a four period, double-blind, placebo-controlled study, apomorphine (0.009 mg kg-1 subcutaneous route) and yohimbine (0.30 mg kg-1 i.v. route) were administered to 10 male healthy volunteers. Penile circumference was monitored using plethysmography and subjective sexual arousal was self-assessed. Data were collected before, during and after a stimulation session during which 50 erotic slides were projected to the subjects. 2. Apomorphine induced an erection starting from the fourth minut...

  2. Reinforcer Magnitude Attenuates Apomorphine's Effects on Operant Pecking

    Science.gov (United States)

    Pinkston, Jonathan W.; Lamb, R. J.

    2012-01-01

    When given to pigeons, the direct-acting dopamine agonist apomorphine elicits pecking. The response has been likened to foraging pecking because it bears remarkable similarity to foraging behavior, and it is enhanced by food deprivation. On the other hand, other data suggest the response is not related to foraging behavior and may even interfere…

  3. Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats.

    NARCIS (Netherlands)

    Elst, M.C.J. van der; Wunderink, Y.S.; Ellenbroek, B.A.; Cools, A.R.

    2007-01-01

    BACKGROUND: Amphetamine is often used to mimic certain aspects of schizophrenia in laboratory animals, such as a decreased prepulse inhibition. MATERIALS AND METHODS: Apomorphine-susceptible and apomorphine-unsusceptible rats represent a well-characterized animal model for individual differences in

  4. Apomorphine-susceptible and apomorphine-unsusceptible rats as model for High-resisting and Low-resisting pigs: Metabolic differences

    NARCIS (Netherlands)

    Degen, S.B.; Hof, M.W.P.; Gerrits, W.J.J.; Heetkamp, M.J.W.; Cools, A.R.

    2003-01-01

    This study was undertaken to provide detailed information on the energy metabolism of apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats, a model for High-resisting (HR) and Low-Resisting (LR) pigs, respectively. It is known that HR and LR pigs differ in the partitionin

  5. Somatosensory Evoked Potentials and Dopaminergic Responsiveness to Apomorphine and Levodopa in Parkinsonian Patients

    Directory of Open Access Journals (Sweden)

    M. Miranda

    1996-01-01

    Full Text Available Short-latency somatosensory evoked potentials (SSEPs were recorded from 10 parkinsonian patients in ‘off’ and ‘on’ states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p

  6. Behavioral sensitization to apomorphine in pigeons (Columba livia) : blockade by the D₁ dopamine antagonist SCH-23390

    OpenAIRE

    Acerbo, Martin J.; Delius, Juan

    2004-01-01

    Repeated administration of apomorphine leads to a context-dependent pecking response sensitization. Previously sensitized pigeons (Columba livia) challenged with saline in the same context show a conditioned response (CR). The authors studied the effects of intrastriatal injections of the dopamine (D₁) antagonist SCH-23390 on both the sensitized response and the CR. When coadministered with apomorphine, SCH-23390 inhibited the initial response to apomorphine, prevented the development of sens...

  7. Role of Dopamine Receptors on Electroencephalographic Changes Produced by Repetitive Apomorphine Treatments in Rats

    OpenAIRE

    Jang, Hwan Soo; Kim, Ji Young; Kim, Sang Heon; Lee, Maan-Gee

    2009-01-01

    Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal pe...

  8. Use of apomorphine in Parkinsonian patients with neuropsychiatric complications to oral treatment

    OpenAIRE

    Ellis, C; Lemmens, Gilbert; Parkes, J D; Abbott, R J; Pye, I F; Leigh, P. N.; Chaudhuri, K.R.

    1997-01-01

    Neuropsychiatric side effects often complicate anti-Parkinsonian therapy and pose a significant problem in the optimal management of idiopathic Parkinson's disease. Several publications report a relative lack of neuropsychiatric side effects in Parkinsonian patients treated with subcutaneous apomorphine. To investigate this further, we have used subcutaneous apomorphine to treat 12 non-demented IPD patients with previous oral drug-related neuropsychiatric problems. Treatment with apomorphine ...

  9. Electronic and vibrational circular dichroism spectra of (R)-(-)-apomorphine

    Energy Technology Data Exchange (ETDEWEB)

    Abbate, Sergio, E-mail: abbate@med.unibs.it [Dipartimento di Scienze Biomediche e Biotecnologie, Universita di Brescia, Viale Europa 11, 25123 Brescia (Italy); CNISM, Consorzio Interuniversitario Scienze Fisiche della Materia, Via della Vasca Navale 84, 00146 Roma (Italy); Longhi, Giovanna; Lebon, France [Dipartimento di Scienze Biomediche e Biotecnologie, Universita di Brescia, Viale Europa 11, 25123 Brescia (Italy); CNISM, Consorzio Interuniversitario Scienze Fisiche della Materia, Via della Vasca Navale 84, 00146 Roma (Italy); Tommasini, Matteo [Dipartimento di Chimica, Materiali e Ingegneria Chimica ' G. Natta' , Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano (Italy); Consorzio Interuniversitario per la Scienza e Tecnologia dei Materiali (INSTM), Unita di Ricerca del Politecnico di Milano (Dip. CMIC), Piazza Leonardo da Vinci 32, 20133 Milano (Italy)

    2012-09-11

    Highlights: Black-Right-Pointing-Pointer ECD and VCD Spectra of (R)-(-)-apomorphine measured in various solvents. Black-Right-Pointing-Pointer DFT calculations allow to study the protonation state and conformations. Black-Right-Pointing-Pointer Contributions from catechol OH vibrations to the VCD spectra is studied. -- Abstract: Apomorphine is a chiral drug molecule; notwithstanding its extraordinary importance, little attention has been paid to the characterization of its chiroptical properties. Here we report on its electronic circular dichroism (ECD) spectra, recorded in methanol and water, and vibrational circular dichroism (VCD) in methanol and dimethyl sulfoxide (DMSO) solutions. Density functional theory (DFT) calculations have allowed us to interpret the spectra and to evaluate the role of possible conformations, charge-states and interactions with counter ions.

  10. Electronic and vibrational circular dichroism spectra of (R)-(-)-apomorphine

    Science.gov (United States)

    Abbate, Sergio; Longhi, Giovanna; Lebon, France; Tommasini, Matteo

    2012-09-01

    Apomorphine is a chiral drug molecule; notwithstanding its extraordinary importance, little attention has been paid to the characterization of its chiroptical properties. Here we report on its electronic circular dichroism (ECD) spectra, recorded in methanol and water, and vibrational circular dichroism (VCD) in methanol and dimethyl sulfoxide (DMSO) solutions. Density functional theory (DFT) calculations have allowed us to interpret the spectra and to evaluate the role of possible conformations, charge-states and interactions with counter ions.

  11. Apomorphine-induced blinking and yawning in healthy volunteers.

    OpenAIRE

    Blin, O; Masson, G.; Azulay, J P; Fondarai, J; Serratrice, G

    1990-01-01

    Yawning and spontaneous blink rate (SBR) are two physiological reflexes which have been incompletely examined but one neurobiological step of these two behaviours seems, at least in part, dopamine-dependent. The reference dopaminergic agonist, apomorphine hydrochloride (0.5, 1, and 2 micrograms kg-1 s.c.), was compared with a placebo in a double-blind latin-square design, and was shown to induce yawning and increase SBR in a population of eight healthy volunteers. These two behavioral effects...

  12. REINFORCER MAGNITUDE ATTENUATES: APOMORPHINE'S EFFECTS ON OPERANT PECKING

    OpenAIRE

    Pinkston, Jonathan W; Lamb, R J

    2012-01-01

    When given to pigeons, the direct-acting dopamine agonist apomorphine elicits pecking. The response has been likened to foraging pecking because it bears remarkable similarity to foraging behavior, and it is enhanced by food deprivation. On the other hand, other data suggest the response is not related to foraging behavior and may even interfere with food ingestion. Although elicited pecking interferes with food capture, it may selectively alter procurement phases of feeding, which can be iso...

  13. Turmeric active substance, curcumin, enhanced apomorphine-induced yawning in rats

    Directory of Open Access Journals (Sweden)

    Esmaeal Tamaddonfard

    2013-05-01

    Full Text Available Objective: Curcumin is a major constituent of turmeric and influences many functions of the brain. In the present study, we investigated the effect of curcumin on yawning induced by apomorphine in rats. Materials and Methods: Curcumin administered orallyfor 10 consecutive days. Yawning was induced by subcutaneous (s.c. injection of apomorphine (a dopamine receptor agonist and the number of yawns was recorded for a period of 30 min. Results: Apomorphine (0.05 and 0.1 mg/kg produced yawning. Haloperidol (a dopamine receptors antagonist at a dose of 0.05 mg/kg partially and at a dose of 0.2 mg/kg completely inhibited apomorphine-induced yawning. Curcumin alone produced no yawning, whereas at doses of 30 and 60 mg/kg, it increased yawning induced by 0.1 mg/kg of apomorphine. Curcumin at the high doses (30 and 60 mg/kg produced yawning when apomorphine (0.1 mg/kg action was partially blocked with 0.5 mg/kg of haloperidol. In the presence of complete blockade of apomorphine (0.1 mg/kg action with 0.2 mg/kg of haloperidol, curcumin did not produce yawning. Conclusion: The results showed that curcumin at high doses increased apomorphine-induced yawning. In the presence of partial, but not complete blockade of apomorphine action, curcumin produced yawning. Curcumin produced a dopamine-like effect on yawning.

  14. Apomorphine and its esters: Differences in Caco-2 cell permeability and chylomicron affinity.

    Science.gov (United States)

    Borkar, Nrupa; Chen, Zhizhong; Saaby, Lasse; Müllertz, Anette; Håkansson, Anders E; Schönbeck, Christian; Yang, Mingshi; Holm, René; Mu, Huiling

    2016-07-25

    Oral delivery of apomorphine via prodrug principle may be a potential treatment for Parkinson's disease. The purpose of this study was to investigate the transport and stability of apomorphine and its esters across Caco-2 cell monolayer and their affinity towards chylomicrons. Apomorphine, monolauroyl apomorphine (MLA) and dilauroyl apomorphine (DLA) were subjected to apical to basolateral (A-B) and basolateral to apical (B-A) transport across Caco-2 cell monolayer. The stability of these compounds was also assessed by incubation at intestinal pH and physiological pH with and without Caco-2 cells. Molecular dynamics (MD) simulations were performed to understand the stability of the esters on a molecular level. The affinity of the compounds towards plasma derived chylomicrons was assessed. The A-B transport of intact DLA was about 150 times lower than the transport of apomorphine. In contrast, MLA was highly unstable in the aqueous media leading to apomorphine appearance basolaterally. MD simulations possibly explained the differences in hydrolysis susceptibilities of DLA and MLA. The affinity of apomorphine diesters towards plasma derived chylomicrons provided an understanding of their potential lymphatic transport. The intact DLA transport is not favorable; therefore, the conversion of DLA to MLA is an important step for intestinal apomorphine absorption. PMID:27282537

  15. Subcutaneous apomorphine infusion in Parkinson's disease: does it have a role?

    OpenAIRE

    Muhiddin, K. A.; Roche, M. T.; Pearce, V. R.

    1994-01-01

    Apomorphine is a potent dopamine agonist at both D1 and D2 receptors and has been used successfully for treating the 'on/off' phenomenon in Parkinson's disease. We report our experience with apomorphine in treating the 'on/off' phenomenon in L-dopa responsive idiopathic Parkinson's disease. Thirteen such patients were commenced on apomorphine infusions. Their mean age was 69 (range 53-80) years and the mean duration of the disease was 15 (range 6-28) years. The clinical response to apomorphin...

  16. Effects of acute and chronic apomorphine on sex behavior and copulation-induced neural activation in the male rat

    NARCIS (Netherlands)

    Olivier, Jocelien D A; de Jong, Trynke R; Jos Dederen, P; van Oorschot, Ruud; Heeren, Dick; Pattij, Tommy; Waldinger, Marcel D; Coolen, Lique M; Cools, Alexander R; Olivier, Berend; Veening, Jan G

    2007-01-01

    Apomorphine is a non-selective dopaminergic receptor agonist. Because of its pro-erectile effects, apomorphine is clinically used for treatment of erectile dysfunction. We investigated the effects of subcutaneous apomorphine administration (0.4 mg/kg rat) on sexual behavior and mating-induced Fos-ex

  17. AUTOSOMAL AND Y-CHROMOSOMAL EFFECTS ON THE STEREOTYPED RESPONSE TO APOMORPHINE IN WILD HOUSE MICE

    NARCIS (Netherlands)

    SLUYTER, F; BOHUS, B; BELDHUIS, HJA; VANOORTMERSSEN, GA

    1995-01-01

    The behavioral response to apomorphine, a dopamine agonist, was shown to be different between a selection line characterized by Short Attack Latencies (SAL) and a selection line having Long Attack Latencies (LAL) (4). Aggressive SAL mice were more sensitive to apomorphine than nonaggressive LAL male

  18. Nucleus basalis prosencephali, a substrate of apomorphine-induced pecking in pigeons

    OpenAIRE

    Delius, Juan; Lindenblatt, Ulrike

    1988-01-01

    Microinjections of the dopamine agonist apomorphine into the nucleus basalis prosencephali of pigeons elicit stereotyped pecking behaviour. Injections of 6-hydroxydopamine, a toxic dopamine antagonist, into the same nucleus impair stereotyped pecking induced by systemic apomorphine administration, but do not interfere with pecking in the normal feeding context.

  19. Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

    International Nuclear Information System (INIS)

    Highlights: •Ebselen, chelerythrine and apomorphine were identified as glutaminase inhibitors. •These had greater affinities and efficiency of inhibition than known prototypes. •Their previously reported biological activity could be due to glutaminase inhibition. -- Abstract: Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC1280)) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease

  20. Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, Ajit G.; Rojas, Camilo [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tanega, Cordelle; Shen, Min; Simeonov, Anton; Boxer, Matthew B.; Auld, Douglas S. [National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850 (United States); Ferraris, Dana V. [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Tsukamoto, Takashi [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Slusher, Barbara S., E-mail: bslusher@jhmi.edu [Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States)

    2013-08-23

    Highlights: •Ebselen, chelerythrine and apomorphine were identified as glutaminase inhibitors. •These had greater affinities and efficiency of inhibition than known prototypes. •Their previously reported biological activity could be due to glutaminase inhibition. -- Abstract: Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC{sup 1280})) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.

  1. Subcutaneous apomorphine in the treatment of Parkinson's disease.

    OpenAIRE

    Frankel, J P; Lees, A. J.; Kempster, P A; Stern, G M

    1990-01-01

    Apomorphine a dopamine receptor agonist was given subcutaneously to 57 levodopa treated parkinsonian patients with refractory off-period disabilities for a median period of 16 months. In 30 given intermittent suprathreshold injections the mean number of hours spent in a disabling off state fell from 6.9 to 2.9. Similar benefit was observed in 21 patients receiving continuous infusions with additional boluses on demand by mini-pump (mean reduction of hours off from 9.9 to 4.5). Twelve patients...

  2. Relationship of Dopamine of the Nucleus Accumbens with Intra-infralimbic Apomorphine Microinjection

    Directory of Open Access Journals (Sweden)

    Abbas Alimoradian

    2013-06-01

    Full Text Available   Objective(s: The dopamine level of the nucleus accumbens changes during some stereotyped behaviors. To study dopamine level of the nucleus accumbens in intra infralimbic apomorphine-induced climbing, microdialysis probes were implanted into the nucleus accumbens shell of male Sprague Dawley rats weighting 275–400 g.   Materials and Methods: The rats were divided into two groups (apomorphine and control of least eleven rats in each group. Apomorphine at dose of 5 μg/0.5 μl or its vehicle was microinjected into the infralimbic in apomorphine and control groups respectively. Then, changes in dopamine levels in the nucleus accumbens shell were monitored. The concentration of dopamine was measured by High-Performance Liquid Chromatography-Electochemical (HPLC-ECD. Finally, the stereotyped behaviors were recorded. Results: The mean of dopamine levels for all of after microinjection period in control and drug groups were 450% and 150% respectively compared to those of before microinjection period. However, there was no significant difference between groups of apomorphine and control. In addition, the return of dopamine level to the baseline was faster in apomorphine group than the control group. Conclusion: The intra infralimbic apomorphine -induced climbing at dose of 5 μg/0.5 μl was not modulated via the increase of dopamine level in the nucleus accumbens area.

  3. MCH and apomorphine in combination enhance action potential firing of nucleus accumbens shell neurons in vitro

    Directory of Open Access Journals (Sweden)

    F Woodward Hopf

    2013-04-01

    Full Text Available The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for some aspects of schizophrenia. Importantly, MCH can enhance the effects of lower doses of apomorphine, suggesting that co-modulation of dopamine and MCH receptors might alleviate some symptoms of schizophrenia with a lower dose of dopamine receptor modulator and thus fewer potential side effects. Here, we investigated whether MCH and apomorphine could enhance action potential firing in vitro in the nucleus accumbens shell (NAshell, a region which has previously been shown to mediate some behavioral effects of MCH. Using whole-cell patch-clamp electrophysiology, we found that MCH, which has no effect on firing on its own, was able to increase NAshell firing when combined with a subthreshold dose of apomorphine. Further, this MCH/apomorphine increase in firing was prevented by an antagonist of either a DA1 or a DA2 receptor, suggesting that apomorphine acts through both receptor types to enhance NAshell firing. The MCH/apomorphine-mediated firing increase was also prevented by an MCH receptor antagonist or a PKA inhibitor. Taken together, our results suggest that MCH can interact with lower doses of apomorphine to enhance NAshell firing, and thus that MCH and apomorphine might interact in vivo within the NAshell to suppress pre-pulse inhibition.

  4. A comparison of motor behaviours in groups of rats distinguished by their climbing response to apomorphine.

    OpenAIRE

    Davis, A.S.; Jenner, P.; Marsden, C. D.

    1986-01-01

    Administration of apomorphine hydrochloride (0.5 mg kg-1 s.c.) to adult male or female Wistar rats previously acclimatized to the test environment induced climbing behaviour in approximately 50% of animals examined. The proportion of animals climbing was related to age, being maximal at 8-9 weeks. Those animals showing an initial climbing response to apomorphine (0.5 mg kg-1 s.c.), climbed when challenged with this dose of apomorphine on subsequent occasions. In 'climbing' animals the intensi...

  5. The effect of apomorphine on exocytosis and metabolic burst of polymorphonuclear leukocytes.

    OpenAIRE

    Elferink, J G

    1987-01-01

    1 In rabbit polymorphonuclear leukocytes (PMNLs) apomorphine at 10-100 microM inhibits fMet-Leu-Phe and A23187-induced exocytosis, and the phorbol myristate acetate- and fMet-Leu-Phe-induced activation of the metabolic burst. The secretory response was not restored by washing the cells after pretreatment with apomorphine. 2 The inhibitory effect of apomorphine was not prevented by the dopamine receptor antagonists haloperidol and pimozide, nor did dopamine itself inhibit fMet-Leu-Phe-induced ...

  6. Turmeric active substance, curcumin, enhanced apomorphine-induced yawning in rats

    OpenAIRE

    Esmaeal Tamaddonfard

    2013-01-01

    Objective: Curcumin is a major constituent of turmeric and influences many functions of the brain. In the present study, we investigated the effect of curcumin on yawning induced by apomorphine in rats. Materials and Methods: Curcumin administered orally for 10 consecutive days. Yawning was induced by subcutaneous (s.c.) injection of apomorphine (a dopamine receptor agonist) and the number of yawns was recorded for a period of 30 min. Results: Apomorphine (0.05 and 0.1 mg/kg) produced yawning...

  7. Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum

    OpenAIRE

    Matsumoto, Kenshi; Yoshida, Masaki; Andersson, Karl-Erik; Hedlund, Petter

    2005-01-01

    The study was performed to clarify if apomorphine at the level of the rat corpus cavernosum can produce erectile responses or interfere with nerve-induced penile erection.Apomorphine (10−9–10−4 M) exhibited a 10-fold higher potency to relax phenylephrine (Phe)- than endothelin-1 (ET-1)-induced contractions. Relaxant effects of apomorphine in Phe-activated corpus cavernosum did not change tissue levels of cyclic nucleotides, and were unaffected by inhibition of the synthesis of nitric oxide, o...

  8. Relationship of Dopamine of the Nucleus Accumbens with Intra-infralimbic Apomorphine Microinjection

    OpenAIRE

    Abbas Alimoradian; Javad Sajedianfard; Faegheh Baha-aldini Beigy; Mohammad Reza Panjehshahin; Ali Akbar Owji

    2013-01-01

      Objective(s): The dopamine level of the nucleus accumbens changes during some stereotyped behaviors. To study dopamine level of the nucleus accumbens in intra infralimbic apomorphine-induced climbing, microdialysis probes were implanted into the nucleus accumbens shell of male Sprague Dawley rats weighting 275–400 g.   Materials and Methods: The rats were divided into two groups (apomorphine and control) of least eleven rats in each group. Apomorphine at dose of 5 μg/0.5 μl or its vehicle w...

  9. Prejunctional actions of piribedil on the isolated kidney of the rabbit: comparison with apomorphine

    OpenAIRE

    Chevillard, C.; Mathieu, M. N.; Recommis, D.

    1980-01-01

    1 The effects of piribedil on contractile responses and noradrenaline release evoked by sympathetic nerve stimulation have been studied in the isolated kidney of the rabbit. These effects were compared to those of apomorphine.

  10. Apomorphine-induced pecking in pigeons classically conditioned to environmental cues

    OpenAIRE

    Delius, Juan; Lindenblatt, Ulrike

    1987-01-01

    The dopamine agonist apomorphine elicits protracted pecking when injected systemically (1 mg/kg) into pigeons. In two experiments it was investigated whether apomorphine would function as an unconditioned stimulus in the classical conditioning of pecking in these animals. An experimental design based on a differentiation procedure was used so that possible pseudoconditioning effects were controlled. Two differently coloured test chambers served as negative (CS-) and positive conditioned (CS+)...

  11. Apomorphine-induced inhibition of histamine release in rat peritoneal mast cells.

    OpenAIRE

    Battistella, A.; Boarato, E.; Bruni, A; Mietto, L.; Palatini, P.; Toffano, G.

    1986-01-01

    The apomorphine-induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation. Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P, ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 microM to 24 microM at concentrations of secretagogues releasing 30-50% of mast cell histamine. Howeve...

  12. Apomorphine and Levodopa Infusion Therapies for Advanced Parkinson’s Disease

    OpenAIRE

    Angelo Antonini

    2009-01-01

    Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson’s disease (PD). Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement...

  13. Repeated apomorphine administration alters dopamine D1 and D2 receptor densities in pigeon basal telencephalon

    OpenAIRE

    Acerbo, Martin J.; Výboh, Pavel; Košťál, Ľubor; Kubíková, Ľubica; Delius, Juan

    2005-01-01

    When pigeons are repeatedly administered a dose of apomorphine they show an increasing behavioral response, much as rodents do. In birds this expresses itself in an augmented pecking response. This sensitization is assumed to be largely due to a conditioning process. Here we present evidence that sensitization is accompanied by an alteration of the D1 to D2 dopamine receptor densities. An experimental group of pigeons was repeatedly injected with apomorphine, and a control group with saline. ...

  14. Chronic subcutaneous infusion with apomorphine in Parkinson's disease: A pharmacological point of view

    OpenAIRE

    Auffret, Manon; Drapier, Sophie; Verin, Marc; Sauleau, Paul

    2016-01-01

    National audience Subcutaneous infusion with apomorphine is one of the treatments available for Parkinson's disease. Even if increasing evidence of its efficacy on both motor and non-motor symptoms is found in the literature, it is still underused. This article reviews pharmacological and pharmacokinetic properties of apomorphine and its impact on clinical decision making. Despite their complexity, those properties are a key to understanding the effect of the drug and its variability of ef...

  15. Comparison of motor response to apomorphine and levodopa in Parkinson's disease.

    OpenAIRE

    Kempster, P A; Frankel, J P; Stern, G M; A. J. Lees

    1990-01-01

    The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's ...

  16. Behavioural differences between artificially selected aggressive and non-aggressive mice: response to apomorphine

    OpenAIRE

    Benus, Rensina F.; Bohus, Bela; Koolhaas, Jaap M.; Oortmerssen, Geert A. van

    1991-01-01

    The present study reports a first attempt to unravel the neurochemical background that underlies the difference in behavioural profiles between aggressive and non-aggressive male mice. For this purpose two bidirectionally selected lines for attack latency (SAL and LAL) were used. In pursuit of another approach, the susceptibility of individuals of both selection lines to the dopamine agonist apomorphine was measured. The apomorphine was injected subcutaneously at dose levels of 2.5 and 5.0 mg...

  17. Lipophilic prodrugs of apomorphine I: Preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media

    DEFF Research Database (Denmark)

    Borkar, Nrupa Nitin; Li, Boyang; Holm, René;

    2015-01-01

    biorelevant media before and after incorporating them into self-emulsifying drug delivery systems (SEDDS) for oral delivery. Two apomorphine diester prodrugs were synthesised: dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA). The in vitro enzymatic hydrolysis of diesters was performed using...... about 4% and 28% of the intact diester, respectively. The incorporation of the diesters into SEDDS reduced the enzymatic degradation of diesters. In addition, the chain length of diester and the type of oil used in formulations affected diester hydrolysis. The lipophilic apomorphine diesters were...

  18. Cocaine strongly reduces prepulse inhibition in apomorphine-susceptible rats, but not in apomorphine-unsusceptible rats: regulation by dopamine D2 receptors.

    NARCIS (Netherlands)

    Elst, M.C.J. van der; Ellenbroek, B.A.; Cools, A.R.

    2006-01-01

    Dopaminergic agonists, such as apomorphine and amphetamine, have been shown to drastically reduce prepulse inhibition of the acoustic startle reflex. The effects of the indirect dopamine agonist cocaine on prepulse inhibition have only been described in a few reports and have yielded conflicting res

  19. A Critical Review of Repurposing Apomorphine for Smoking Cessation.

    Science.gov (United States)

    Morales-Rosado, Joel A; Cousin, Margot A; Ebbert, Jon O; Klee, Eric W

    2015-12-01

    Tobacco use disorder is the leading cause of preventable death and disability in the United States, with one in five Americans currently smoking cigarettes. Only two non-nicotine medications are FDA approved for treating tobacco use disorder, and advances in drug discovery are profoundly outpaced by the morbidity and mortality caused by tobacco dependence. Drug repurposing may provide an approach for addressing this health hazard, offering hope to tobacco users attempting to quit who have failed existing therapies. The focus of this review is to evaluate the potential role of apomorphine (APO) in treating tobacco dependence. Previously described in the literature as a non-specific dopamine agonist effective in treating Parkinson's disease and erectile dysfunction, APO's dopaminergic targeting activity may be effective in counteracting the modified response arising from tobacco use. Here, the literature describing APO's activity is reviewed and presented in the context of known nicotine-induced response in neurotransmitter systems. Based on these data, whether APO may be an effective smoking cessation agent by ameliorating a tobacco user's anhedonic state is critically appraised, along with withdrawal symptoms and the chemical reinforcement associated with drug-seeking behaviors. PMID:26690764

  20. Dopamine transporter genotype dependent effects of apomorphine on cold pain tolerance in healthy volunteers.

    Directory of Open Access Journals (Sweden)

    Roi Treister

    Full Text Available The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105 participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and tolerance were evaluated before and for up to 120 min after the administration of 1.5 mg apomorphine/placebo. A polymorphism (3'-UTR 40-bp VNTR within the dopamine transporter gene (SLC6A3 was investigated. Apomorphine had an effect only on tolerance to cold pain, which consisted of an initial decrease and a subsequent increase in tolerance. An association was found between the enhancing effect of apomorphine on pain tolerance (120 min after its administration and the DAT-1 polymorphism. Subjects with two copies of the 10-allele demonstrated significantly greater tolerance prolongation than the 9-allele homozygote carriers and the heterozygote carriers (p = 0.007 and p = 0.003 in comparison to the placebo, respectively. In conclusion, apomorphine administration produced a decrease followed by a genetically associated increase in cold pain tolerance.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-09-16

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

  2. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease - Clinical practice recommendations

    NARCIS (Netherlands)

    Trenkwalder, Claudia; Chaudhuri, K. Ray; Garcia Ruiz, Pedro J.; LeWitt, Peter; Katzenschlager, Regina; Sixel-Doering, Friederike; Henriksen, Tove; Sesar, Angel; Poewe, Werner; Baker, Mary; Ceballos-Baumann, Andres; Deuschl, Guenther; Drapier, Sophie; Ebersbach, Georg; Evans, Andrew; Fernandez, Hubert; Isaacson, Stuart; van Laar, Teus; Lees, Andrew; Lewis, Simon; Martinez Castrillo, Juan Carlos; Martinez-Martin, Pablo; Odin, Per; O'Sullivan, John; Tagaris, Georgios; Wenzel, Karoline

    2015-01-01

    Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical p

  3. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease - Clinical practice recommendations

    DEFF Research Database (Denmark)

    Trenkwalder, Claudia; Chaudhuri, K Ray; García Ruiz, Pedro J;

    2015-01-01

    Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical....... Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off' periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and...... predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusion(1) is suited for patients whose...

  4. Apomorphine and Levodopa Infusion Therapies for Advanced Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Angelo Antonini

    2009-05-01

    Full Text Available Continuous infusion of levodopa or apomorphine provide constant dopaminergic stimulations are good alternatives to deep brain stimulation to control motor fluctuations in patients with advanced Parkinson’s disease (PD. Apomorphine provides motor benefit similar to dopamine, but its long-term use is limited by compliance, mostly injection site skin reactions. Administration of levodopa/carbidopa by continuous duodenal infusion allows replacement of all oral medications and permits achievement of a satisfactory therapeutic response paralleled by a reduction in motor complication severity. However, this procedure is more invasive than apomorphine as it requires a percutaneous endoscopic gastrostomy Clinical experience with infusions shows that continuous dopaminergic stimulation of dopaminergic medications reduces dyskinesia and widens the therapeutic window in advanced PD.

  5. The Pharmacological Properties and Therapeutic Use of Apomorphine

    Directory of Open Access Journals (Sweden)

    Samo Ribarič

    2012-05-01

    Full Text Available Apomorphine (APO is an aporphine derivative used in human and veterinary medicine. APO activates D1, D2S, D2L, D3, D4, and D5 receptors (and is thus classified as a non-selective dopamine agonist, serotonin receptors (5HT1A, 5HT2A, 5HT2B, and 5HT2C, and α-adrenergic receptors (α1B, α1D, α2A, α2B, and α2C. In veterinary medicine, APO is used to induce vomiting in dogs, an important early treatment for some common orally ingested poisons (e.g., anti-freeze or insecticides. In human medicine, it has been used in a variety of treatments ranging from the treatment of addiction (i.e., to heroin, alcohol or cigarettes, for treatment of erectile dysfunction in males and hypoactive sexual desire disorder in females to the treatment of patients with Parkinson's disease (PD. Currently, APO is used in patients with advanced PD, for the treatment of persistent and disabling motor fluctuations which do not respond to levodopa or other dopamine agonists, either on its own or in combination with deep brain stimulation. Recently, a new and potentially important therapeutic role for APO in the treatment of Alzheimer’s disease has been suggested; APO seems to stimulate Ab catabolism in an animal model and cell culture, thus reducing the rate of Ab oligomerisation and consequent neural cell death.

  6. EFFECTS OF WHITE AND INFRARED LIGHTING ON APOMORPHINE-INDUCED PECKING IN PIGEONS

    OpenAIRE

    Pinkston, Jonathan W; Madden, Gregory J; Fowler, Stephen C.

    2008-01-01

    The present experiment was concerned with the role of environment in the production and form of apomorphine-induced pecking of pigeons. Previous literature has suggested that the pecking occurs even when pigeons are placed in complete darkness, but there are no systematic or quantitative reports of such pecking. Six pigeons were tested with doses of 0.1, 0.3, and 1.0 mg/kg apomorphine. Tests were made in conditions of white and infrared light. The apparatus employed novel force transduction m...

  7. Subcutaneous apomorphine increases regional cerebral blood flow in parkinsonian patients via peripheral mechanisms.

    OpenAIRE

    Sabatini, U.; Rascol, O; Celsis, P; Houin, G; Rascol, A; Marc-Vergnes, J P; Montastruc, J. L.

    1991-01-01

    1. We have measured regional cerebral blood flow (rCBF) and motor function before and after the subcutaneous (s.c.) injection of apomorphine in parkinsonian patients deprived of their usual treatment for at least 48 h. 2. Nineteen patients, pretreated with domperidone (20 mg three times daily for 48 h), received a mean dose of 5.8 mg s.c. apomorphine. All patients switched 'on'. The mean motor score was significantly improved (-65%, P less than 0.01) but no significant change in rCBF was obse...

  8. Low tryptophan diet decreases brain serotonin and alters response to apomorphine

    Science.gov (United States)

    Sahakian, B. J.; Wurtman, R. J.; Barr, J. K.; Millington, W. R.; Chiel, H. J.

    1979-01-01

    The role of the serotoninergic system in the regulation of apomorphine-induced behavior, a behavior primarily controlled by dopaminergic neurotransmission, was investigated in rats fed on a low tryptophan diet since weaning. It was found that reductions in brain seritonin (5-HT) produced by diet result in decreased stereotypy after apomorphine administration. This indicates that although stereotyped behavior is primarily mediated by dopaminergic mechanisms, it can also be modulated by other neurotransmitter including 5-HT. It was also shown that changes in brain seritonin levels can affect psychomotor stimulant-induced hypothermia.

  9. Microwave facilitation of domperidone antagonism of apomorphine-induced stereotypic climbing in mice

    Energy Technology Data Exchange (ETDEWEB)

    Quock, R.M.; Kouchich, F.J.; Ishii, T.K.; Lange, D.G.

    1987-01-01

    The dopaminergic agonist apomorphine produced dose-dependent stereotypic climbing behavior in mice housed in cages with vertical bars. This drug effect was competitively inhibited by systemic pretreatment with the centrally acting dopaminergic antagonist haloperidol but not by microwave irradiation (2.45 GHz, 20 mW/cm2, CW, 10 min) nor by systemic pretreatment with domperidone, a dopaminergic antagonist that only poorly penetrates the blood-brain barrier (BBB). Yet when mice were systemically pretreated with domperidone and then subjected to microwave irradiation (as above), the apomorphine effect was significantly reduced. Microwave irradiation also facilitated antagonism of the apomorphine effect by low and otherwise ineffective systemic pretreatment doses of haloperidol. Apomorphine-induced stereotypic climbing behavior was also reduced by domperidone administered intracerebrally, which bypassed the BBB. Exposure of intracerebral domperidone-pretreated animals to microwave irradiation failed to increase the degree of antagonism. These findings indicate that microwave irradiation can facilitate central effects of domperidone, a drug which acts mainly in the periphery. One possible explanation for these findings is that microwave irradiation alters the permeability of the BBB and increases the entry of domperidone to central sites of action.

  10. Combined strategies of apomorphine diester prodrugs and nanostructured lipid carriers for efficient brain targeting

    Science.gov (United States)

    Liu, Kuo-Sheng; Wen, Chih-Jen; Yen, Tzu-Chen; Sung, K. C.; Ku, Ming-Chuan; Wang, Jhi-Joung; Fang, Jia-You

    2012-03-01

    Our aim is to develop nanostructured lipid carriers (NLCs) for loading the apomorphine diester prodrugs, diacetyl apomorphine (DAA) and diisobutyryl apomorphine (DIA), into the brain. NLCs were prepared using sesame oil/cetyl palmitate as the lipid matrices. Experiments were performed with the objective of evaluating the physicochemical characteristics, drug release, safety and brain-targeting efficacy of the NLCs. The size of regular NLCs (N-NLCs) was 214 nm. The addition of Forestall (FE) and polyethylene glycol (PEG) to the NLCs (P-NLCs) increased the particle diameter to 250 nm. The zeta potentials of N-NLCs and P-NLCs were respectively shown to be - 21 and 48 mV. Diester prodrugs were more lipophilic and more chemically stable than the parent apomorphine. The hydrolysis study indicated that the prodrugs underwent bioconversion in plasma and brain extract, with DAA exhibiting faster degradation than DIA. Sustained release was achieved through the synergistic effect of integrating strategies of prodrugs and NLCs, with the longer carbon chain showing the slower release (DIA < DAA). None of the NLCs tested here exhibited a toxicity problem according to the examination of neutrophil lactate dehydrogenase (LDH) release and hemolysis. Results of a bioimaging study in mice showed that P-NLCs largely accumulated in the brain. The distribution duration of the fluorescent dye in the brain region was also prolonged by the nanocarriers.

  11. Dopamine D-2 activity of R-(-)-apomorphine and selected analogs : a microdialysis study

    NARCIS (Netherlands)

    Rodenhuis, N; Dijkstra, D; Vermeulen, ES; Timmerman, W; Wikstrom, HV

    2000-01-01

    In the present study, R-(-)-apomorphine and three of its analogs were studied for their potency in decreasing the release of dopamine in the striatum after subcutaneous administration and for their oral bioavailability using the microdialysis technique in freely moving rats. The analogs R-(-)-N-n-pr

  12. Neuropeptides related to neurohypophyseal hormones interfere with apomorphine-induced behavioral changes

    NARCIS (Netherlands)

    Xiao, X S; Veldhuis, H D; Van Ree, J M

    1984-01-01

    The interaction between peptides related to neurohypophyseal hormones and brain dopaminergic systems was studied by investigating in rats the effect of these peptides on behavioral changes induced by graded doses of the specific dopamine agonist apomorphine. Low doses of this drug induce hypoactivit

  13. Chicks from a high and low feather pecking line of laying hens differ in apomorphine sensitivity

    NARCIS (Netherlands)

    van Hierden, YM; Koolhaas, JM; Kost'al, L; Vyboh, P; Sedlackova, M; Rajman, M; Jurani, M; Korte, SM; Hierden, Yvonne M. van; Koolhaas, Jaap M.; Košt’ál, L’ubor; Sedlačková, Monika

    2005-01-01

    Proactive rodents show a larger behavioral response to apomorphine (APO) than reactive copers, suggesting a more sensitive DA system in proactive individuals. Previously, chicks from a high feather pecking (HFP) and low feather pecking line (LFP) have been suggested to display a proactive and reacti

  14. Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine

    OpenAIRE

    Varma, T; Fox, S.; Eldridge, P; Littlechild, P; Byrne, P.; Forster, A; Marshall, A.; Cameron, H.; McIver, K; Fletcher, N; Steiger, M.

    2003-01-01

    Objectives: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication.

  15. Ventricular Bigeminy after Subcutaneous Administration of Apomorphine in a Patient with Refractory Parkinson’s Disease: A Case Report

    Directory of Open Access Journals (Sweden)

    Anastasia N. Kaminioti

    2013-05-01

    Full Text Available Apomorphine is a well established treatment for the management of sudden, unexpected and refractory levodopa-induced “off” states in fluctuating Parkinson’s disease either as bolus injections or as continuous infusions. Incidents of atrial fibrillation associated with the administration of the drug have been reported in the past but no incidents of ventricular arrhythmias. We report a case of ventricular bigeminy recorded in a female patient after the administration of apomorphine.

  16. A double-blind study of the efficacy of apomorphine and its assessment in "off-periods in Parkinson's disease

    OpenAIRE

    Laar, van, J.A.; Jansen, E.N.H.; Essink, A.W.G.; Neef, C.; Oosterloo, S.

    1993-01-01

    Five patients with idiopathic Parkinson's disease with severe response fluctuations were selected for a randomized double-blind placebo-controlled study, concerning the clinical effects of subcutaneous apomorphine and its assessment in `off¿-periods. The study was designed as five n = 1 studies, in which every patient was his own control. The effect of apomorphine was studied by using the Columbia rating scale and quantitative assessments, using tapping, walking and pinboard. There was a sign...

  17. Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa induced interdose dyskinesias in Parkinson's disease

    OpenAIRE

    Colzi, A; Turner, K.; Lees, A.

    1998-01-01

    OBJECTIVES—To determine whether continous waking day dopaminergic stimulation with the dopamine agonist apomorphine can reduce levodopa induced dyskinesias in Parkinson's disease
METHODS—19 patients with severe unpredictable refractory motor fluctuations and functionally disabling levodopa induced dyskinesias were treated with continuous subcutaneoius apomorphine monotherapy for a minimum duration of 2.7 years
RESULTS—A mean 65% reduction in dyskinetic severity and a mean 85...

  18. Ventricular Bigeminy after Subcutaneous Administration of Apomorphine in a Patient with Refractory Parkinson’s Disease: A Case Report

    OpenAIRE

    Kaminioti, Anastasia N.; Nikitas, Georgios T.; Terlis, Apostolos K.; Manolis, Athanasios G.; Thomas Thomaides; Panousopoulou, Aggeliki N.

    2013-01-01

    Apomorphine is a well established treatment for the management of sudden, unexpected and refractory levodopa-induced “off” states in fluctuating Parkinson’s disease either as bolus injections or as continuous infusions. Incidents of atrial fibrillation associated with the administration of the drug have been reported in the past but no incidents of ventricular arrhythmias. We report a case of ventricular bigeminy recorded in a female patient after the administration of apomorphine.

  19. A Genetic Mouse Model of Parkinson's Disease Shows Involuntary Movements and Increased Postsynaptic Sensitivity to Apomorphine.

    Science.gov (United States)

    Brehm, N; Bez, F; Carlsson, T; Kern, B; Gispert, S; Auburger, G; Cenci, M A

    2015-12-01

    Alpha-synuclein (SNCA) protein aggregation plays a causal role in Parkinson's disease (PD). The SNCA protein modulates neurotransmission via the SNAP receptor (SNARE) complex assembly and presynaptic vesicle trafficking. The striatal presynaptic dopamine deficit is alleviated by treatment with levodopa (L-DOPA), but postsynaptic plastic changes induced by this treatment lead to a development of involuntary movements (dyskinesia). While this process is currently modeled in rodents harboring neurotoxin-induced lesions of the nigrostriatal pathway, we have here explored the postsynaptic supersensitivity of dopamine receptor-mediated signaling in a genetic mouse model of early PD. To this end, we used mice with prion promoter-driven overexpression of A53T-SNCA in the nigrostriatal and corticostriatal projections. At a symptomatic age (18 months), mice were challenged with apomorphine (5 mg/kg s.c.) and examined using both behavioral and molecular assays. After the administration of apomorphine, A53T-transgenic mice showed more severe stereotypic and dystonic movements in comparison with wild-type controls. Molecular markers of extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and dephosphorylation, and Fos messenger RNA (mRNA), were examined in striatal tissue at 30 and 100 min after apomorphine injection. At 30 min, wild-type and transgenic mice showed a similar induction of phosphorylated ERK1/2, Dusp1, and Dusp6 mRNA (two MAPK phosphatases). At the same time point, Fos mRNA was induced more strongly in mutant mice than in wild-type controls. At 100 min after apomorphine treatment, the induction of both Fos, Dusp1, and Dusp6 mRNA was significantly larger in mutant mice than wild-type controls. At this time point, apomorphine caused a reduction in phospho-ERK1/2 levels specifically in the transgenic mice. Our results document for the first time a disturbance of ERK1/2 signaling regulation associated with apomorphine-induced involuntary movements

  20. Selective effects of low doses of apomorphine on spatiotemporal contrast sensitivity in healthy volunteers: a double-blind placebo-controlled study.

    OpenAIRE

    Blin, O; Mestre, D; Masson, G.; Serratrice, G

    1991-01-01

    1. Apomorphine (1 and 5 micrograms kg-1) and placebo were given to nine normal volunteers, using a Latin-square design and double-blind procedures. The visual perception of static and moving patterns (static and motion contrast sensitivity) was evaluated before and 15 min after the dose administration. 2. Apomorphine (1 and 5 micrograms kg-1), as compared with placebo, led to a significant overall reduction of the visual perception of movement. This effect was dose-related, and apomorphine (5...

  1. Electronic and vibrational circular dichroism spectra of (R)-(−)-apomorphine

    International Nuclear Information System (INIS)

    Highlights: ► ECD and VCD Spectra of (R)-(−)-apomorphine measured in various solvents. ► DFT calculations allow to study the protonation state and conformations. ► Contributions from catechol OH vibrations to the VCD spectra is studied. -- Abstract: Apomorphine is a chiral drug molecule; notwithstanding its extraordinary importance, little attention has been paid to the characterization of its chiroptical properties. Here we report on its electronic circular dichroism (ECD) spectra, recorded in methanol and water, and vibrational circular dichroism (VCD) in methanol and dimethyl sulfoxide (DMSO) solutions. Density functional theory (DFT) calculations have allowed us to interpret the spectra and to evaluate the role of possible conformations, charge-states and interactions with counter ions.

  2. Iodine-123 lodobenzamide imaging, MRI and apomorphine testing in the evaluation of patients with Parkinsonism.

    Energy Technology Data Exchange (ETDEWEB)

    Van der Schaaf, A.A.; Stell, R.; Groom, G.N.; Lambrecht, R.; Najdovski, L.; Collier, T.L.; Cardaci, G.; Davis, S.; Laing, B.; Mastaglia, F.L.; O`Brien, J. [Sir Charles Gairdner Hospital, Perth, WA, (Australia)]|[ANSTO, Lucas Heights, NSW, (Australia). The Biomedicine and Health Program

    1997-09-01

    Full text; The clinical distinction between idiopathic Parkinson`s disease (IPD) and other neurodegenerative disorders which mimic this condition is important in patient management. Iodine-123 lodobenzamide (IBZM) SPECT imaging of cerebral dopamine-2 (D{sub 2}) receptors has been proposed as a means of distinguishing between IPD and atypical variants, including such Parkinsonian syndromes (PS) as multi-system atrophy and progressive supranuclear palsy, and to predict long-term responsiveness to dopaminergic drugs. Apomorphine testing is currently in use for the latter purpose. To assess the role of IBZM SPECT, MRI and apomorphine testing in categorising patients with Parkinsonian symptoms and for predicting therapeutic response, we studied 40 subjects, 18 of whom had IPD. SPECT brain studies were carried out two hours after the intravenous injection of approximately 185 MBq of {sup 123}I IBZM. Semiquantitative IBZM striatal/occipital cortex uptake ratios in the IPD group were 1.53 + 0.17 (mean + S.D.), and in the non-lPD group 1.53 {+-} 0.29. Of the 11 IPD patients and 19 non-lPD patients who had MRI, none and two, respectively, showed iron deposition in the basal ganglia. Eleven of 13 IPD and 3 of 18 non-lPD subjects had a positive apomorphine test, while 15 of 15 IPD and 5 of 19 non-lPD subjects responded to dopaminergic therapy. When patients were classified into responders (R) (n 20) and non-responders (NR) (n = 14), the IBZM ratios were 1.56 {+-} 0.22 and 1.47 {+-} 0.29 respectively (no significant difference between the groups). The apomorphine test accurately predicted response, being positive in 13 of 15 R and negative in 11 of 12 NR. We conclude that {sup 123}I SPECT is not helpful in differentiating IPD from PS, nor in predicting response to dopaminergic drugs.

  3. MCH and apomorphine in combination enhance action potential firing of nucleus accumbens shell neurons in vitro

    OpenAIRE

    F. Woodward Hopf; Taban Seif; Shinjae Chung; Olivier Civelli

    2013-01-01

    The MCH and dopamine receptor systems have been shown to modulate a number of behaviors related to reward processing, addiction, and neuropsychiatric conditions such as schizophrenia and depression. In addition, MCH and dopamine receptors can interact in a positive manner, for example in the expression of cocaine self-administration. A recent report (Chung et al., 2011a) showed that the DA1/DA2 dopamine receptor activator apomorphine suppresses pre-pulse inhibition, a preclinical model for so...

  4. Effect of blood sampling on apomorphine-induced penile tumescence in erectile impotence: a case report.

    OpenAIRE

    Kiely, M E; Thavundayil, J X; Lal, S

    1995-01-01

    Apomorphine HCl (Apo) (0.5 mg sc), but not placebo, induced an erectile response (monitored with a mercury strain gauge) lasting 40 min in an impotent hyperprolactinemic patient. Serial blood sampling modified the 40 min erectile response. Prompt detumescence followed by complete or partial restoration of tumescence occurred each time blood was drawn. This observation points to the sensitivity of the Apo-erectile response to experimental procedures subjectively perceived as anxiogenic.

  5. Effect of bromocriptine in patients with apomorphine-responsive erectile impotence: an open study.

    OpenAIRE

    Lal, S; Kiely, M E; Thavundayil, J X; Stewart, J. D.; Assalian, P; Ackman, C. F.

    1991-01-01

    An open pilot study was undertaken to investigate the therapeutic effect of the dopaminergic agent, bromocriptine (BC), in impotent patients who developed an erectile response to the dopamine receptor agonist, apomorphine. Eight out of 17 patients reported improvement in ability to obtain an erection; five of these 8 subjects were able to achieve penetration. The optimum dose of BC was 2.5 - 11.25 mg/day. A double-blind placebo-controlled study is merited.

  6. Dopamine Transporter Genotype Dependent Effects of Apomorphine on Cold Pain Tolerance in Healthy Volunteers

    OpenAIRE

    Roi Treister; Dorit Pud; Ebstein, Richard P.; Elon Eisenberg

    2013-01-01

    The aims of this study were to assess the effects of the dopamine agonist apomorphine on experimental pain models in healthy subjects and to explore the possible association between these effects and a common polymorphism within the dopamine transporter gene. Healthy volunteers (n = 105) participated in this randomized double-blind, placebo-controlled, cross-over trial. Heat pain threshold and intensity, cold pain threshold, and the response to tonic cold pain (latency, intensity, and toleran...

  7. Dopamine-transporter levels drive striatal responses to apomorphine in Parkinson's disease

    OpenAIRE

    Passamonti, Luca; Salsone, Maria; Toschi, Nicola; Cerasa, Antonio; Giannelli, Marco; Chiriaco, Carmelina; Cascini, Giuseppe Lucio; Fera, Francesco; Quattrone, Aldo

    2013-01-01

    Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriata...

  8. Frontal forebrain lesions : effects on the foraging and apomorphine pecking of pigeons

    OpenAIRE

    Wynne, Brigitte; Delius, Juan

    1996-01-01

    The role of the nucleus basalis prosencephali (Bas), a frontal forebrain structure peculiar to birds, in the control of forage pecking and apomorphine-induced pecking was investigated. In a quasi-natural grit-grain selection task bilateral coagulations of the Bas and the associated neostriatum frontolaterale (Nfl) caused a marked fall in grain per peck uptake and a simultaneous increase in grit per peck uptake. Bas lesions also has a reducing effect on the compulsive pecking elicited by syste...

  9. Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging

    Directory of Open Access Journals (Sweden)

    Wen CJ

    2012-03-01

    Full Text Available Chih-Jen Wen1,*, Li-Wen Zhang2,*, Saleh A Al-Suwayeh3, Tzu-Chen Yen1, Jia-You Fang2,4 1Molecular Imaging Center, Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan; 2Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Gueishan, Taoyuan, Taiwan; 3Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 4Department of Cosmetic Science, Chang Gung University of Science and Technology, Gueishan, Taoyuan, Taiwan *These authors contributed equally to this workAbstract: Quantum dots (QDs and apomorphine were incorporated into liposomes to eliminate uptake by the liver and enhance brain targeting. We describe the preparation, physicochemical characterization, in vivo bioimaging, and brain endothelial cell uptake of the theranostic liposomes. QDs and the drug were mainly located in the bilayer membrane and inner core of the liposomes, respectively. Spherical vesicles with a mean diameter of ~140 nm were formed. QDs were completely encapsulated by the vesicles. Nearly 80% encapsulation percentage was achieved for apomorphine. A greater fluorescence intensity was observed in mouse brains treated with liposomes compared to free QDs. This result was further confirmed by ex vivo imaging of the organs. QD uptake by the heart and liver was reduced by liposomal incorporation. Apomorphine accumulation in the brain increased by 2.4-fold after this incorporation. According to a hyperspectral imaging analysis, multifunctional liposomes but not the aqueous solution carried QDs into the brain. Liposomes were observed to have been efficiently endocytosed into bEND3 cells. The mechanisms involved in the cellular uptake were clathrin- and caveola-mediated endocytosis, which were energy-dependent. To the best of our knowledge, our group is the first to develop liposomes with a QD-drug hybrid for the aim of imaging and treating brain disorders.Keywords: liposomes, quantum dots, apomorphine

  10. Sensitization to apomorphine in pigeons : unaffected by latent inhibition but still due to classical conditioning

    OpenAIRE

    Wynne, Brigitte; Delius, Juan

    1995-01-01

    When administered apomorphine, pigeons exhibit protracted bouts of pecking behavior. This response is subject to sensitization, as it initially increases with repeated drug injections. The hypothesis is examined that the sensitization is due to a Pavlovian conditioning of the drug-induced pecking to the environment in which it first takes effect. In a first experiment, we attempted to suppress this conditioning by extensively pre-exposing the birds to the test environment and saline injection...

  11. Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up

    OpenAIRE

    Pietz, K; Hagell, P; Odin, P

    1998-01-01

    OBJECTIVES—Despite the recent introduction of new peroral drugs as well as neurosurgical methods for Parkinson's disease, treatment of late stage parkinsonian patients remains difficult and many patients become severely handicapped because of fluctuations in their motor status. Injections and infusions of apomorphine has been suggested as an alternative in the treatment of these patients, but the number of studies describing the effects of such a treatment over longer tim...

  12. Effect of apomorphine on cognitive performance and sensorimotor gating in humans

    OpenAIRE

    Arnt F.A. Schellekens; Grootens, K. P.; Neef, C.; Movig, Kris L. L.; Buitelaar, J K; Ellenbroek, B.; Verkes, R. J.

    2009-01-01

    Introduction Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level. Methods Fifteen healthy male volunteers received apomorphine sublingually (2 mg),...

  13. Chicks from a high and low feather pecking line of laying hens differ in apomorphine sensitivity

    OpenAIRE

    van Hierden, YM; Koolhaas, JM; Kost'al, L; Vyboh, P; Sedlackova, M; Rajman, M.; Jurani, M; Korte, SM; Hierden, Yvonne M. van; Koolhaas, Jaap M.; Košt’ál, L’ubor; Sedlačková, Monika

    2005-01-01

    Proactive rodents show a larger behavioral response to apomorphine (APO) than reactive copers, suggesting a more sensitive DA system in proactive individuals. Previously, chicks from a high feather pecking (HFP) and low feather pecking line (LFP) have been suggested to display a proactive and reactive cooing strategy, respectively. therefore, at approximately 4 weeks of age, the behavior of 48 LFP and 48 HFP chicks in response to an APO injection Was studied using an open field. Another objec...

  14. Iodine-123 lodobenzamide imaging, MRI and apomorphine testing in the evaluation of patients with Parkinsonism

    International Nuclear Information System (INIS)

    Full text; The clinical distinction between idiopathic Parkinson's disease (IPD) and other neurodegenerative disorders which mimic this condition is important in patient management. Iodine-123 lodobenzamide (IBZM) SPECT imaging of cerebral dopamine-2 (D2) receptors has been proposed as a means of distinguishing between IPD and atypical variants, including such Parkinsonian syndromes (PS) as multi-system atrophy and progressive supranuclear palsy, and to predict long-term responsiveness to dopaminergic drugs. Apomorphine testing is currently in use for the latter purpose. To assess the role of IBZM SPECT, MRI and apomorphine testing in categorising patients with Parkinsonian symptoms and for predicting therapeutic response, we studied 40 subjects, 18 of whom had IPD. SPECT brain studies were carried out two hours after the intravenous injection of approximately 185 MBq of 123I IBZM. Semiquantitative IBZM striatal/occipital cortex uptake ratios in the IPD group were 1.53 + 0.17 (mean + S.D.), and in the non-lPD group 1.53 ± 0.29. Of the 11 IPD patients and 19 non-lPD patients who had MRI, none and two, respectively, showed iron deposition in the basal ganglia. Eleven of 13 IPD and 3 of 18 non-lPD subjects had a positive apomorphine test, while 15 of 15 IPD and 5 of 19 non-lPD subjects responded to dopaminergic therapy. When patients were classified into responders (R) (n 20) and non-responders (NR) (n = 14), the IBZM ratios were 1.56 ± 0.22 and 1.47 ± 0.29 respectively (no significant difference between the groups). The apomorphine test accurately predicted response, being positive in 13 of 15 R and negative in 11 of 12 NR. We conclude that 123I SPECT is not helpful in differentiating IPD from PS, nor in predicting response to dopaminergic drugs

  15. Synergistic actions of apomorphine and m-chlorophenylpiperazine on ejaculation, but not penile erection in rats.

    Science.gov (United States)

    Yonezawa, Akihiko; Yoshizumi, Masaru; Ise, Shin-Nosuke; Watanabe, Chizuko; Mizoguchi, Hirokazu; Furukawa, Katsuo; Tsuru, Hiromichi; Kimura, Yukio; Kawatani, Masahito; Sakurada, Shinobu

    2009-04-01

    It has been suggested that dopamine (DA) and serotonin (5-HT) and their receptors, particularly D(2)-like and 5-HT(2C) receptors, may play a significant role in the control of male sexual function. The purpose of this study was to investigate whether the combination of a dopamine receptor agonist apomorphine and a 5-HT(2) receptor agonist m-CPP would potentiate penile erection and ejaculation in male rats. Systemic administration of either apomorphine (0.01-0.1 mg/kg, s.c.) or m-CPP (0.01-0.3 mg/kg, i.p.) dose-dependently elicited penile erections, but did not induce ejaculation. When combined, there was a drastic increase in both the incidence of ejaculation and the amount of ejaculated seminal materials, while the proerectile effect induced by each drug was not potentiated. The proejaculatory effect induced by the combination of apomorphine (0.1 mg/kg, s.c.) and m-CPP (0.3 mg/kg, i.p.) was completely blocked by pretreatment with the D(2)-like receptor antagonists haloperidol and sulpiride, but not by the D(1)-like receptor antagonist SCH-23390. The synergistic action for ejaculation was also blocked by domperidone, the D(2)-like receptor antagonist that dose not cross the blood-brain barrier. The rats pretreated with the 5-HT(2C) receptor antagonist SB242084 did not show the synergistic action by the combination of apomorphine and m-CPP, whereas the rats pretreated with the 5-HT(2A) receptor antagonist ketanserin and the 5-HT(2B) receptor antagonist SB204741 showed the combination-induced synergistic action. These results suggest that the combination of a small dose of apomorphine and m-CPP potently and selectively facilitates the ejaculatory response through the activation of D(2)-like and 5-HT(2C) receptors, respectively. The D(2)-like receptors involved in the synergistic action may be, at least in part, located in the peripheral sites. PMID:19420729

  16. The detection of novelty relies on dopaminergic signaling: evidence from apomorphine's impact on the novelty N2.

    Directory of Open Access Journals (Sweden)

    Mauricio Rangel-Gomez

    Full Text Available Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist and measure the change in neurological indices of novelty processing. In separate drug and placebo sessions, participants completed a von Restorff task. Apomorphine speeded and potentiated the novelty-elicited N2, an Event-Related Potential (ERP component thought to index early aspects of novelty detection, and caused novel-font words to be better recalled. Apomorphine also decreased the amplitude of the novelty-P3a. An increase in D1/D2 receptor activation thus appears to potentiate neural sensitivity to novel stimuli, causing this content to be better encoded.

  17. Effects of harmane, norharmane and harmine on apomorphine-induced pecking behavior in chick

    Directory of Open Access Journals (Sweden)

    Davood Farzin

    2009-01-01

    Full Text Available .(Received 3 January, 2009; Accepted 27 May, 2009AbstractBackground and purpose: -carboline alkaloids, also known as harmala's alkaloids have a wide spectrum of pharmacological actions including a stimulatory action on release of dopamine and other catecholamines in several brain regions and an inhibitory action on monoamine oxidase (MAO. These findings suggest that -carbolines should alleviate at least some of the dopaminergic stereotyped behaviors. The purpose of present study is to determine the effects of -carbolines harmane, norharmane and harmine on apomorphine-induced pecking behavior in chick.Materials and methods: All experiments were carried out on male/female chicks (40-60 g. The modulatory effects of -Carbolines on stereotyped behavior were assessed using the pecking behavior induced by apomorphine. Subcutaneous (s.c. injection of apomorphaine (0.025 mg/kg, mixed agonist of dopamine D1/D2 receptors induced pecking. The pecking response was counted by direct observation and recorded for a 40-minute period.Results: S.C. injection of harmane (2.5-10 mg/kg and harmine (1.25-5 mg/kg significantly decreased the pecking behavior induced by apomorphine (0.25 mg/kg. The norharmane (2.5-15 mg/kg, i.p. response was biphasic. The inhibitory effects of harmane, norharmane and harmine were blocked by flumazenil (5 mg/kg, i.e., 30 minutes before the test or reserpine (5 mg/kg, i.e., 18 hours before the test.Conclusion: Results suggest that the modulatory effect of harmane, norharmane and harmine on the pecking behavior may be mediated through an inverse agonistic/monoaminergic mechanism.J Mazand Univ Med Sci 2009; 19(70: 1-8 (Persian

  18. Iodine-123-iodobenzamide imaging, MRI and apomorphine testing in the evaluation of patients with Parkinsonism

    Energy Technology Data Exchange (ETDEWEB)

    Van der Schaaf, A.A.; Stell, R.; Groom, G.N. [Sir Charles Gairdner Hospital, Perth, WA (Australia); Lambrecht, R.; Najdovski, L.; Cardaci, G.; Davis, S.; Dikic, B.; Laing, B.; Mastaaglia, F.L.; O``Brein, J. [Australian Nuclear Science and Technology Organisation (ANSTO), Lucas Heights, NSW (Australia)

    1998-03-01

    Full text: Idiopathic Parkinson``s disease (IPD) is characterised by a loss of dopaminergic neurons in the substantia nigra. Other neurodegenerative disorders may mimic IPD, and the clinical distinction is important in patient management. Iodine-123-iodobenzamide (IBZM) has high specific binding to dopamine-2 (D2) receptors enabling SPECT studies of these receptors in the human brain. A significant reduction of D2 receptor binding of {sup 123}I-lBZM has been shown in the basal ganglia of patients with Parkinsonian syndromes (PS) but normal uptake is seen in patients with IPD. Iodine-123-lBZM SPECT imaging has been proposed as a means of distinguishing between patients with IPD and PS and may be of value in predicting the long-term responsiveness to dopaminergic drugs. Magnetic resonance imaging has also been used to distinguish IPD from PS, and apomorphine testing is in use as a clinical means of predicting response to dopaminergic drugs. We plan to evaluate the sensitivity and specificity of {sup 123}I-lBZM SPECT, MRI and apomorphine testing for categorisation of patients and the prediction of responsiveness to dopaminergic drugs. To date we have studied 17 patients. SPECT imaging of the brain was carried out two hours after the i.v. administration of 185 MBq of {sup 123}I-lBZM and visual and semi-quantitative analysis, using ratios of uptake in basal ganglia to frontal cortex, occipital cortex and cerebellum have been carried out. Although the data are incomplete, preliminary results suggest that there is a poor correlation of {sup 123}I-lBZM uptake with the provisional clinical diagnosis and with apomorphine testing, but that {sup 123}I-lBZM uptake is a predictor of dopaminergic response.

  19. Apomorphine in treatment of Parkinson's disease: comparison between subcutaneous and sublingual routes.

    OpenAIRE

    Deffond, D; Durif, F; Tournilhac, M

    1993-01-01

    The efficacy of two routes of apomorphine, subcutaneous (SC) and sublingual (SL), successively administered in 7 Parkinsonian patients with motor fluctuations, was compared in reducing the daily duration of "off" phases. The mean duration of SC and SL treatment was 7.7 and 6.8 months respectively. The mean time spent in "off" phase was 55% after SC and 68% after SL treatment. The mean time before turning "on" after an "off" period was 14 minutes after SC and 28 minutes after SL treatment. Two...

  20. Extensive study of the autooxidation products of apomorphine and its pharmacologically active derivatives

    Science.gov (United States)

    Udvardy, Antal; Gyulai, Zsuzsanna; Sipos, Attila

    2011-09-01

    The autooxidation phenomenon of apomorphine and the products of this procedure were analytically and pharmacologically studied, however we found that there have been some unclarified details of this filed. Therefore the synthesis and structure of the autooxidation products of three clinically and pharmacologically relevant aporphinoids (apomoprine, N-propyl-norapomorphine and 2-hydroxy- N-propyl-norapomorphine) were thoroughly investigated. The autooxidation of apomorphine achieved at physiological pH resulted two products; one of them is the known tetracyclic, tertiary amino ortho quinone and the hitherto unknown, fluorescent, derivatized phenanthrene-3,4-quinone. Under the same conditions N-propyl congeners resulted only the expected 1,2-dione products. The analytical structure elucidation involved the full 1H and 13C NMR assignment, UV and IR characterizations of the four isolated ortho quinone-type products exploiting the possibilities of DFT calculations for geometry optimization, NMR and IR simulations. The phenanthrene-3,4-quinone compound can be relevant in further pharmacological studies of aporphine-related oxidation products due to its potential toxicity and investigated fluorescent character.

  1. Effects of chronic mild stress on apomorphine induced behavioral sensitization in different brain regions of rats in relation to serotonin change

    Directory of Open Access Journals (Sweden)

    Muhammad Farhan

    2015-11-01

    Full Text Available Background: The impacts of unpredictable stressors have influence on neurochemical and behavioral parameters in laboratory animals. Stress induced behavioral changes particularly those associated with anxiety like behavior may activate topographically organized mesolimbic cortical serotonergic system. This study was designed to investigate the influence of unpredictable stress on behavioral and neurochemical parameters in apomorphine treated rats. Methods: Initially, the animals were divided into two groups as Unstressed and stressed (uncontrollable chronic mild stress or UCMS. Both groups of animals were subdivided into two groups; i.e. saline and apomorphine administrated animals at dose 1.0 mg/kg. Behavioral manipulations was observed by monitoring the locomotor activity and exploratory activity. Neurochemical estimation of 5-hydroxytryptamine (5-HT was done by High performance liquid chromatography (HPLC. Animals were decapitated 24hr post apomorphine injection and different regions of brain (dorsal and ventral striatum, of animals were collected and stored at -70°C. Results: This preclinical study showed that the UCMS induced hypophagia were promoted in apomorphine administrated animals. Apomorphine induced hyperlocomotion were more prominent in unstressed animals than that of stressed groups. It implies that apomorphine is effective in the retrieval from UCMS induced depressive symptoms in rats. Neurochemical study showed decreased level of 5-HT in unstressed animals than stressed animals in response to apomorphine administration. Conclusion: This study, therefore establish the relation between stress and addiction at behavioral as well as neurochemical level to better understand the idea whether intolerable stress promotes addiction.

  2. Apomorphine induced conditioned place preference and sensitization is greater in rats exposed to unpredictable chronic mild stress.

    Science.gov (United States)

    Kanwal, Sumera; Ikram, Huma; Farhan, Muhammad; Haleem, Darakhshan Jabeen

    2015-11-01

    CNS stimulants are the class of the drugs that may be used to get relief from depression. Apomorphine is a D1 and D2 receptor agonist with a CNS stimulatory effect used for the treatment of Parkinson's disease is also abused. Although many drugs of abuse produce tolerance and dependence. Long term use of pshycostimulants produce reverse tolerance described as sensitization. These drugs also have a number of other beneficial effects but their therapeutic use is limited because of abuse potential. Conditioned place preference (CPP) test is used to monitor the reinforcing effect of drugs of abuse. Stress is an important factor that precipitates and potentiates addictive effects of different drugs of abuse. The present study was designed to investigate the addictive effect of apomorphine (1mg/kg) in rats previously exposed to repeated unpredictable chronic mild stress for 10 days (animal model of depression). Results from present study illustrate that unpredictable chronic mild stress potentiates the reinforcing effects of apomorphine as the number of entries and the time spent in the CPP compartment associated with drug administration is increased. Motor activity was taken as a parameter for behavioral sensitization which is induced by repeated administration of apomorphine, monitored as the number of cage crossings in light compartment of the CPP apparatus, also increased. PMID:26639488

  3. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Science.gov (United States)

    Hsu, Shu-Hui; Wen, Chih-Jen; Al-Suwayeh, S. A.; Chang, Hui-Wen; Yen, Tzu-Chen; Fang, Jia-You

    2010-10-01

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  4. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    NARCIS (Netherlands)

    Radhakishun, F.S.; Ree, J.M. van

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not cha

  5. Effects of apomorphine upon local cerebral glucose utilization in conscious rats and in rats anesthetized with chloral hydrate

    Energy Technology Data Exchange (ETDEWEB)

    Grome, J.J.; McCulloch, J.

    1983-02-01

    The effects of the dopaminergic agonist apomorphine upon local cerebral glucose utilization in 43 anatomically discrete regions of the CNS were examined in conscious, lightly restrained rats and in rats anesthetized with chloral hydrate by means of the quantitative autoradiographic (/sup 14/C)2-deoxyglucose technique. In animals anesthetized with chloral hydrate, glucose utilization was reduced throughout all regions of the CNS from the levels observed in conscious animals. With chloral hydrate anesthesia, the proportionately most marked reductions in glucose use were noted in primary auditory nuclei, thalmaic relay nuclei, and neocortex, and the least pronounced reductions in glucose use (by 15-25% from conscious levels) were observed in limbic areas, some motor relay nuclei, and white matter. In conscious, lightly restrained rats, the administration of apomorphine effected significant increases in glucose utilization in 15 regions of the CNS, and significant reductions in glucose utilization in two regions of the CNS. In rats anesthetized with chloral hydrate, the effects of apomorphine upon local glucose utilization were less widespread and less marked than in conscious animals. The profound effects of chloral hydrate anesthesia upon local cerebral glucose use, and the modification by this anesthetic regime of the local metabolic responses to apomorphine, emphasize the difficulties which exists in the extrapolation of data from anesthetized animals to the conditions which prevail in the conscious animal.

  6. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    International Nuclear Information System (INIS)

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  7. Physicochemical characterization and in vivo bioluminescence imaging of nanostructured lipid carriers for targeting the brain: apomorphine as a model drug

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Shu-Hui [Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China); Wen, Chih-Jen; Yen, Tzu-Chen [Animal Molecular Imaging Center, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan (China); Al-Suwayeh, S A; Fang, Jia-You [Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh (Saudi Arabia); Chang, Hui-Wen, E-mail: fajy@mail.cgu.edu.tw [Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan 333, Taiwan (China)

    2010-10-08

    Nanostructured lipid carriers (NLCs) were prepared to investigate whether the duration of brain targeting and accumulation of drugs in the brain can be improved by intravenous delivery. NLCs were developed using cetyl palmitate as the lipid matrix, squalene as the cationic surfactant, and Pluronic F68, polysorbate 80 and polyethylene glycol as the interfacial additives. Solid lipid nanoparticles (SLNs) and lipid emulsions (LEs) were also prepared for comparison. An anti-Parkinson's drug, apomorphine, was used as the model drug. Nuclear magnetic resonance and differential scanning calorimetry showed possible interactions between the solid and liquid lipids in the inner core. The lipid nanoparticles with different compositions were characterized by mean size, zeta potential, apomorphine encapsulation and in vitro drug release. NLCs were 370-430 nm in size, which was between the sizes of the SLNs and LEs. A cationic surfactant was used to produce a positive surface charge of 42-50 mV. The base form of apomorphine was successfully entrapped by NLCs with an entrapment percentage of > 60%. The loading of apomorphine in nanoparticles resulted in a slower release behavior compared to the aqueous solution, with LEs showing the lowest release. In vivo real-time bioluminescence imaging of the rat brain revealed that NLCs could be targeted, through certain vessels, to selected brain regions. This effect was further confirmed by imaging the entire brain and brain slices. The results indicated that NLCs with moderate additives are a promising controlled-release and drug-targeting system.

  8. The substituted (S)-3-phenylpiperidine (-)-OSU6162 reduces apomorphine- and amphetamine-induced behaviour in Cebus apella monkeys

    DEFF Research Database (Denmark)

    Brandt-Christensen, Anne Mette; Andersen, M B; Fink-Jensen, A;

    2006-01-01

    Low affinity dopamine (DA) D2 antagonists such as the substituted (S)-3-phenylpiperidine (-)-OSU6162 have been proposed to be putative antipsychotic agents not endowed with extrapyramidal side effects (EPS). In the present study we investigated the effects of (-)-OSU6162 on (-)-apomorphine and d-...

  9. The effect of acute Lithium and AMI-193, a new 5HT2 antagonist, on Apomorphine-induced pecking in pigeon

    OpenAIRE

    Bagheri T; Ejtemaei Mehr Sh; Shamshirgaran Sh

    2002-01-01

    Intramascular (IM) administration of apomorphine (a mixed D1/D2 dopamine receptors agonist 0.2-1.6 mg/kg) induced pecking, a stereotype behavior in pigeons in a dose- dependent manner. In this study the effect of lithium (Li+, 240 mg/kg, IM) and AMI-193 (a new 5-HT2 antagonist, 0.003 mg/pigeon) on apomorphine-induced peking (AIP) were investigated. This study showed that Li+ and AMI-193 did not induce pecking by itself but administration of each of these agents before apomorphine increased an...

  10. The Effect of Aging on Erectile Function Induced by Apomorphine and Electric Field Stimulation to Rat

    Institute of Scientific and Technical Information of China (English)

    李铮; 郑松; 向祖琼; 刘勇; 王益鑫

    2002-01-01

    Objective To explore the effect and mechanism of aging on erection by using ratmodel.Materials & Methods Forty male SD rats of 3, 9, 18 and 24 months old were divid-ed into 4 groups equally according to their age. Apomorphine given subcutaneously andcavernous nerve electric field stimulation was used to induce erection of rats.Results The successful erection rate, number of erection times, and intracavernouspressure (ICP) in the rats of 18 and 24 month old was significantly lower than that of3 and 9 month old.Conclusion The erectile function in aging rats is deteriorated. The damage mecha-nism with aging might be related to dopaminergic system in central nerves.

  11. Increased burst firing in substantia nigra pars reticulata neurons and enhanced response to selective D2 agonist in hemiparkinsonian rats after repeated administration of apomorphine.

    OpenAIRE

    Lee, J. I.; Nam, D H; J.S. Kim; Hong, S.C.; Shin, H. J.; K. Park; Eoh, W.; Kim, J. H.; Lee, W.Y.

    2001-01-01

    Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, i...

  12. Motor response to acute dopaminergic challenge with apomorphine and levodopa in Parkinson's disease: implications for the pathogenesis of the on-off phenomenon.

    OpenAIRE

    Colosimo, C.; MERELLO, M; Hughes, A J; Sieradzan, K; A. J. Lees

    1996-01-01

    OBJECTIVES--To evaluate the contribution of postsynaptic changes to motor fluctuations, three groups of parkinsonian patients with differing responses to treatment were acutely challenged with two dopaminergic drugs-apomorphine and levodopa-having different mechanisms of action. METHODS--Forty two patients with Parkinson's disease (14 untreated, eight with a stable response to levodopa, and 20 with levodopa induced motor fluctuations) were challenged on two consecutive days with apomorphine a...

  13. Differential diagnosis in patients with extrapyramidal movement disorders: [sup 123]I-IBZM-SPECT vs. apomorphine-test. Differentialdiagnose der Parkinson-Erkrankungen - [sup 123]I-IBZM-SPECT vs. Apomorphin-Test

    Energy Technology Data Exchange (ETDEWEB)

    Hierholzer, J. (Strahlenklinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); Cordes, M. (Strahlenklinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); Schelosky, L. (Neurologische Klinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); Sander, B. (Strahlenklinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); Boeck, J.C. (Strahlenklinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); David, I. (Strahlenklinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany)); Horowski, R. (Schering AG, Berlin (Germany)); Poewe, W. (Neurologische Klinik und Poliklinik, Klinikum Rudolf Virchow, Freie Univ. Berlin (Germany))

    1993-07-01

    The aim of our study was to compare the striatal dopamine D2-receptor density as measured by [sup 123]I-IBZM-SPECT with the results of the apomorphine-test. 30 patients were studied; 21 with idiopathic Parkinson's disease (IPD), 9 with Parkinson plus syndromes (PPS). Patients with IPD showed a significantly higher striatal IBZM binding as compared to patients with PPS (p=0.006). A good correlation between IBZM binding and outcome of the apomorphine test was found (p=0.006). Low striatal IBZM binding indicates reduced dopamine D2-receptor density. This compromises successful dopaminergic medical therapy and is indicative of non-IPD disease. [sup 123]I-IBZM-SPECT could be diagnostic aid in the work-up of patients with extrapyramidal movement disorders. The response to dopaminergic drug treatment might be precluded by IBZM-SPECT in patients with Parkinsonian syndromes. (orig.)

  14. Apomorphine Penject – Emerging Evidence and Treatment Strategies for Delayed on and off Periods in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Olivier Rascol

    2014-07-01

    Full Text Available This educational symposium was held during the Joint Congress of European Neurology (EFNS–ENS, which took place from 31st May to 3rd June 2014 in Istanbul, Turkey, and was sponsored by Britannia Pharmaceuticals Limited. The symposium debated the problem of delayed ON and OFF periods in Parkinson’s disease that can occur even in patients optimised on oral medication. Emerging evidence for the rapid and effective resolution of such complications using apomorphine intermittent injection (penject was reviewed with particular reference to the positive results of the recent AM IMPAKT trial in patients with morning akinaesia. The discussions were illustrated with examples of ‘real life’ patient case studies to help determine which patients might be best suited for treatment with apomorphine injection.

  15. Differential diagnosis in patients with extrapyramidal movement disorders: 123I-IBZM-SPECT vs. apomorphine-test

    International Nuclear Information System (INIS)

    The aim of our study was to compare the striatal dopamine D2-receptor density as measured by 123I-IBZM-SPECT with the results of the apomorphine-test. 30 patients were studied; 21 with idiopathic Parkinson's disease (IPD), 9 with Parkinson plus syndromes (PPS). Patients with IPD showed a significantly higher striatal IBZM binding as compared to patients with PPS (p=0.006). A good correlation between IBZM binding and outcome of the apomorphine test was found (p=0.006). Low striatal IBZM binding indicates reduced dopamine D2-receptor density. This compromises successful dopaminergic medical therapy and is indicative of non-IPD disease. 123I-IBZM-SPECT could be diagnostic aid in the work-up of patients with extrapyramidal movement disorders. The response to dopaminergic drug treatment might be precluded by IBZM-SPECT in patients with Parkinsonian syndromes. (orig.)

  16. Langzeitergebnisse und Patientenzufriedenheit bei der kontinuierlichen subkutanen Apomorphin-Infusionstherapie (csAI) - katamnestische Erhebung von Patienten mit Parkinson

    OpenAIRE

    Kavaldjieva, Galina

    2016-01-01

    Die kontinuierliche subkutane Apomorphin-Infusionstherapie (csAI) mit portabler Minipumpe ist eine etablierte aber nicht standardisierte Therapieoption für Patienten mit idiopathischem Parkinsonsyndrom im Stadium der Wirkungsfluktuationen. In der vorliegenden Arbeit wurden mit einem semistrukturierten Interview die Langzeittherapieergebnisse, die Gründe für einen eventuellen Therapieabbruch und relevante Nebenwirkungen aller jener Patienten der Schön Klinik Schwabing, Neurologische Klinik der...

  17. Beginning-of-dose motor deterioration following the acute administration of levodopa and apomorphine in Parkinson's disease.

    OpenAIRE

    MERELLO, M; A. J. Lees

    1992-01-01

    Six Parkinsonian patients on long term levodopa therapy complained of short-lived deterioration of Parkinsonian symptoms immediately after levodopa intake. After withdrawal of the drug overnight, and following an oral challenge with levodopa/carbidopa (250/25) in all six cases, and with subcutaneous apomorphine (3 mg) in two, deterioration below base line levels of disability were observed which would not be explained by loss of sleep benefit. This occurred 10-20 minutes after levodopa challe...

  18. Intravenous administration of apomorphine does not induce long QT syndrome: Experimental evidence from in vivo canine models

    OpenAIRE

    渡辺, 雄大

    2016-01-01

    主査 : 杉薫 / タイトル : Intravenous administration of apomorphine does not induce long QT syndrome: Experimental evidence from in vivo canine models /著者 : Yudai Watanabe, Yuji Nakamura, Xin Cao, Hiroshi Ohara, Yukiko Yamazaki, Norie Murayama, Yosuke Sugiyama, Hiroko Izumi-Nakaseko, Kentaro Ando, Hiroshi Yamazaki, Atsushi Sugiyama /掲載誌 : Basic & Clinical Pharmacology & Toxicology /巻号・発行年等 : 116 (6):468-475, 2015 /

  19. The Detection of Novelty Relies on Dopaminergic Signaling: Evidence from Apomorphine's Impact on the Novelty N2

    OpenAIRE

    Mauricio Rangel-Gomez; Clayton Hickey; Therese van Amelsvoort; Pierre Bet; Martijn Meeter

    2013-01-01

    Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist) and measure the change in neurological indices of novelty processing. In sepa...

  20. Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models.

    Directory of Open Access Journals (Sweden)

    Masato Asanuma

    Full Text Available Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-parkinsonian model rats or mice lesioned with 6-hydroxydopamine. Marked improvement in apomorphine-induced rotation was noted at day 40 after intrastriatal melanoma cell transplantation. Transplantation of tyrosinase cDNA-transfected hepatoma cells, which constitutively produce L-DOPA, resulted in marked amelioration of the asymmetric apomorphine-induced rotation in hemi-parkinsonian mice and the effect was present up to 2 months. Moreover, parkinsonian mice transplanted with melanocytes from the back skin of black newborn mice, but not from albino mice, showed marked improvement in the apomorphine-induced rotation behavior up to 3 months after the transplantation. Dopamine-positive signals were seen around the surviving transplants in these experiments. Taken together with previous studies showing dopamine synthesis and metabolism by tyrosinase, these results highlight therapeutic potential of intrastriatal autograft cell transplantation of melanocytes in patients with Parkinson's disease.

  1. Potentiation of apomorphine effect on sildenafil-induced penile erection in conscious rabbits

    Institute of Scientific and Technical Information of China (English)

    Jae-YoungPark; HwancheolSon; SooWoongKim; Jae-SeungPaick

    2004-01-01

    Aim: To investigate a possible potentiation effect of apomorphine (APO) on sildenafil-induced penile erection in the conscious rabbit. Methods: Erection of male New Zealand White rabbits (3.5 - 4.0 kg, n=12) was assessed by measuring the length of the uncovered penile mucosa and the duration of erection before and after intravenous administration of agents. After injection of APO (0, 0.05, 0.1 and 0.4 mg/kg), sildenafil was administered intravenously in a dose-response manner (0.5, 1 and 5 mg/kg). In additional experiments, the effect of increasing doses of sildenafil in combination with APO on systemic blood pressure was evaluated. Results: Systemic administration of sildenafil induced a dose-dependent increase in the penile length. Intravenous injection of APO alone did not produce any change in the penile length, while significantly enhanced the penile erection induced by sildenafil. The co-administration of 0.1 mg/kg of APO and 1 mg/kg of sildenafil was found to be the most effective combination in producing penile erection. Intravenous administration of sildenafil caused a concentration-dependent decrease in systemic blood pressure, but no additional decrease was observed with co-administration of APO. Conclusion: APO enhances the penile erection induced by sildenafil in the conscious rabbit without causing an additional decrease in blood pressure. (Asian J Androl 2004 Sep; 6: 205-209)

  2. Chicks from a high and low feather pecking line of laying hens differ in apomorphine sensitivity.

    Science.gov (United States)

    van Hierden, Yvonne M; Koolhaas, Jaap M; Kost'ál, L'ubor; Výboh, Pavel; Sedlacková, Monika; Rajman, Marek; Juráni, Marian; Mechiel Korte, S

    2005-03-16

    Proactive rodents show a larger behavioral response to apomorphine (APO) than reactive copers, suggesting a more sensitive DA system in proactive individuals. Previously, chicks from a high feather pecking (HFP) and low feather pecking line (LFP) have been suggested to display a proactive and reactive coping strategy, respectively. Therefore, at approximately 4 weeks of age, the behavior of 48 LFP and 48 HFP chicks in response to an APO injection was studied using an open field. Another objective of the present study was to determine whether behavioral variation (in an open field) between HFP and LFP birds, after APO injection, is also reflected by variation of D(1) and D(2) receptor densities in the brain. Receptor binding capacities were assessed by measuring specific binding of tritiated D(1) and D(2) receptor ligands in different regions of the brain of control HFP and LFP chicks. In the present study, it is shown that indeed HFP chicks display a more enhanced behavioral response to acute APO treatment (0.5 mg/kg BW) than LFP birds in an open field. This difference was not reflected by variation of D(1) and D(2) receptor densities in the brain between both lines. PMID:15763586

  3. Non-opiate [beta]-endorphin fragments and dopamine--II [beta]-endorphin 2-9 enhances apomorphine-induced stereotypy following subcutaneous and intra-striatal injection

    NARCIS (Netherlands)

    Ree, J.M. van

    1982-01-01

    The non-opiate β-endorphin (βE) fragment 2–16 (des Tyr1-α-endorphin) enhanced apomorphine-induced stereotyped sniffing in rats, but did not interfere with the hypoactivity elicited by small doses of apomorphine. Structure-activity relationship studies revealed that the active moiety of α-endorphin f

  4. Effect of apomorphine on growth hormone and prolactin secretion in schizophrenic patients, with or without oral dyskinesia, withdrawn from chronic neuroleptic therapy.

    Science.gov (United States)

    Ettigi, P; Nair, N P; Lal, S; Cervantes, P; Guyda, H

    1976-01-01

    Serum growth hormone (GH) and prolactin (PRL) concentrations were measured after administration of the dopamine receptor agonist, apomorphine HC1 (0.75 mg subcutaneously), to 17 chronic schizophrenic patients, four of whom had an oral dyskinesia, who were withdrawn from chronic neuroleptic therapy for periods of two to 15 weeks, and in 21 control subjects (normal volunteers or physically healthy alcoholics not exposed to neuroleptics). Six of the schizophrenic patients, but none of the controls, had raised baseline levels of GH (greater than 6 ng/ml). After apomorphine all controls showed an increase in serum GH with a peak concentration of 9 ng/ml or more, whereas eight subjects withdrawn from neuroleptics showed an inadequate response (peak less than 6 ng/ml) and in two others an inadequate response was obtained on one of two trials. The peak GH concentration was significantly less after apomorphine in patients withdrawn from neuroleptics (11.90 +/- 3.19 ng/ml) compared with controls (20.80 +/- 2.11 ng/ml) (P less than 0.05). Among patients withdrawn from neuroleptics, those with an oral dyskinesia had significantly lower peak GH concentration 2.46 +/- 0.93 ng/ml) after apomorphine compared with those without (14.85 +/- 3.83 ng/ml) (P less than 0.05). There were no differences in serum PRL concentrations, before or after apomorphine administration, between patients withdrawn from neuroleptics and controls. In uncontrolled observations none of the four patients with an oral dyskinesia showed any worsening of the movement disorder after apomorphine. These data provide no evidence for supersensitivity of dopamine receptors in chronic schizophrenic patients withdrawn from chronic neuroleptic therapy. PMID:993808

  5. R-apomorphine protects against 6-hydroxydopamine-induced nigrostriatal damage in rat.

    Science.gov (United States)

    Yuan, Hong; Liang, Li-Wu; Chen, Zheng-Jing; Ji, Hui-Ru; Wang, Mei-Kang; Zhang, Hai-Ying; Li, Cao; Xu, Jian-Yang

    2006-11-01

    Objective The aim of the present study was not only to assess the retrograde degenerative changes in the dopaminergic neurons of the substantia nigra (SN) and ventral tegmental area (VTA) after injection of 6-hydroxydopamine (6-OHDA) into the striatum, but also to use this 6-OHDA model of Parkinson's disease to explore the possible neuroprotective effect of R-apomorphine (R-APO). Methods The partial lesion was obtained by intrastriatal administration of 6-OHDA. R-APO administration (10 mg/kg, s.c.) started 15 min prior to lesioning and continued daily for another 22 days post surgery. Testing was carried out 5 weeks after lesioning. We investigated the histology and associated behavior and neurochemical changes. Structural and functional deficits were quantified by tyrosine hydroxylase (TH) / Nissl-staining cell number counting, striatal dopamine (DA) content determination and amphetamine-induced rotation analysis. Results R-APO-treatment attenuated the amphetamine-induced ipsiversive rotation 5 weeks after the lesion induction. R-APO administration for 22 days significantly reduced the size of the lesion at the level of the SN from 50% (control group) to 69%. Moreover, the cell shape resembled that observed in the intact animals. R-APO treatment significantly increased the number of cells in both the lesion and the intact sides of VTA by 60%, suggesting selective neurotrophic effect of R-APO in this area. Finally, R-APO-treatment significantly attenuated the 6-OHDA-induced striatal DA depletion and normalized dihydroxyphenylacetic acid (DOPAC)/DA ratios. Conclusion We conclude that R-APO has neuroprotective and possible neurotrophic effect on a striatal lesion with 6-OHDA, suggesting that this drug may have rescuing properties in patients with early stage Parkinson's disease. These effects are more pronounced in VTA and enhance with duration of treatment. PMID:17690718

  6. Quality of life in Parkinson's disease improved by apomorphine pump: the OPTIPUMP cohort study.

    Science.gov (United States)

    Drapier, Sophie; Eusebio, Alexandre; Degos, Bertrand; Vérin, Marc; Durif, Franck; Azulay, Jean Philippe; Viallet, François; Rouaud, Tiphaine; Moreau, Caroline; Defebvre, Luc; Fraix, Valerie; Tranchant, Christine; Andre, Karine; Courbon, Christine Brefel; Roze, Emmanuel; Devos, David

    2016-06-01

    To report on OPTIPUMP, a cohort study, investigating the impact in real-life clinical settings of continuous subcutaneous apomorphine infusion (CSAI) on the quality of life (HRQoL) of patients with Parkinson's disease. OPTIPUMP was a prospective, open-label, observational cohort study involving 30 investigational sites in France. CSAI was proposed as part of routine clinical care to patients aged ≥18 years, in absence of dementia, with a PD diagnosis and based on the presence of motor fluctuations not controlled by oral treatments. The impact of APO-pump on quality of life was evaluated as the difference in PDQ-39 scores between the initiation treatment and the follow-up visit after 6 months' treatment. All adverse events were recorded. Hyper- and hypodopaminergic behavioral tolerance was assessed on the Ardouin Scale of Behavior in Parkinson's Disease. Between September 2011 and January 2013, we enrolled 142 patients: 42 patients were withdrawn due to pump removal (33), death (4), lost of follow-up (4), no available data (1). 100 completed the study. At 6 months, their HRQoL had significantly improved (p = 0.011), as had their total UPDRS score (p < 0.001). Regarding the safety profile, Ardouin scale scores indicated that their hyperdopaminergic behaviors had not increased. CSAI had a favorable impact on HRQoL, with benefits outweighing risks. The analysis of the withdrawn patients highlights the heterogeneity of the use of the pump having an impact on its efficacy and tolerability. PMID:27060084

  7. Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice.

    Science.gov (United States)

    Orikasa, Shuzo; Nabeshima, Kazumi; Iwabuchi, Noriyuki; Xiao, Jin-Zhong

    2016-01-01

    Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (10(9) CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia. PMID:27508116

  8. Intravenous administration of apomorphine does not induce long QT syndrome: Experimental evidence from in vivo canine models

    OpenAIRE

    渡辺, 雄大

    2016-01-01

    主査 : 杉薫 / タイトル : Intravenous administration of apomorphine does not induce long QT syndrome: Experimental evidence from in vivo canine models /著者 : Yudai Watanabe, Yuji Nakamura, Xin Cao, Hiroshi Ohara, Yukiko Yamazaki, Norie Murayama, Yosuke Sugiyama, Hiroko Izumi-Nakaseko, Kentaro Ando, Hiroshi Yamazaki, Atsushi Sugiyama /掲載誌 : Basic & Clinical Pharmacology & Toxicology /巻号・発行年等 : 116 (6):468-475, 2015 /本文ファイル: 査読後原稿 /This is the peer reviewed version of the following article:Basic & Clinic...

  9. The hypomotility elicited by small doses of apomorphine seems exclusively mediated by dopaminergic systems in the nucleus accumbens

    OpenAIRE

    Radhakishun, F.S.; de Ree, J M

    1987-01-01

    The reduction of motor activity elicited in rats by a subcutaneous injection of a small dose of apomorphine was reversed by pretreatment of the nucleus accumbens with haloperidol (10 pg), sulpride (10 pg) or desenkephalin-γ-endorphin (DEγE) (100 pg or 10 ng). These doses of the compounds did not change motor activity in placebo-treated rats. Pretreatment of the nucleus caudatus with the same neuroleptics or DEγE did not diminish the effect of subcutaneously administered low doses of apomorphi...

  10. The effects of apomorphine upon local cerebral glucose utilization in conscious rats and in rats anesthetized with chloral hydrate

    Energy Technology Data Exchange (ETDEWEB)

    Grome, J.J.; McCulloch, J.

    1983-02-01

    The effects of the dopaminergic agonist apomorphine (1 mg . kg-1 i.v.) upon local cerebral glucose utilization in 43 anatomically discrete regions of the CNS were examined in conscious, lightly restrained rats and in rats anesthetized with chloral hydrate by means of the quantitative autoradiographic (/sup 14/C)2-deoxyglucose technique. In animals anesthetized with chloral hydrate, glucose utilization was reduced throughout all regions of the CNS from the levels observed in conscious animals, although the magnitude of the reductions in glucose use displayed considerable regional heterogeneity. With chloral hydrate anesthesia, the proportionately most marked reductions in glucose use (by 40-60% from conscious levels) were noted in primary auditory nuclei, thalmaic relay nuclei, and neocortex, and the least pronounced reductions in glucose use (by 15-25% from conscious levels) were observed in limbic areas, some motor relay nuclei, and white matter. In conscious, lightly restrained rats, the administration of apomorphine (1 mg . kg-1) effected significant increased in glucose utilization in 15 regions of the CNS (e.g., subthalamic nucleus, ventral thalamic nucleus, rostral neocortex, substantia nigra, pars reticulata), and significant reductions in glucose utilization in two regions of the CNS (lateral habenular nucleus and anterior cingulate cortex).

  11. The effect of acute Lithium and AMI-193, a new 5HT2 antagonist, on Apomorphine-induced pecking in pigeon

    Directory of Open Access Journals (Sweden)

    Bagheri T

    2002-06-01

    Full Text Available Intramascular (IM administration of apomorphine (a mixed D1/D2 dopamine receptors agonist 0.2-1.6 mg/kg induced pecking, a stereotype behavior in pigeons in a dose- dependent manner. In this study the effect of lithium (Li+, 240 mg/kg, IM and AMI-193 (a new 5-HT2 antagonist, 0.003 mg/pigeon on apomorphine-induced peking (AIP were investigated. This study showed that Li+ and AMI-193 did not induce pecking by itself but administration of each of these agents before apomorphine increased and decreased the AIP (apomor-phine 0.8 mg/kg respectively whereas concomitant use of Li+ (240 mg/kg IM and AMI-193 decreased AIP significantly. These results suggested that 5-HT2 antagonists inhibit the inhibitory effect of serotonin on the dopamine release in the raphe-striatal pathway but Li+ can modulate dopamine and serotonin function by different mechanisms and decrease this effect. As a result, it is mechanisms and decrease this effect. As a result, it is concluded serotonin can decrease the AIP through 5-HT2 receptors indirectly by decrease the dopamine release.

  12. Effects of chronic mild stress on apomorphine induced behavioral sensitization in different brain regions of rats in relation to serotonin change

    OpenAIRE

    Muhammad Farhan; Darakshan Jabeen Haleem

    2015-01-01

    Background: The impacts of unpredictable stressors have influence on neurochemical and behavioral parameters in laboratory animals. Stress induced behavioral changes particularly those associated with anxiety like behavior may activate topographically organized mesolimbic cortical serotonergic system. This study was designed to investigate the influence of unpredictable stress on behavioral and neurochemical parameters in apomorphine treated rats. Methods: Initially, the animals were divid...

  13. Non-opiate [beta]-endorphin fragments and dopamine--I the neuroleptic-like [gamma]-endorphin fragments interfere with the behavioural effects elicited by small doses of apomorphine

    OpenAIRE

    de Ree, J M; Innemee, H.; Louwerens, J. W.; Kahn, R.S.; Wied, D. de

    1982-01-01

    In rats, the β- endorphin fragment, 6–17 (des-enkephalin-γ-endorphin, DEγE), dose-dependently antagonized the reduction of the rate of locomotion and rearing induced by small doses of apomorphine. Structure-activity studies revealed that the active moiety of γ-endorphin fragments with respect to counteracting apomorphine-induced behavioural changes resides in the fragment 6–17. The influence of DEγE appeared to be specific for dopamine systems mediating apomorphine-induced hypomotility, since...

  14. Non-opiate [beta]-endorphin fragments and dopamine--II [beta]-endorphin 2-9 enhances apomorphine-induced stereotypy following subcutaneous and intra-striatal injection

    OpenAIRE

    de Ree, J M

    1982-01-01

    The non-opiate β-endorphin (βE) fragment 2–16 (des Tyr1-α-endorphin) enhanced apomorphine-induced stereotyped sniffing in rats, but did not interfere with the hypoactivity elicited by small doses of apomorphine. Structure-activity relationship studies revealed that the active moiety of α-endorphin fragments with respect to their potentiating effects on apomorphine-induced stereotyped sniffing resides in the βE fragment 2–9. Subsequent studies showed that the potentiating influence of βE 2–9 w...

  15. Effect of continuous exposure to apomorphine and acute exposure to fluphenazine-N-mustard on dopaminergic behavior and radioligand binding in supersensitive mice

    Energy Technology Data Exchange (ETDEWEB)

    Winkler, J.D.

    1987-01-01

    Mice with unilateral, 6-hydroxydopamine-induced lesions of the corpus striatum were exposed to continuous infusion of apomorphine via a subcutaneously implanted osmotic pump. The turning response of these mice when challenged with an acute injection of apomorphine was significantly reduced at one day after chronic implantation and was totally absent at two and four days after implantation. This effect of continuous exposure to apomorphine was found to be concentration- and time-dependent as well as reversible when the implant was removed. Mice tolerant to apomorphine were cross-tolerant to the rotational effects of the D{sub 1} dopaminergic agonist SKF 38393 and the D{sub 2} dopaminergic agonist Ly 171555, but not to amphetamine. Continuous exposure to apomorphine resulted in a decrease in the binding of ({sup 3}H)spiroperidol (D{sub 2} sites) by 44%, whereas the binding of ({sup 3}H)SCH 23390 (D{sub 1} sites) was not affected. Fluphenazine-N-mustard (FNM) has been shown to bind irreversibly to dopaminergic sites. Experiments using varying doses of FNM demonstrated that FNM inhibited Ly 171555-induced rotational behavior at doses ten fold lower than those required to block rotations induced by SKF 38393. In vitro, FNM inhibited the specific binding of ({sup 3}H) spiroperidol at concentrations ten fold lower than those required to inhibit the binding of ({sup 3}H)Sch23390. In vivo, FNM inhibited the binding of ({sup 3}H) spiroperidol measured ex vivo, but did not inhibit the binding of ({sup 3}H) Sch 23390, even when given in doses as high as 100 mg/kg. These studies indicate that FNM was approximately ten times more potent at inhibiting D{sub 2} than D{sub 1} mediated behavior and at displacing D{sub 2} versus D{sub 1} ligands, suggesting that FNM may be useful for studying and differentiating D{sub 2} and D{sub 1} mediated events.

  16. Presynaptic inhibitory dopamine receptors on noradrenergic nerve terminals: analysis of biphasic actions of dopamine and apomorphine on the release of endogenous norepinephrine in rat hypothalamic slices

    Energy Technology Data Exchange (ETDEWEB)

    Misu, Y.; Goshima, Y.; Ueda, H.; Kubo, T.

    1985-12-01

    Electrical field stimulation (5 Hz)- or high K+ (20 mM)-evoked release of endogenous norepinephrine from superfused rat hypothalamic slices in the presence of cocaine (20 microM) was measured by high-performance liquid chromatography with an electrochemical detector. Apomorphine (10-1000 nM) dose-dependently facilitated the electrically evoked release. Apomorphine (1 microM)-induced facilitation was abolished by pretreatment with yohimbine (100 nM), was converted to inhibition by yohimbine (1 microM), but was not antagonized by propranolol (300 nM). Epinephrine (100 nM) decreased the electrically evoked release and the decrease was antagonized by yohimbine (100 nM) and by apomorphine (100 nM), but not by S-sulpiride (100 nM). In the presence of yohimbine (1 microM), apomorphine (10-1000 nM) dose-dependently inhibited the electrically evoked release. Furthermore, in the presence of tetrodotoxin (300 nM), apomorphine (100 nM) also decreased the high K+-evoked release and this decrease was antagonized by S-sulpiride (100 nM). Dopamine produced biphasic actions on the electrically evoked release, a dose-dependent decrease at 30 and 100 nM and an increase at 300 and 1000 nM. Dopamine (300 nM)-induced increase was antagonized by propranolol (300 nM) but not by yohimbine (100 nM). The dopamine (100 nM)-induced decrease was antagonized by S-sulpiride (1 nM), but not by the R-isomer. S-sulpiride (10 to 100 nM) alone dose-dependently increased the electrically evoked release, whereas the R-isomer had no effect. Haloperidol (100 nM) also increased the electrically evoked release.

  17. Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

    OpenAIRE

    Suemaru, Katsuya; Yasuda, Kayo; Umeda, Kenta; Araki, Hiroaki; Shibata, Kazuhiko; Choshi, Tominari; Hibino, Satoshi; Gomita, Yutaka

    2004-01-01

    Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats.Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrup...

  18. Effects of cholecystokinin octapeptide on striatal dopamine metabolism and on apomorphine-induced stereotyped cage-climbing in mice

    International Nuclear Information System (INIS)

    The effects of sulfated (CCK-8-SE) and non-sulfated (CCK-8-NS) cholecystokinin octapeptide on striatal dopamine (DA) metabolism have been investigated on mice. CCK-8-NS facilitated the disappearance of striatal DA, measured after synthesis inhibition with 350 mg/kg of α-methyl-p-tyrosine. CCK-8-SE did not affect DA disappearance. In vitro uptake of [3H]DA by striatal slices was affected by neither CCK-8-SE, nor CCK-8-NS (10-5 M). Potassium-induced in vitro release of [3H]DA from striatal slices was significantly increased by 10-5 M CCK-8-NS: however, CCK-8-SE likewise increased DA release in this model system. Apomorphine-induced (1.0 mg/kg) stereotyped cage-climbing behavior was not affected by CCK-8-SE but was enhanced by CCK-8-NS. This effect could be antagonized by haloperidol, but not by naloxone. The data suggest that CCK-8-NS affects striatal DA release, disappearance and receptor sensitivity in the mouse. Dopaminergic mechanisms should therefore be regarded as a possible mode of action of CCK-8-NS on brain functions. (Auth.)

  19. Non-opiate [beta]-endorphin fragments and dopamine--I the neuroleptic-like [gamma]-endorphin fragments interfere with the behavioural effects elicited by small doses of apomorphine

    NARCIS (Netherlands)

    Ree, J.M. van; Innemee, H.; Louwerens, J.W.; Kahn, R.S.; Wied, D. de

    1982-01-01

    In rats, the β- endorphin fragment, 6–17 (des-enkephalin-γ-endorphin, DEγE), dose-dependently antagonized the reduction of the rate of locomotion and rearing induced by small doses of apomorphine. Structure-activity studies revealed that the active moiety of γ-endorphin fragments with respect to cou

  20. Regional blockade by neuroleptic drugs of in vivo 3H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    International Nuclear Information System (INIS)

    The regional prevention by neuroleptic drugs of specific in vivo 3H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the 3H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific 3H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal 3H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the 3H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal 3H-spiperone binding in vivo which reached 60-80% in this structure. (Author)

  1. Regional blockade by neuroleptic drugs of in vivo /sup 3/H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, C.; Haglund, L.; Oegren, S.O.; Aengeby, T. (Astra Lackemedel AB, Soedertaelje (Sweden). Dept. of Pharmacology)

    1981-01-01

    The regional prevention by neuroleptic drugs of specific in vivo /sup 3/H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the /sup 3/H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific /sup 3/H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal /sup 3/H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the /sup 3/H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal /sup 3/H-spiperone binding in vivo which reached 60-80% in this structure.

  2. Binding Interactions of Dopamine and Apomorphine in D2High and D2Low States of Human Dopamine D2 Receptor Using Computational and Experimental Techniques.

    Science.gov (United States)

    Durdagi, Serdar; Salmas, Ramin Ekhteiari; Stein, Matthias; Yurtsever, Mine; Seeman, Philip

    2016-02-17

    We have recently reported G-protein coupled receptor (GPCR) model structures for the active and inactive states of the human dopamine D2 receptor (D2R) using adrenergic crystal structures as templates. Since the therapeutic concentrations of dopamine agonists that suppress the release of prolactin are the same as those that act at the high-affinity state of the D2 receptor (D2High), D2High in the anterior pituitary gland is considered to be the functional state of the receptor. In addition, the therapeutic concentrations of anti-Parkinson drugs are also related to the dissociation constants in the D2High form of the receptor. The discrimination between the high- and low-affinity (D2Low) components of the D2R is not obvious and requires advanced computer-assisted structural biology investigations. Therefore, in this work, the derived D2High and D2Low receptor models (GPCR monomer and dimer three-dimensional structures) are used as drug-binding targets to investigate binding interactions of dopamine and apomorphine. The study reveals a match between the experimental dissociation constants of dopamine and apomorphine at their high- and low-affinity sites of the D2 receptor in monomer and dimer and their calculated dissociation constants. The allosteric receptor-receptor interaction for dopamine D2R dimer is associated with the accessibility of adjacent residues of transmembrane region 4. The measured negative cooperativity between agonist ligand at dopamine D2 receptor is also correctly predicted using the D2R homodimerization model. PMID:26645629

  3. Post-trial dopaminergic modulation of conditioned catalepsy: A single apomorphine induced increase/decrease in dopaminergic activation immediately following a conditioned catalepsy response can reverse/enhance a haloperidol conditioned and sensitized catalepsy response.

    Science.gov (United States)

    Oliveira, Lucas Rangel; Dias, Flávia Regina Cruz; Santos, Breno Garone; Silva, Jade Leal Loureiro; Carey, Robert J; Carrera, Marinete Pinheiro

    2016-09-15

    Haloperidol can induce catalepsy and this drug effect can be conditioned as well as sensitized to contextual cues. We used a paired/unpaired Pavlovian conditioning protocol to establish haloperidol catalepsy conditioned and sensitized responses. Groups of rats were given 10 daily catalepsy tests following administration of vehicle (n=24) or haloperidol (1.0mg/kg) either paired (n=18) or unpaired (n=18) to testing. Subsequently, testing for conditioning was conducted and conditioning and sensitization of catalepsy were observed selectively in the paired group. Immediately following a second test for catalepsy conditioning, the groups were subdivided into 4 vehicle groups, 3 unpaired haloperidol groups and 3 paired haloperidol groups and were given one of three post-trial treatments (vehicle, 0.05mg/kg or 2.0mg/kg apomorphine). One day later the conditioned catalepsy test 3 was carried out and on the next day, a haloperidol challenge test was performed. The post-trial apomorphine treatments had major effects on the paired groups upon both conditioning and the haloperidol challenge test. The low dose apomorphine post-trial treatment enhanced both the conditioned and the haloperidol sensitized catalepsy responses. The high dose apomorphine post-trial treatment eliminated conditioned catalepsy and eliminated the initial acute catalepsy response to haloperidol that was induced in the vehicle control groups. These results demonstrate the sensitivity of conditioned drug cues to modification by increases/decreases in activity of the dopamine system in the immediate post-trial interval after a conditioning trial. This demonstration that post-trial dopaminergic drug treatments can modify conditioned drug behavior has broad implications for conditioned drug effects. PMID:27173428

  4. The effect of apomorphine on visual discrimination learning and reversal learning in rats%阿扑吗啡注射对大鼠视觉线索辨别学习和逆反学习的影响

    Institute of Scientific and Technical Information of China (English)

    邵枫; 李量; 王玮文

    2008-01-01

    Objective Using apomorphine, a potent dopamine receptor agonist and rotating T-maze, the effect of apomorphine on the visual discrimination learning and reversal learning in rats was investigated. Methods All rats were trained in a visual discrimination task (food reward and light stimulus) in rotating T-maze. After reaching the acquisition criterion, rats were trained in a reversal task (food reward and without light stimulus) in the same maze. During the period of visual discrimination task, apomorphine was administrated either 30 minutes prior to learning or after learning immediately. Results The results showed that apomorphine, which was given either 30 minutes prior to visual discrimination learning or after learning, could impair the acquisition of discrimination learning( 259.20±26.29 and 264.00±16.97, compared to 168.00±16.97 and 163.20±20.08) and apomorphine, which was given only after visual discrimination learning, could impair the acquisition of reversal learning (451.20±39.44 compared to 360.00±29.39). Conclusion The results showed that apomorphine, which was given either 30 minutes prior to visual discrimination learning or after learning, could impair the acquisition of discrimination learning and apomorphine, which was given only after visual discrimination learning, could impair the acquisition of reversal learning.%目的 利用阿扑吗啡和旋转T迷宫装置,观察阿扑吗啡对大鼠视觉线索辨别学习和逆反学习的影响.方法 首先通过食物奖励与灯光线索的结合,训练所有动物的视觉线索辨别学习任务.在此期间,分别在每次学习前30 min或学习后立即腹腔注射阿扑吗啡(0.5 mg/kg).当动物达到所规定的学习标准后,开始逆反学习的训练.结果 与生理盐水注射组相比[学习次数分别为(168.00±16.97)次和(163.20±20.08)次],视觉线索辨别学习前、后的阿扑吗啡注射都能干扰视觉线索辨别学习任务的获得[学习次数分别为(259.20

  5. Efficacy of Compound Xuanju Capsule combined with apomorphine hydrochloride on erectile dysfunction%复方玄驹胶囊联合盐酸阿朴吗啡治疗勃起功能障碍的临床研究

    Institute of Scientific and Technical Information of China (English)

    王宝庆

    2012-01-01

    To investigate the clinical effect of Compound Xuanju Capsule combined with apomorphine hydrochloride on penile erectile dysfunction (ED). Methods: We treated 115 ED patients with Compound Xuanju Capsule plus apomorphine hydro-chlorid (trial group) , and another 111 with apomorphine hydrochloride alone (control group) , both for two months. Then we compared the IIEF-5 scores between the two groups. Results: After treatment, the IIEF-5 scores were 17. 85 ±2. 68 and 13. 96 ±3. 25 in the trial and control group, respectively, significantly higher than 11.42 ±2.68 and 13.96 ±3.25 before treatment (P<0.01). There were statistically significant differences between the two groups either in post-treatment IIEF-5 scores (P < 0.01) or in the rates of obvious effectiveness, effectiveness and total effectiveness. Conclusion: Compound Xuanju Capsule combined with apomorphine hydrochloride has a good curative effect on ED, and deserves general clinical application.%目的:观察复方玄驹胶囊联合盐酸阿朴吗啡治疗阴茎勃起功能障碍(ED)的疗效. 方法:采用复方玄驹胶囊联合盐酸阿朴吗啡治疗115例ED患者为治疗组,单用盐酸阿朴吗啡治疗111例作为对照组,经连续2个月的治疗后,观察两组的国际勃起功能问卷(IIEF-5)的评分改变情况. 结果:治疗组与对照组IIEF-5的评分在治疗前分别为(11.42±2.38)、(11.56±2.65)分,两组比较差异无显著性(P>0.05);治疗后分别为(17.85±2.68)、(13.96±3.25)分,均有明显提高(P<0.01),而治疗组在治疗后的评分明显高于对照组(P<0.01);治疗组的显效率、有效率和总有效率均高于对照组. 结论:复方玄驹胶囊联合盐酸阿朴吗啡治疗ED有较好疗效,值得临床推广使用.

  6. 液相色谱-串联质谱法测定人血浆中阿扑吗啡%Liquid Chromatographic-Tandem Mass Spectrometric Assay for Determination of the Apomorphine in Human Plasma

    Institute of Scientific and Technical Information of China (English)

    郭继芬; 张爱军; 赵玲; 孙晓红; 乔善义; 赵毅民

    2004-01-01

      盐酸阿扑吗啡(apomorphine hydrochloride)为吗啡的衍生物,系中枢多巴胺D2受体激动剂,其舌下片制剂是目前用于治疗男性勃起机能障碍的新药[1,2].为了研究该制剂中阿扑吗啡的药代动力学特性,我们建立了阿扑吗啡血药浓度测定的液相色谱-串联质谱法.测定了28名健康志愿者口服阿扑吗啡舌下片后阿扑吗啡的血药浓度.……

  7. 阿朴吗啡诱导黑质毁损大鼠腹侧被盖区c-jun表达%Apomorphine induce c-jun expression in ventral tagmental area of 6-OHDA-lesioned rats

    Institute of Scientific and Technical Information of China (English)

    陈晓宇; 姚玉芹; 沈韶辉; 韩卉

    2006-01-01

    目的:观察6-羟基多巴胺(6-hydroxydopamine,6-OHDA)毁损黑质DA能神经元后,不同时间点腹腔注射阿朴吗啡(Apomorphine,APO)大鼠行为学及中脑腹侧被盖区(ventraltagmental area,VTA)形态学、c-jun表达情况,探讨其可能机制.方法:6-OHDA单侧一点注射大鼠右黑质致密区(substantianigracompacta,SNc),特异性毁损DA能神经元;术后1、3、7、14、21d腹腔注射APO,观察旋转行为;利用电镜、尼氏染色、免疫组织化学ABC法,观察各时间点VTA DA能神经元形态学变化和酪氨酸羟化酶(TH)、c-jun表达情况.结果:毁损侧VTA DA能神经元逐渐减少,超微结构损伤逐渐加重;DA神经元丢失≥75%时,APO诱导的旋转实验≥7r/min,VTA毁损侧c-jun表达.结论:APO能诱导毁损侧VTA表达c-jun;c-jun表达与DA能神经元毁损程度有一定的关系.

  8. Effects of puberty apomorphine injection on the latent inhibition and elevated plus-maze behaviors of rats%青春期阿扑吗啡注射对大鼠潜伏抑制和高架十字迷宫行为的影响

    Institute of Scientific and Technical Information of China (English)

    刘美; 王玮文; 金暕; 邵枫

    2008-01-01

    目的 观察青春期(出生后38~51 d)阿扑吗啡注射对大鼠精神相关行为的影响.方法 以Wistar大鼠为实验对象,利用大鼠穿梭程序自动控制仪和高架十字迷宫,观察青春期(出生后38~51 d)阿扑吗啡注射对青春期和成年早期大鼠潜伏抑制和高架十字迷宫行为的影响.结果 (1)对于青春期大鼠,与生理盐水注射组动物相比[前呈现组和非前呈现组分别为(38.1±18.7)次和(23.0±6.9)次],声音刺激的前呈现未能显著地降低阿扑吗啡注射组动物的条件化联合反应[前呈现组和非前呈现组分别为(23.0±16.4)次和(26.7±13.5)次],即表现出潜伏抑制缺失;对于成年早期大鼠,与生理盐水注射组动物相比[前呈现组和非前呈现组分别为(37.2±17.5)次和(15±6.2)次],青春期阿扑吗啡注射的大鼠同样表现出潜伏抑制缺失[前呈现组和非前呈现组分别为(21.5±15.2)次和(17.2±8)次];(2)与相应的生理盐水组动物相比,青春期阿扑吗啡注射的青春期和成年早期动物的高架十字迷宫行为均差异无显著性.结论 青春期持续两周(出生后38~51 d)的慢性阿扑吗啡注射,能诱发青春期和成年早期大鼠的潜伏抑制缺失,但不影响高架十字迷宫行为.%Objective To investigate the effect of puberty (PN38~51) apomorphine injection on the psychotic behaviors of rats. Methods Using computer-controlled automatic shuttle box and elevated plus-maze, the effects of puberty apomorphine injection on the latent inhibition and elevated plus-maze behaviors in puberty and early adult wistar rats were observed. Results (1) For puberty rats, compared to saline injection rats(conditioned reaction in preexposure and non-preexposure group was 38.1±18.7 and 23.0±6.9, respectively), conditioned reaction of apomorphine injection rats could not be reduced significantly by the pre-exposed sound stimulus (23.0±16.4 and 26.7±13.5, respectively), that is latent inhibition deficient

  9. Apomorphine reduces subthalamic neuronal entropy in parkinsonian patients

    OpenAIRE

    Lafreniere-Roula, M; Darbin, O; Hutchison, WD; Wichmann, T; Lozano, A.; Dostrovsky, JO

    2010-01-01

    Dopamine depletion in Parkinson's disease (PD) alters the neuronal activity in basal ganglia circuits. Characterizing these changes in network activity is an important step in understanding the disease and how therapies mitigate symptoms. Non-linear analysis methods can complement the traditional description of neuronal firing characteristics. Here we examine the entropy of subthalamic neurons in PD patients undergoing stereotactic surgery for deep brain stimulation (DBS). The activity of 8 n...

  10. Theranostic liposomes loaded with quantum dots and apomorphine for brain targeting and bioimaging

    OpenAIRE

    Wen CJ; Zhang LW; Al-Suwayeh SA; Yen TC; Fang JY

    2012-01-01

    Chih-Jen Wen1,*, Li-Wen Zhang2,*, Saleh A Al-Suwayeh3, Tzu-Chen Yen1, Jia-You Fang2,4 1Molecular Imaging Center, Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan; 2Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Gueishan, Taoyuan, Taiwan; 3Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 4Department of Cosmetic Science, Chang Gung University of Science and Technology, Gueishan, Taoyuan, Taiwan *These ...

  11. Parkinson's disease, visual hallucinations and apomorphine : A review of the available evidence

    NARCIS (Netherlands)

    Borgemeester, Robbert W. K.; Lees, Andrew J.; van Laar, Teus

    2016-01-01

    Background: Visual hallucinations (VH) occur in the clinical course of Parkinson's disease (PD) and are predictive for PD dementia. The genesis of VH is related to impaired bottom-up and/or top-down visual processing which can be linked to cholinergic dysfunction and mono-amine imbalance. The risk o

  12. Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats.

    NARCIS (Netherlands)

    Kam, E.L. van der; Coolen, E.J.; Ellenbroek, B.A.; Cools, A.R.

    2006-01-01

    Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two

  13. Apomorphine and Erectile Dysfunction%阿扑吗啡与勃起功能障碍

    Institute of Scientific and Technical Information of China (English)

    谭大清; 姚颐; 张杰

    2007-01-01

    ED是男科的常见病之一,其一线治疗方法是口服药物.阿扑吗啡(APO)作为中枢多巴胺受体激动剂,其舌下含片几乎对不同程度的ED患者都有效,且起效快、耐受性好、安全性高,特别是对于接受硝酸盐治疗而禁用西地那非的患者.现对其药代动力学、作用机制及疗效、安全性进行综述.

  14. BEHAVIORAL-DIFFERENCES BETWEEN ARTIFICIALLY SELECTED AGGRESSIVE AND NONAGGRESSIVE MICE - RESPONSE TO APOMORPHINE

    NARCIS (Netherlands)

    BENUS, RF; BOHUS, B; KOOLHAAS, JM; VANOORTMERSSEN, GA

    1991-01-01

    The present study reports a first attempt to unravel the neurochemical background that underlies the difference in behavioural profiles between aggressive and non-aggressive male mice. For this purpose two bidirectionally selected lines for attack latency (SAL and LAL) were used. In pursuit of Cools

  15. Behavioural differences between artificially selected aggressive and non-aggressive mice : response to apomorphine

    NARCIS (Netherlands)

    Benus, Rensina F.; Bohus, Bela; Koolhaas, Jaap M.; Oortmerssen, Geert A. van

    1991-01-01

    The present study reports a first attempt to unravel the neurochemical background that underlies the difference in behavioural profiles between aggressive and non-aggressive male mice. For this purpose two bidirectionally selected lines for attack latency (SAL and LAL) were used. In pursuit of anoth

  16. The effect of apomorphine administration on smooth pursuit ocular movements in early Parkinsonian patients

    Czech Academy of Sciences Publication Activity Database

    Bareš, M.; Brázdil, M.; Kaňovský, P.; Jurák, Pavel; Daniel, P.; Kukleta, M.; Rektor, I.

    2003-01-01

    Roč. 9, č. 3 (2003), s. 139 - 144. ISSN 1353-8020 Institutional research plan: CEZ:AV0Z2065902 Keywords : supplementary eye field * smooth eye movements * Parkinson's disease Subject RIV: FA - Cardiovascular Disease s incl. Cardiotharic Surgery Impact factor: 2.143, year: 2003

  17. The development of various somatic markers is retarded in an animal model for schizophrenia, namely apomorphine-susceptible rats.

    NARCIS (Netherlands)

    Degen, S.; Ellenbroek, B.A.; Wiegant, V.M.; Cools, A.R.

    2005-01-01

    Although schizophrenia usually sets on after puberty, deviations of normal development exist in pre-schizophrenic children. To investigate the presence of early developmental abnormalities in a valid animal model for schizophrenia, we delineated line-specific developmental differences between apomor

  18. Transplantation of Melanocytes Obtained from the Skin Ameliorates Apomorphine-Induced Abnormal Behavior in Rodent Hemi-Parkinsonian Models

    OpenAIRE

    Masato Asanuma; Ikuko Miyazaki; Diaz-Corrales, Francisco J.; Youichirou Higashi; Masayoshi Namba; Norio Ogawa

    2013-01-01

    Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-park...

  19. Effective Delivery of Apomorphine in the Management of Parkinson Disease : Practical Considerations for Clinicians and Parkinson Nurses

    NARCIS (Netherlands)

    Bhidayasiri, Roongroj; Chaudhuri, K. Ray; LeWitt, Peter; Martin, Anne; Boonpang, Kamolwan; van Laar, Teus

    2015-01-01

    The clinical utility of long-term oral levodopa therapy in Parkinson disease (PD) is often limited by the emergence of motor complications. Over time, many patients with PD experience regular and/or unpredictable "off" periods, despite taking optimized oral medication regimens, with a major negative

  20. Transplantation of melanocytes obtained from the skin ameliorates apomorphine-induced abnormal behavior in rodent hemi-parkinsonian models

    OpenAIRE

    Asanuma, Masato; Miyazaki, Ikuko; Francisco J., Diaz-Corrales; Higashi, Youichirou; Namba, Masayoshi; Ogawa,Norio

    2013-01-01

    Tyrosinase, which catalyzes both the hydroxylation of tyrosine and consequent oxidation of L-DOPA to form melanin in melanocytes, is also expressed in the brain, and oxidizes L-DOPA and dopamine. Replacement of dopamine synthesis by tyrosinase was reported in tyrosine hydroxylase null mice. To examine the potential benefits of autograft cell transplantation for patients with Parkinson's disease, tyrosinase-producing cells including melanocytes, were transplanted into the striatum of hemi-park...

  1. (±)-盐酸阿朴吗啡的合成%Synthesis of (±)-Apomorphine Hydrochloride

    Institute of Scientific and Technical Information of China (English)

    倪峰; 商海霞; 严鸣乐; 施小新; 杨凯

    2006-01-01

    异喹啉在氰化钾作用下和苯甲酰氯经Reissert反应、偶联反应和消除反应、与碘化钾反应成季铵盐、还原成四氢异喹啉、硝基还原、重氮化后经Pschorr环化反应制得(±)-阿朴吗啡二甲醚,再经氢溴酸脱甲基及与盐酸成盐得到(±)-盐酸阿朴吗啡,总收率31%.

  2. The Change in Smooth Pursuit Eye Movements in L-dopa- naive Parkinsonian Patients Following Administration of Subcutaneous Apomorphine

    Czech Academy of Sciences Publication Activity Database

    Bareš, M.; Brázdil, M.; Jurák, Pavel; Kaňovský, P.; Daniel, P.

    1998-01-01

    Roč. 13, 2-Suppl. (1998), s. 181. ISSN 0885-3185. [ Parkinson's Disease and Movement Disorders /5./. 10.10.1998-14.10.1998, New York] Subject RIV: FA - Cardiovascular Disease s incl. Cardiotharic Surgery

  3. Determination of related substances of Apomorphine hydrochloride sublingual tablet by HPLC%HPLC测定盐酸阿扑吗啡舌下片的有关物质

    Institute of Scientific and Technical Information of China (English)

    周益芬; 刘峰; 杨蕾

    2009-01-01

    目的 采用HPLC测定盐酸阿扑吗啡舌下片的有关物质.方法 采用Dimasil C18柱(250 mm×4.6 mm,5 μm);乙腈-0.04 mol·L-1磷酸二氢钾溶液(磷酸调pH3)(2:8)为流动相;检测波长272 nm.结果 盐酸阿扑吗啡进样量0.8~12.4μg与峰面积的线性关系良好(r=0.9999);最低检测限为0.8 ng.结论 所建方法准确、简便、快速,适用于盐酸阿扑吗啡舌下片的质量控制.

  4. 盐酸阿扑吗啡片的均匀度测定%Determination in homogeneous degree of apomorphine hydrochloride

    Institute of Scientific and Technical Information of China (English)

    田秀荣; 孟祥军; 王凤秋; 吕洁

    2003-01-01

    @@盐酸阿扑吗啡(apomorphine,HCI)(Ⅰ)为多巴胺受体激动剂,据报道可提高男性勃起功能障碍患者性交成功的次数[1,2]。其机理是通过兴奋脑部勃起中枢,由下丘脑发出勃起冲动,经脊髓传递,加快血液流向阴茎以治疗男性勃起功能障碍。

  5. Synthesis of derivatives of apomorphine and their biological activities%阿朴吗啡衍生物的合成及生物活性

    Institute of Scientific and Technical Information of China (English)

    何晓春; 朱蓓蓓; 周嘉伟

    2007-01-01

    目的:合成高稳定性的能提高碱性成纤维细胞生长因子(FGF-2)活性的阿朴吗啡衍生物.方法和结果:以左旋阿朴吗啡盐酸盐为原料,以酰氯为酰基化试剂合成阿朴吗啡酯类衍生物;以碘代烷为烷基化试剂合成阿朴吗啡醚类衍生物.产物结构经1H NMR、元素分析确证.对其中3个衍生物进行了促进FGF-2活性的试验.结论:此方法原料易得,反应条件温和,得到的产物有较明显的生物活性.

  6. Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior

    OpenAIRE

    Glass, Michael J.; Robinson, Danielle C.; Waters, Elizabeth; Pickel, Virginia M.

    2013-01-01

    The nucleus accumbens (Acb) contains subpopulations of neurons defined by their receptor content and potential involvement in sensorimotor gating and other behaviors that are dysfunctional in schizophrenia. In Acb neurons, the NMDA NR1 (NR1) subunit is co-expressed not only with the dopamine D1 receptor (D1R), but also with the μ-opioid receptor (μ-OR), which mediates certain behaviors that are adversely impacted by schizophrenia. The NMDA-NR1 subunit has been suggested to play a role in the ...

  7. 高效液相色谱法测定盐酸阿扑吗啡鼻喷剂中阿扑吗啡的含量及有关物质%Determination apomorphine hydrochloride and its relative substances in apomorphine hydrochloride nasal spray by HPLC

    Institute of Scientific and Technical Information of China (English)

    徐世芳; 陈爱瑛; 姜丽霞

    2006-01-01

    目的 建立盐酸阿扑吗啡鼻喷剂的含量测定及有关物质检查方法.方法 采用高效液相色谱法,色谱柱为Diamonsil C18 (5 μm,4.6 mm×150 mm),流动相为乙腈-水-磷酸(16∶ 84∶0.4),流速1.0mL·min-1,柱温30℃,UV 273 nm检测.结果 盐酸阿扑吗啡在7.2~ 934μg·mL-1(n=9)范围内线性关系良好(r=0.999 9);检测限为0.5ng,方法精密度RSD为0.8%(n=9).3批样品盐酸阿扑吗啡的含量为标示量的98.0%~98.1%,有关物质含量为0.52%~0.68%.结论 本方法专属性强,灵敏度高,重现性好,操作简便;可用于该品的质量控制.

  8. Drug: D02004 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 080(1812+1813) Neuroactive ligand-receptor interaction hsa04540(1812+1813) Gap junction map07057 Antiparkinson...tral nervous system 116 Antiparkinsonian agents 1169 Others D02004 Apomorphine hydrochloride hydrate (JAN); ... classification [BR:br08302] Antiparkinson Agents Dopamine Agonists Apomorphine D02004 Apomorphine hydrochlo

  9. 瓜蒂散与阿朴吗啡戒酒治疗的对照研究%Contrastive Study on Effects of Guadi Powder and Apomorphine on Alcohol Withdrawal

    Institute of Scientific and Technical Information of China (English)

    王文林; 李松梅; 王辉

    2008-01-01

    目的 比较瓜蒂散与阿朴吗啡戒酒的疗效.方法 利用瓜蒂散和阿朴吗啡的催吐作用,分别对30例酒依赖者进行厌恶疗法戒酒.观察并比较两组患者治疗后是否建立条件反射,不良反应和半年戒断率.结果 两组患者均建立了条件反射.瓜蒂散组患者中,16例出现腹泻,但无需做特殊处理.两组患者半年戒断率间差别无统计学意义(P>0.05).结论 瓜蒂散戒酒疗效与阿朴吗啡相当,但其价格低廉,服药方便,更有利于临床推广使用.

  10. RP-HPLC法测定盐酸阿扑吗啡舌下片含量及其有关物质%RP- HPLC Determination of Apomorphine Hydrochloride and Its Related Substance in Sublingual Tablets

    Institute of Scientific and Technical Information of China (English)

    董顺玲; 张丽容

    2005-01-01

    目的:测定盐酸阿扑吗啡舌下片含量及其有关物质吗啡.方法:以DIKMA Diamonsil C18(4.6 mm×150 mm,5 μm)为色谱柱,0.05 mol·L-1磷酸二氢钠、0.005 mol·L-1辛烷磺酸钠混合溶液(用磷酸调节pH=2.5)-乙腈(75:25)为流动相的高效液相离子对色谱法;检测波长为220 nm,流速为1.0 mL·min-1,检测浓度为100 μg·mL-1,进样量为20μL.结果:盐酸阿扑吗啡和吗啡的回收率(n=5)分别为99.6%±0.6%和99.0%±0.8%;吗啡最低检测浓度限(S/N=3)为6.8 μg·L-1.结论:本方法简便快速,分离效果好,灵敏度高,结果准确,可用于盐酸阿扑吗啡舌下片的含量测定及其有关物质研究等.

  11. Effects of NSC Transplantation on Apomorphine-Induced Rotational Behavior in the Rat Models of Parkinson Disease%神经干细胞移植对帕金森病鼠旋转行为的影响

    Institute of Scientific and Technical Information of China (English)

    梅斌; 戴冀斌; 章军建; 李进

    2003-01-01

    目的:观察神经干细胞定向移植后对帕金森病(Park inson disease,PD)鼠的旋转行为的影响.方法:建立PD模型大鼠以及体外培养神经干细胞,然后将神经干细胞悬液立体定向移植到PD模型鼠黑质纹状体区 ,测定PD模型鼠旋转行为的变化,并与对照组相比.结果:神经干细胞移植后PD模型鼠旋转行为比对照组明显减少.结论:神经干细胞移植能减轻6-羟基多巴胺对黑质纹状体多巴胺能神经元的损伤.

  12. Determination of the Content of Apomorphine Hydroehloride in its Tablets by Ultraviolet Spectrophotometry%紫外分光光度法测定盐酸阿扑吗啡片的含量

    Institute of Scientific and Technical Information of China (English)

    黄红谦; 董伍爱; 陈海峰

    2002-01-01

    目的:建立盐酸阿扑吗啡片中盐酸阿扑吗啡含量的紫外分光光度测定法。方法:以盐酸溶液为溶剂(9→1000),检测波长为272 nm。结果:线性范围、为3.16~15.80μg/ml(r=1.000);平均回收率为99.7%,RSD为0.24%(n=5)。结论:本法简便、准确、快速,利于盐酸阿扑吗啡片的质量控制。

  13. Apomorphine induced c-fos expression in the striatum of 6-OHDA-lesioned rats%阿朴吗啡诱导黑质毁损大鼠纹状体c-fos表达

    Institute of Scientific and Technical Information of China (English)

    冯定庆; 陈晓蓉

    2005-01-01

    目的观察6-羟基多巴胺(6-OHDA)毁损黑质后,不同时间点腹腔注射阿朴吗啡(APO)大鼠纹状体c-fos表达情况,探讨其可能机制.方法利用6-OHDA单侧一点注射大鼠黑质致密区(SNc),特异毁损DA能神经元;术后1、7、14、21 d腹腔注射APO,观察旋转行为;利用免疫组织化学和电镜的方法,观察各时间点黑质DA能神经元形态学变化和纹状体c-fos表达情况.结果毁损侧DA能神经元逐渐减少,超微结构损伤逐渐加重;DA神经元丢失≥80%时,APO诱导的旋转实验>7 r·min-1,纹状体毁损侧c-fos表达.结论 APO能诱导毁损侧纹状体表达c-fos,c-fos表达与DA能神经元毁损程度有一定的关系.

  14. Determination of Apomorphine Hydrochloride in Rabbits Plasma by HPLC with Fluorescence Detection%兔血浆中盐酸阿扑吗啡的HPLC-荧光法测定

    Institute of Scientific and Technical Information of China (English)

    江文明; 蒋新国; 陈钧; 高小玲; 陆伟

    2006-01-01

    建立了HPLC-荧光法测定兔血浆中盐酸阿扑吗啡的浓度.以吡哌酸为内标,采用C18柱,流动相为1mmol/LEDTA-2Na缓冲液(含0.1%三乙胺,磷酸调至pH 3.2)-乙腈(85:15).荧光检测的激发波长270nm、发射波长450nm.血浆样品经液液萃取后进样测定.盐酸阿扑吗啡在4~500ng/ml范围内线性良好,定量限为4ng/ml.平均提取回收率均大于70%,日内、日间RSD均小于10%.

  15. RP-HPLC法测定盐酸阿扑吗啡舌下片中的有关物质%Determination of related substances by RP-HPLC in apomorphine hydrochloride sublingual tablets

    Institute of Scientific and Technical Information of China (English)

    童成亮; 钟淮滨; 邵旭

    2003-01-01

    目的:建立测定盐酸阿扑吗啡舌下片有关物质的RP-HPLC法.方法:采用ODS C18色谱柱(5μm,6.0mm×150mm), 以乙腈-40mmol*L-1磷酸二氢钾溶液(用磷酸调pH至3.0)(20∶80)为流动相,检测波长为212nm,柱温为室温,流速为1mL*min-1.结果:最低检测限为2ng,精密度良好(RSD为0.62%).结论:采用RP-HPLC法测定盐酸阿扑吗啡片中的有关物质方法简便,结果准确.

  16. Apomorphine hydrochloride nasal spray validation method for microbial limit tests%盐酸阿扑吗啡鼻喷剂微生物限度检查方法的验证

    Institute of Scientific and Technical Information of China (English)

    王连兰; 郭小红

    2013-01-01

    目的 建立盐酸阿扑吗啡鼻喷剂微生物限度检查方法,所检测的样品及检验程序不得对可能存在的各类微生物产生抑制作用.方法 2010年版二部附录收载的微生物限度检查法中的薄膜过滤法进行实验.结果 薄膜过滤法试验中稀释剂对照组的菌回收率和试验组的菌回收率均大于70%,微生物没有抑制作用.结论 微生物限度检查方法可以采用薄膜过滤法.

  17. Methylxanthine-induced attenuation of pecking in chickens.

    OpenAIRE

    Zarrindast, M. R.; Nasir, T.

    1991-01-01

    1. Apomorphine induced dose-dependent pecking in chickens. 2. The response was decreased by theophylline or caffeine in a dose-dependent manner. 3. Administration of theophylline or caffeine alone did not exert any effect on pecking behaviour. 4. Dipyridamole administration neither induced pecking nor altered the pecking induced by apomorphine. 5. Administration of 5-N-ethylcarboxamide-adenosine to animals caused variable effects on pecking induced by apomorphine. The drug did not induce peck...

  18. Dopaminergic sensitization in pigeons: conditioning and other influences

    OpenAIRE

    Keller, Sabine

    2001-01-01

    Apomorphine, a direct agonist of the neurotransmitter dopamine, elicits oral stereotypies when administered in low dosage. Pigeons react with longlasting bursts of pecks. When repeatedly administered a dose of apomorphine, pigeons show a behavioural sensitization expressed as an increasing pecking response to the drug. This increase is found to be partly dependent on conditioning to the environmental context in which apomorphine takes effect. The results of various experiments which led to th...

  19. Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice

    Energy Technology Data Exchange (ETDEWEB)

    Silverman, P.B.

    1987-03-09

    Mice with unilateal striatal lesions created by 6-hydroxydopamine (6HDA) injection were screened for rotational (circling) behavior in response to injection of amphetamine and apomorphine. Those that rotated ipsilaterally in response to amphetamine and contralaterally in response to apomorphine were subsequently challenged with 1 to 3 g/kg (i.p.) ethanol. Surprisingly, ethanol induced dose related contralateral (apomorphine-like) rotation which, despite gross intoxication, was quite marked in most animals. No significant correlation was found between the number of turns made following ethanol and made after apomorphine or amphetamine. 14 references, 2 figures, 1 table.

  20. Further evidence on the relationship between dopamine and novelty seeking: a neuroendocrine study

    OpenAIRE

    Hansenne, Michel; Pinto, Emmanuel; Pitchot, William; REGGERS, Jean; Scantamburlo, Gabrielle; Moor, Marie; Ansseau, Marc

    2002-01-01

    In the biosocial model of Cloninger, three major personality dimensions, novelty seeking (NS), harm avoidance (HA), and reward dependence (RD) are dependent on central monoaminergic systems, respectively dopaminergic, serotonergic, and noradrenergic. This study investigated the relationships between these major personality dimensions and growth hormone (GH) responses to both apomorphine and clonidine challenge tests in healthy subjects. GH responses to apomorphine were significantly correlate...

  1. Drug: D07460 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nteraction hsa04540(1812+1813) Gap junction map07057 Antiparkinsonian agents map07213 Dopamine receptor agon...ERGIC AGENTS N04BC Dopamine agonists N04BC07 Apomorphine D07460 Apomorphine (BAN) USP drug classification [BR:br08302] Antiparkinson

  2. 盐酸阿扑吗啡片剂对去势大鼠的壮阳作用和生殖器官质量的影响%Effects of Apomorphine Hydrochloride Tablet on Castrated Rats' Vital Function (yang) and the Weight of Their Genital Organ

    Institute of Scientific and Technical Information of China (English)

    符健; 邝少轶; 王世雄

    2003-01-01

    制备雄性去势大鼠模型,测定给药各组去势大鼠阴茎勃起潜伏期和生殖器官质量. 结果表明:与单纯模型组相比,盐酸阿扑吗啡在外部刺激下能提高雄性去势大鼠阴茎的兴奋性,阴茎勃起潜伏期缩短,而给药各组生殖器官的质量和脏器指数与去势大鼠模型组比较均无明显差异.盐酸阿扑吗啡对雄性去势大鼠具有壮阳作用,对生殖器官组织无明显影响.

  3. 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.

  4. Duodopa pump treatment in patients with advanced Parkinson's disease

    DEFF Research Database (Denmark)

    Karlsborg, Merete; Korbo, Lise; Regeur, Lisbeth;

    2010-01-01

    Patients with advanced Parkinson's disease (PD) often develop motor complications including fluctuations and involuntary movements (dyskinesias). In Denmark, treatment has comprised Deep Brain Stimulation (DBS) since the late 1990s, and as from 2002 use of a subcutaneous apomorphine pump...

  5. Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to normal common marmosets

    OpenAIRE

    Löschmann, P A; Smith, L A; Klaus W. Lange; Jaehnig, P.; Jenner, P.; Marsden, C. D.

    1991-01-01

    In normal common marmosets administration of the D-1/D-2 agonist apomorphine or the selective D-2 agonist quinpirole caused a dose-dependent increase in motor activity and induced stereotyped behaviour. Both the selective D-2 antagonist raclopride and the selective D-1 antagonist SCH 23390 inhibited normal locomotor activity and induced catalepsy. Quinpirole- and apomorphine-induced motor activity were potently inhibited by pretreatment with raclopride. The effects of quinpirole, but not apom...

  6. The effects of dihydropyridine compounds in behavioural tests of dopaminergic activity.

    OpenAIRE

    Bourson, A.; Gower, A. J.; Mir, A. K.; Moser, P C

    1989-01-01

    1. The effects of the dihydropyridine calcium channel blocker nifedipine and the activator Bay K 8644 were investigated in different behavioural tests involving dopaminergic systems. These were the discriminative stimulus induced by amphetamine, rotational behaviour in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions and apomorphine-induced yawning in rats. 2. The yawning induced by apomorphine (40 micrograms kg-1 s.c.) was significantly potentiated by nifedipine (5-10 mgkg-1 i.p.). Ba...

  7. Synthesis and binding studies of 2-arylapomorphines

    DEFF Research Database (Denmark)

    Søndergaard, Kåre; Kristensen, Jesper Langgaard; Palner, Mikael;

    2005-01-01

    From codeine, four different 2-aryl substituted apomorphines were synthesised in 6 steps each. Oxidation of codeine with IBX followed by acid catalysed rearrangement gave morphothebaine, which was selectively triflylated at the 2-position and subsequently O-acetylated at the 11-position. The resu......-(4-Hydroxyphenyl)- apomorphine exhibited high affinity for the dopamine D receptor. A putative ligand-receptor interaction was put forward. © The Royal Society of Chemistry 2005....

  8. INTERACTIVE EFFECTS OF DIFFERENT DURATION OF LITHIUM PRETREATMENT WITH AMIKACIN AND GENTAMICIN ONAPOMORPHINE-INDUCED LICKING IN RATS

    Directory of Open Access Journals (Sweden)

    MOHAMMAD SHARIFZADEH

    2000-07-01

    Full Text Available In this study the hypothesis that aminoglycoside antibiotics and lithium may influence apomorphine-induced licking via their effects on phosphoinositide pathways and calcium stores were investigated in male rats. Subcutaneous administration of apomorphine (0.1,0.25 and 0.5 mg/kg to rats induced licking in a dose-dependent manner and the maximum response was obtained by the dose of 0.5 mg/kg of the drug. Intracerebroventricular injections of amikacin (5, 25 and 50 ug/rat and gentamicin (10, 20 and 40 ug/rat decreased the apomorphine-induced licking significantly. Pretreatment of animals with lithium (600 mg/1 for 7,14 and 21 days increased licking induced by apomorphine. The inhibitory effects of amikacin and high dose of gentamicin were not affected by lithium pretreatment for 14 and 28 days. These findings indicate the possible involvement of phosphoinositide cascade in alterations of apomorphine-induced licking by aminoglycoside antibiotics and lithium in the brain. Also it is suggested that type and dose of aminoglycoside antibiotics and duration of lithium administration probably have different effects on responses mediated by phosphoinositide hydrolysis.

  9. Mesolimbic dopaminergic supersensitivity following electrical kindling of the amygdala

    International Nuclear Information System (INIS)

    Limbic seizures developed in rats following daily electrical stimulation of the basolateral nucleus of the amygdala. Animals were designated as kindled after five complete (stage 5) behavioral seizures were observed. A subgroup, designated as superkindled, received three additional weeks of electrical stimulations. Kindled rats were significantly subsensitive to the stereotypy-inducing effects of apomorphine, a direct dopamine agonist, compared to controls. Superkindled rats were supersensitive to the effects of apomorphine. However, both kindled and superkindled rats demonstrated an increase in 3H-spiperone Bmax values, reflecting dopamine D2-receptor densities, in the nucleus accumbens ipsilateral to the stimulating electrode. The number of interictal spikes recorded from the stimulating amygdaloid electrode during the last week of kindling was correlated with changes in apomorphine sensitivity in individual animals

  10. Mesolimbic dopaminergic supersensitivity following electrical kindling of the amygdala

    Energy Technology Data Exchange (ETDEWEB)

    Csernansky, J.G.; Mellentin, J.; Beauclair, L.; Lombrozo, L.

    1988-02-01

    Limbic seizures developed in rats following daily electrical stimulation of the basolateral nucleus of the amygdala. Animals were designated as kindled after five complete (stage 5) behavioral seizures were observed. A subgroup, designated as superkindled, received three additional weeks of electrical stimulations. Kindled rats were significantly subsensitive to the stereotypy-inducing effects of apomorphine, a direct dopamine agonist, compared to controls. Superkindled rats were supersensitive to the effects of apomorphine. However, both kindled and superkindled rats demonstrated an increase in /sup 3/H-spiperone Bmax values, reflecting dopamine D2-receptor densities, in the nucleus accumbens ipsilateral to the stimulating electrode. The number of interictal spikes recorded from the stimulating amygdaloid electrode during the last week of kindling was correlated with changes in apomorphine sensitivity in individual animals.

  11. Effects of lead exposure on licking and yawning behaviour in rats

    Energy Technology Data Exchange (ETDEWEB)

    Ghazi-Khansari, Mahmoud; Rezvani, Niloufar; Bani-Assadi, Shadi; Zarrindast, Mohammad-Reza [Tehran Univ. of Medical Sciences, School of Medicine, Dept. of Pharmacology (Iran, Islamic Republic of)

    1998-12-01

    In the present study, effects of lead exposure on licking and yawning behaviour have been studied. The dopaminergic receptor agonist, apomorphine (0.15, 0.25 and 0.5 mg/kg), induced dose-dependent licking in rats. The maximum response was obtained with 0.5 mg/kg of the apomorphine. Lead acetate (0.5%) exposure significantly increased apomorphine-induced licking. Yawning induced by the D{sub 2} dopaminergic agonist, bromocriptine (2, 3, 4, 8 mg/kg), and the cholinergic drug, physostigmine (0.1 or 0.3 mg/kg), was significantly decreased by lead acetate (0.05%) exposure. It may be concluded that the behaviour induced by dopaminergic or cholinergic agents can be affected by lead subchronic exposure. (au) 30 refs.

  12. The effect of Dopamine receptor agonists on twich response of Guinea-pig ileum longitudinal muscle and its relation to Nitric Oxide

    OpenAIRE

    Keshavarz M; Karimian M; Dehpoor A; Parviz M

    1998-01-01

    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 inhi...

  13. [Undate on Current Care Guideline: Parkinson's disease].

    Science.gov (United States)

    2016-01-01

    The treatment of Parkinson's disease may be initiated with dopamine agonist or MAO-B-inhibitor for people under 60-65 years of age. For older patients, the treatment may also be started with levodopa. If there are motor complications, such as on-off-symptoms, apomorphin injections can be beneficial in addition to other medications. In the case of difficult on-off-symptoms and dyskinesias in spite of optimal treatment, deep brain stimulation, duodenal levodopa infusion and apomorphine infusion should be considered. Rehabilitation can improve gait speed and balance, decrease falls and improve speech. However, with advancing disease the results are not maintained if trainino is discontinued. PMID:27044185

  14. INTERACTIVE EFFECTS OF DIFFERENT DURATION OF LITHIUM PRETREATMENT WITH AMIKACIN AND GENTAMICIN ONAPOMORPHINE-INDUCED LICKING IN RATS

    OpenAIRE

    MOHAMMAD SHARIFZADEH; ELHAM KHAJVAND-FIROOZ; MOHAMMAD ABDOLLAHI

    2000-01-01

    In this study the hypothesis that aminoglycoside antibiotics and lithium may influence apomorphine-induced licking via their effects on phosphoinositide pathways and calcium stores were investigated in male rats. Subcutaneous administration of apomorphine (0.1,0.25 and 0.5 mg/kg) to rats induced licking in a dose-dependent manner and the maximum response was obtained by the dose of 0.5 mg/kg of the drug. Intracerebroventricular injections of amikacin (5, 25 and 50 ug/rat) and gentamicin (10, ...

  15. Modification of the actions of some neuroactive drugs by growth hormone

    Energy Technology Data Exchange (ETDEWEB)

    Tang, L.C.; Cotzias, G.C.

    1976-02-01

    The flat serum growth hormone (GH) patterns of untreated parkinsonian patients develop diurnal rises during treatment with levodopa. This chronic exposure to excesses of GH might lead to the eventual emergence of the ''on-off'' phenomenon, which would indicate a need for animal experiments. Pretreatment of mice with GH increased (1) cerebral dopa and dopamine concentrations in levodopa-treated mice, (2) cerebral accumulation of injected tritiated apomorphine and tritiated thymidine, and (3) behavioral responses to levodopa, L-m-tyrosine, apomorphine hydrochloride, and oxotremorine. (auth)

  16. HYPERACTIVITY AND HYPOACTIVITY PRODUCED BY LESIONS TO THE MESOLIMBIC DOPAMINE SYSTEM

    Science.gov (United States)

    Spontaneous locomotor activity and the locomotor response to amphetamine and apomorphine were studied in rats subjected to either radiofrequency(RF), 6-hydroxydopamine (6-OHDA) of both RF and 6-OHDA lesions of the mesolimbic dopamine (DA) system. Large 6-OHDA lesions of the ventr...

  17. EuroInf

    DEFF Research Database (Denmark)

    Martinez-Martin, Pablo; Reddy, Prashanth; Katzenschlager, Regina;

    2015-01-01

    Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinson's disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two str...

  18. Effects of the inducible nitric oxide synthase inhibitor aminoguanidine in two different rat models of schizophrenia.

    Science.gov (United States)

    Lafioniatis, Anastasios; Orfanidou, Martha A; Papadopoulou, Evangelia S; Pitsikas, Nikolaos

    2016-08-01

    Several lines evidence indicate that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induce schizophrenia-like symptoms in rodents, including memory impairments and social withdrawal. Nitric oxide (NO) has been proposed to act as an intracellular messenger in the brain and its overproduction is associated with schizophrenia. The current study was designed to investigate the ability of the inducible NO synthase (iNOS) inhibitor aminoguanidine (AG) to counteract schizophrenia-like behavioural deficits produced by ketamine and apomorphine in rats. The efficacy of AG to antagonize extinction of recognition memory, ketamine and apomorphine-induced recognition memory impairments was tested utilizing the novel object recognition task (NORT). Further, the efficacy of AG to attenuate ketamine-induced social withdrawal was examined in the social interaction test. AG (25 and 50mg/kg) antagonized extinction of recognition memory and reversed ketamine (3mg/kg) and apomorphine (1mg/kg)-induced recognition memory deficits. In contrast, AG (50 and 100mg/kg) did not counteract the ketamine (8mg/kg)-induced social isolation. The present data show that the iNOS inhibitor AG counteracted extinction of recognition memory and reversed recognition memory deficits produced by dysfunction of the glutamatergic and the dopaminergic (DAergic) system in rats. Therefore, AG may be efficacious in attenuating memory impairments often observed in schizophrenia patients. PMID:27132765

  19. 04038 Vernalis公司购买Apokyn

    Institute of Scientific and Technical Information of China (English)

    李雅娟(摘)

    2006-01-01

    Vernalis公司从Mylan公司获得了帕金森治疗药Apokyn(apomorphine hydrochloride,盐酸阿扑吗啡注射剂)的北美权利。2004年7月该产品在美国上市,专有权到2011年期满。

  20. Elektrochemické stanovení alkaloidů morfinové řady

    Czech Academy of Sciences Publication Activity Database

    Volke, Jiří; Volkeová, V.

    2000-01-01

    Roč. 94, č. 12 (2000), s. 1075-1080. ISSN 0009-2770 Institutional research plan: CEZ:AV0Z4040901; CEZ:A54/98:Z4-040-9-ii Keywords : apomorphine * heroin e * morphine Subject RIV: CG - Electrochemistry Impact factor: 0.278, year: 2000

  1. Antipsychotic-like activity of Noni (Morinda citrifolia Linn. in mice

    Directory of Open Access Journals (Sweden)

    Pandy Vijayapandi

    2012-10-01

    Full Text Available Abstract Background Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn. using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing. Methods In acute study, the methanolic extract of Morinda citrifolia (MMC at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p and methamphetamine ( 5 mg/kg, i.p injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI® Juice, TNJ was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time. Results The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o significantly decreased the apomorphine-induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice. Conclusions The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies

  2. Pharmacological evaluation of bee venom and melittin

    Directory of Open Access Journals (Sweden)

    Camila G. Dantas

    2014-01-01

    Full Text Available The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field, catalepsy, anxiety (elevated plus-maze, depression (forced swimming test and apomorphine-induced stereotypy. Haloperidol, imipramine and diazepam were administered alone (positive control or as a pre-treatment (haloperidol.The bee venom reduced motor activity and promoted cataleptic effect, in a similar manner to haloperidol.These effects were decreased by the pretreatment with haloperidol. Both melittin and bee venom decreased the apomorphine-induced stereotypies. The data indicated the antipsychotic activity of bee venom and melittin in a murine model.

  3. The action of prolyl-leucyl-glycinamide (PLG on the nigrostriatal pathway of the rat

    Directory of Open Access Journals (Sweden)

    João S. Pereira

    1990-06-01

    Full Text Available In order to study the nigrostriatal pathway, we obtained the rotatory behavior model in male Wistar rats by electrolytic lesion of the left lateral hypothalamic region. Animals thus lesioned displayed rotations toward the same side of lesion when apomorphine was administered, a result in disagreement with what has been obtained in the model with 6-hydroxydopamine lesion. The administration of PLG alone was not followed by rotatory behavior but when the compound was administered in low doses (0.25 to 1mg/kg simultaneously with apomorphine to animals previously submitted to REM sleep deprivation, a significant increase in the number of rotations was observed in comparison with controls and groups receiving higher doses of PLG. These results indicate that PLG may act as, a modulator on dopamine receptors in the striatum.

  4. Enhanced striatial /sup 3/H-spiroperidol binding induced by chronic haloperidol treatment inhibited by peptides administered during the withdrawal phase

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.

    1984-02-27

    Chronic intragastric administration of haloperidol (1.5 mg/kg/day) for 21 days followed by a 3-day withdrawal period resulted in the development of enhanced locomotor activity response to apomorphine, and an increase in the number of binding sites for /sup 3/H-spiroperidol in the striatal membranes of the rat brain. Subcutaneous administration of Pro-Leu-Gly-NH/sub 2/ or cyclo-(Leu-Gly) in doses of 2 mg/kg/day given for 3-days after termination of haloperidol treatment inhibited the enhanced response to apomorphine, as well as the increases in the number of /sup 3/H-spiroperidol binding sites in the striatum. If indeed, the supersensitivity of striatal dopamine receptors is one of the mechanisms in the development of tardive dyskinesia symptoms, the present results suggest that the above peptides may be helpful in ameliorating some of the symptoms of tardive dyskinesia induced by neuroleptic drugs. 31 references, 3 figures.

  5. The beneficial effect of the flavonoid quercetin on behavioral changes in hemi-Parkinsonian rats

    Directory of Open Access Journals (Sweden)

    Mehdi Mehdizadeh

    2010-01-01

    Full Text Available   Abstract   Introduction: A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson's disease (PD. Flavonoids like quercetin have been reported to prevent neuronal degeneration caused by increased oxidative burden, therefore, this study examined whether quercetin administration at a high dose would attenuate behavioral abnormalities in experimental model of PD in rat.   Methods: For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA-lesioned rats were pretreated with quercetin (20 mg/kg; i.p. 1 hour before surgery and treated once a day for one month. After one month, apomorphine-induced rotational behavior was measured postlesion.   Results: Apomorphine-induced rotations were counted after 4 weeks. Quercetin administration could attenuate the rotational behavior in treated lesioned rats as compared to untreated ones.   Discussion: Flavonoid quercetin administration for one month could attenuate behavioral abnormalities in 6-OHDA model of PD.

  6. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Di Paolo, T.; Falardeau, P.

    1987-08-31

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p < 0.001). Competition for (/sup 3/H)-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-(..beta..-..gamma..-imino)triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables.

  7. 针刺结合五苓散治疗中风后尿潴留36例

    Institute of Scientific and Technical Information of China (English)

    马力颖; 孙忠人; 宫树丰; 马政涛

    2012-01-01

    Objective: To explore the effect of anchanling on behavior of Parkinsons disease ( PD ) mice .Methods: Models of Parkinsons disease ( PD ) were made by intraperitoneal injecting 1 - methyl - 4 - phenyl - 1,2,3,6 -four hydrogen pyridine ( MPTP ) ,50 mice of PD were randomly divided into model group and anchanling group , each group contained 10 mice, while another 10 mice were intraperitoneal injecting saline that were taken as normal control group, each group was given the corresponding medicine or saline for three weeks. Respectively peritoneal injecting apomorphine ( APO ) to induced after administrating 1, 2, 3 , weeks, observing and recording apomorphine time.Results: To be compared with model group, the number of rotations of anchanling group mice was significantly reduced, suspension foot increased significantly and pole climbing time was significantly prolonged ( P [2].

  8. Enhanced striatial 3H-spiroperidol binding induced by chronic haloperidol treatment inhibited by peptides administered during the withdrawal phase

    International Nuclear Information System (INIS)

    Chronic intragastric administration of haloperidol (1.5 mg/kg/day) for 21 days followed by a 3-day withdrawal period resulted in the development of enhanced locomotor activity response to apomorphine, and an increase in the number of binding sites for 3H-spiroperidol in the striatal membranes of the rat brain. Subcutaneous administration of Pro-Leu-Gly-NH2 or cyclo-(Leu-Gly) in doses of 2 mg/kg/day given for 3-days after termination of haloperidol treatment inhibited the enhanced response to apomorphine, as well as the increases in the number of 3H-spiroperidol binding sites in the striatum. If indeed, the supersensitivity of striatal dopamine receptors is one of the mechanisms in the development of tardive dyskinesia symptoms, the present results suggest that the above peptides may be helpful in ameliorating some of the symptoms of tardive dyskinesia induced by neuroleptic drugs. 31 references, 3 figures

  9. Guanine nucleotide regulation of dopamine receptor agonist affinity states in rat estradiol-induced pituitary tumors

    International Nuclear Information System (INIS)

    The authors have investigated dopamine (DA) receptor agonist high- and low-affinity states in female rate estradiol-induced prolactin (PRL)-secreting pituitary tumors and intact pituitary tissue. Estradiol treatment increased the anterior pituitary weight 9-fold and plasma prolactin levels 74-fold and these measures are correlated (R = 0.745, n = 73, p 3H]-spiperone binding to the DA receptor by apomorphine was compared in normal and adenomatous pituitary tissue. The inhibition constants (Ki) and the proportions of the two apomorphine sites are unchanged in tumors compared to intact pituitary tissue. Guanosine 5'-[β-γ-imino]triphosphate (Gpp(NH)p) causes complete conversion of the high into low affinity dopaminergic agonist site in normal pituitary and in tumors. These results suggest that rats with primary estradiol-induced pituitary tumors have normal and functional DA receptors. 9 references, 2 tables

  10. Synthesis by pulsed laser ablation of 2D nanostructures for advanced biomedical sensing

    Science.gov (United States)

    Trusso, S.; Zanchi, C.; Bombelli, A.; Lucotti, A.; Tommasini, M.; de Grazia, U.; Ciusani, E.; Romito, L. M.; Ossi, P. M.

    2016-05-01

    Au nanoparticle arrays with controlled nanostructure were produced by pulsed laser ablation on glass. Such substrates were optimized for biomedical sensing by means of SERS keeping fixed all process parameters but the laser pulse (LP) number that is a key deposition parameter. It allows to fine-tune the Au surface nanostructure with a considerable improvement in the SERS response towards the detection of apomorphine in blood serum (3.3 × 10‑6 M), when LP number is increased from 1 × 104 to 2 × 104. This result is the starting point to correlate the intensity of selected SERS signals of apomorphine to its concentration in the blood of patients with Parkinson's disease.

  11. Dopamine agonist-induced penile erection and yawning: differential role of D₂-like receptor subtypes and correlation with nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats.

    Science.gov (United States)

    Sanna, Fabrizio; Succu, Salvatora; Melis, Maria Rosaria; Argiolas, Antonio

    2012-05-01

    The dopamine D₃ preferring agonist pramipexole (50 ng) induced penile erection and yawning when injected into the paraventricular nucleus of the hypothalamus of male rats, like the mixed D₁/D₂-like agonist apomorphine (50 ng), while the D₄ agonist PD 168,077 (100 ng), induced penile erection only. These responses lasted for 45-60 min and occurred with an increase of NO₂- and NO₃- concentrations in the dialysate obtained from the paraventricular nucleus by intracerebral microdialysis. Pramipexole and apomorphine responses were reduced by the D₂ preferring antagonist L-741,626 (5 μg), but not by the D₃ preferring antagonist SB-277011A (10 μg), or the D₄ preferring antagonist L-745,870 (5 μg), injected into the PVN before the dopamine agonist. In contrast, PD 168,077 responses were reduced by L-745,870, but not by L-741,626 or SB-277011A. Pramipexole, apomorphine and PD 168,077 effects were also reduced by the nitric oxide synthase inhibitor S-methyl-L-thiocitrulline (20 μg) and the N-type voltage-dependent Ca²⁺ channels blocker ω-conotoxin (5 ng), given into the paraventricular nucleus, and by the oxytocin antagonist d(CH₂)₅Tyr(Me)²-Orn⁸-vasotocin (2 μg), given intracerebroventricularly but not into the paraventricular nucleus before dopamine agonists. These results suggest that stimulation of D₂, but not D₃ or D₄ receptors, by pramipexole or apomorphine increases Ca²⁺ influx in cell bodies of oxytocinergic neurons. This increases the production of nitric oxide, which activates oxytocinergic neurotransmission in extra-hypothalamic brain areas and spinal cord, leading to penile erection and yawning. However, the stimulation of D₄ receptors by PD 168,077 also increases Ca²⁺ influx/nitric oxide production leading to penile erection, but not yawning. PMID:22391116

  12. Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44.

    Science.gov (United States)

    Weber, Martin; Chang, Wei-Li; Durbin, John P; Park, Paula E; Luedtke, Robert R; Mach, Robert H; Swerdlow, Neal R

    2009-08-01

    Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo. PMID:19426754

  13. Antipsychotic-like effect of minocycline in a rat model

    OpenAIRE

    Dokuyucu, Recep; Kokacya, Hanifi; Inanir, Sema; Copoglu, Umit Sertan; Erbas, Oytun

    2014-01-01

    Objectives: Tetracycline antibiotic drug minocycline has strongly neuroprotective and anti-inflammatory effects. Minocycline has also remarkable brain tissue penetration, is clinically entirely tolerated and properly absorbed when taken orally. In our study, we class with the effects of minocycline and chlorpromazine, a conventional antipsychotic drug, by evaluating the novelty-induced rearing, apomorphine-induced stereotypic behavior, and brain MDA levels in rats. Materials and Methods: Four...

  14. Antipsychotic-like activity of Noni (Morinda citrifolia Linn.) in mice

    OpenAIRE

    Pandy Vijayapandi; Narasingam Megala; Mohamed Zahurin

    2012-01-01

    Abstract Background Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing). Methods...

  15. Nurturing nature: testing the three-hit hypothesis of schizophrenia

    OpenAIRE

    Daskalakis, Nikolaos

    2011-01-01

    Schizophrenia is a devastating mental disorder characterized by a hyperactive dopamine system and deregulated stress system. Human studies have suggested that the schizophrenia symptoms precipitate if a hyperactive dopaminergic genotype interacts with adverse life experiences that activate the stress system. To examine this gene-by-environment interaction, we exposed rats genetically-selected for enhanced apomorphine susceptibility to two stress-provoking life events, poor maternal care early...

  16. Penile erectile dysfunction after brachial plexus root avulsion injury in rats

    OpenAIRE

    Fu, Guo; Qin, Bengang; Jiang, Li; Huang, Xijun; Lu, Qinsen; Zhang, Dechun; Liu, Xiaolin; Zhu, Jiakai; Zheng, Jianwen; Li, Xuejia; Gu, Liqiang

    2014-01-01

    Our previous studies have demonstrated that some male patients suffering from brachial plexus injury, particularly brachial plexus root avulsion, show erectile dysfunction to varying degrees. However, the underlying mechanism remains poorly understood. In this study, we evaluated the erectile function after establishing brachial plexus root avulsion models with or without spinal cord injury in rats. After these models were established, we administered apomorphine (via a subcutaneous injection...

  17. Distinct inhibition of acute cocaine-stimulated motor activity following microinjection of a group III metabotropic glutamate receptor agonist into the dorsal striatum of rats.

    Science.gov (United States)

    Mao, L; Wang, J Q

    2000-09-01

    Group III metabotropic glutamate receptors (mGluRs) are negatively coupled to adenylate cyclase through G-proteins. Activation of this group of mGluRs shows an inhibition of dopaminergic transmission in the forebrain. To define the role of striatal group III mGluRs in the regulation of basal and dopamine-stimulated motor behavior, the recently developed agonist and antagonist relatively selective for group III mGluRs were utilized to pharmacologically enhance and reduce group III mGluR glutamatergic tone in the dorsal striatum of chronically cannulated rats. Bilateral injections of a group III agonist, L-2-amino-4-phosphonobutyrate (L-AP4), did not alter basal levels of motor activity at three doses surveyed (1, 10, and 100 nmol). Neither did intracaudate injection of a group III antagonist, alpha-methyl-4-phosphonophenylglycine (MPPG), at 10, 30, and 100 nmol. However, pretreatment with L-AP4 (10 and 100 nmol) dose dependently blocked hyperlocomotion induced by acute injection of cocaine (20 mg/kg, i.p.), amphetamine (2.5 mg/kg, i.p.), or apomorphine (1 mg/kg, s.c.). The behavioral activity induced by cocaine was much more sensitive to L-AP4 than that induced by amphetamine and apomorphine. At 100 nmol, L-AP4 completely blocked cocaine effect whereas amphetamine- and apomorphine-stimulated behaviors were blocked only by 28% and 31%, respectively. The blocking effect of L-AP4 on cocaine action was reversed by pretreatment with MPPG. MPPG itself did not modify behavioral responses to cocaine, amphetamine, or apomorphine. These data indicate that the glutamatergic tone on the group III mGluRs is not active in the regulation of basal and acute dopamine-stimulated motor activity. However, enhanced group III mGluR glutamatergic transmission by an exogenous ligand is capable of suppressing behavioral responses to acute exposure of dopamine stimulants. PMID:11113488

  18. High Oestradiol Replacement Reverses Response Memory Bias in Ovariectomised Female Rats Regardless of Dopamine Levels in the Dorsal Striatum.

    Science.gov (United States)

    Hussain, D; Cossette, M-P; Brake, W G

    2016-05-01

    Oestrogens influence memory system bias in female rats such that high levels of oestrogen are associated with place (or spatial) memory use, and low oestrogen levels with response (or habitual) memory use. Moreover, striatal-dependent response memory is sensitive to dopamine transmission in the dorsal striatum, and oestrogens have been shown to affect dopamine release in that brain area. In the present study, the effects of oestrogens and dopamine transmission on multiple memory system bias were explored in ovariectomised rats receiving low or high 17β-oestradiol replacement under saline, autoreceptor-activating doses of the dopamine D2 receptor agonist, apomorphine (50 and 80 μg/kg), or amphetamine (0.5 mg/kg) administration. Furthermore, dorsal striatal dopamine release was measured after administration of the same drug conditions using in vivo microdialysis. As expected, high oestradiol rats predominantly used place memory, whereas the opposite pattern was observed in low oestradiol rats. However, the high apomorphine dose statistically significantly altered memory bias in high oestradiol rats from predominant place to predominant response memory, with a similar trend in the low apomorphine dose and the amphetamine group. There was no effect of drugs on memory bias in low oestradiol rats. Rats with high oestradiol replacement receiving amphetamine exhibited greater dorsal striatal dopamine release than low oestradiol replacement rats, and this difference was amplified in the right hemisphere. Furthermore, a logistic regression analysis revealed that oestradiol, but not dorsal striatal dopamine levels, significantly predicted response memory bias. These findings provide further evidence that oestradiol modulates memory system bias, and also that memory bias is changed by systemic apomorphine administration. However, although oestradiol affects dopamine transmission in the dorsal striatum in a lateralised manner, this does not predict memory system bias. PMID

  19. Discriminative learning occasioned by the administration of a dopamine agonist

    OpenAIRE

    Keller, Sabine; Delius, Juan

    2001-01-01

    Rationale: The repeated administration of psychostimulants usually brings about a progressive increment of the behavioral responses that they induce. We examined to what extent this sensitization is due to an associative learning process. Objectives: The dopamine agonist apomorphine elicits stereotyped pecking in pigeons, a response that increases with successive intramuscular injections. We tested whether this sensitized pecking would be discriminatively directed at environmental stimuli tha...

  20. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

    OpenAIRE

    Dayane Pessoa de Araújo; Caren Nádia Soares De Sousa; Paulo Victor Pontes Araújo; Carlos Eduardo de Souza Menezes; Francisca Taciana Sousa Rodrigues; Sarah de Souza Escudeiro; Nicole Brito Cortez Lima; Manoel Claúdio Azevedo Patrocínio; Lissiana Magna Vasconcelos Aguiar; Glauce Socorro de Barros Viana; Silvânia Maria Mendes Vasconcelos

    2013-01-01

    This study aimed to investigate behavioral and neurochemical effects of α -lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of ni...

  1. Inhibition of experimental myopia by a dopamine agonist: different effectiveness between form deprivation and hyperopic defocus in guinea pigs

    OpenAIRE

    Dong, Feng; Zhi, Zhina; Pan, Miaozhen; Xie, Ruozhong; Qin, Xiaoyi; Lu, Runxia; Mao, XinJie; Chen, Jiang-Fan; Willcox, Mark D. P.; Qu, Jia; Zhou, Xiangtian

    2011-01-01

    Purpose The dopamine (DA) system in the retina is critical to normal visual development as lack of retinal DA signaling may contribute to myopic development. The involvement of DA in myopic development is complex and may be different between form deprivation and hyperopic defocus. This study evaluated effects of a non-selective DA receptor agonist, apomorphine (APO) on refractive development in guinea pigs treated with form deprivation or hyperopic defocus. Methods APO was subconjunctivally i...

  2. Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation.

    Science.gov (United States)

    Weber, Martin; Chang, Wei-li; Breier, Michelle; Ko, David; Swerdlow, Neal R

    2008-12-01

    Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine (DA) agonists. Robust heritable strain differences are observed between Sprague-Dawley (SD) and Long-Evans (LE) strains in sensitivity to the PPI-disruptive effects of DA agonists associated with differential gene expression in the nucleus accumbens. Here, we compared the contribution of D2 versus D3 receptors with this heritable difference, using the D3-preferential agonist (pramipexole), the mixed D3/D2 agonist (quinpirole), the mixed D1/D2-like agonist (apomorphine), and the preferential D2 antagonist (L741,626). All DA agonists disrupted PPI in SD and LE rats. Greater sensitivity for this effect was evident with apomorphine and quinpirole in SD than LE rats, but not with pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI 'disruptability' by DA agonists in SD versus LE rats reflects differences in D2 but not D3 receptor-associated mechanisms. PMID:19020413

  3. Value of mink vomit model in study of anti-emetic drugs

    Institute of Scientific and Technical Information of China (English)

    Fang Zhang; Lei Wang; Zhi-Hong Yang; Zhan-Tao Liu; Wang Yue

    2006-01-01

    AIM: To establish a new, reliable vomit model of minks.METHODS: Adult male minks were randomly divided into 8 groups (n=6): cisplatin (7.5 mg/kg)intraperitoneal injection (ip) group, copper sulfate (40mg/kg) intragastric injection (ig) group, apomorphine (1.6 mg/kg) subcutaneous injection (sc) group, and 18Gy whole-body X-irradiation group, ondansetron injection group (2 mg/kg ip) 30 min later followed by cisplatin (7.5 mg/kg) ip, normal saline (NS) ip injection control group, metoclopramide injection group (4 mg/kg ip) 30min later followed by apomorphine (1.6 mg/kg) sc, NS ig control group. The frequency of retching and vomiting was calculated. After behavioral experiment, distribution of 5-HT in the ileum was detected by immunohistologic method.RESULTS: Cisplatin, apomorphine, copper sulfate and X-irradiation administered to minks evoked a profound emetic response in the animals. However, retching and vomiting were significantly inhibited by pretreatment with ondansetron and metoclopramide in cisplatin and copper sulfate groups (P=0.018). Immunohistologic result showed that 5-HT released from enterochromaffin cells (EC cells) was involved in vomiting mechanism.CONCLUSION: Mink vomit model has a great value in studying the vomiting mechanism and screening new antiemetic drugs.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Characterization of radiation-induced emesis in the ferret

    Energy Technology Data Exchange (ETDEWEB)

    King, G.L.

    1988-06-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral /sup 60/Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  6. Characterization of radiation-induced emesis in the ferret

    Energy Technology Data Exchange (ETDEWEB)

    King, G.L.

    1988-01-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral cobalt 60 gamma radiation at 100 cGy min at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED 50 was calculated as 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms /kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n=4) or 401 (n=4) cGy radiation and their emetic responses were compared with NaCi-injected-irradiated controls (n=8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  7. 7-(3-(4-(2,3-dimethylphenyl)piperazinyl)propoxy)-2 (1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Yasuda, Y.; Kikuchi, T.; Suzuki, S.; Tsutsui, M.; Yamada, K.; Hiyama, T.

    1988-01-01

    The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392, 3-PPP and apomorphine. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit /sup 14/C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices.

  8. Experimental Study on Heterograft of Glomus Ccl ls of Carotid Body for Hemioarkinsonian Rats

    Institute of Scientific and Technical Information of China (English)

    曹学兵; 孙圣刚; 童萼塘

    2002-01-01

    Summary: To observe the effects of heterograft of glomus cells of carotid body on hemiparkinsonian rat models, rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the right dopamin ergic neurons of substantia nigra received intrastriatal glomus cells heterograft. Apomorphine-induced rotation was monitored for 30 rmin at various time points after grafting. The striata were cut and ex-amined for dopamine content by HPLC and for immunohistochemical staining of tyrosine hydroxylase positive neurons (TH+ ) at the end of the experiments. The results showed that apomorphine-induced rotational behavior was significantly reduced for 12 weeks and the dopamine contents were signifi cantly elevated after grafting (P<0.01), and TH+ cells survived better. The present study demon strates that intrastriatal heterograft of glomus cells within carotid body in rats with 6-OHDA-elicited lesions could reduce apomorphine-induced rotational behavior and elevate the dopamine contents and numbers of TH+ cell surviving within striatum, and can serve as a new and effective alternative for Parkinson disease.

  9. Maternal care affects the phenotype of a rat model for schizophrenia

    Directory of Open Access Journals (Sweden)

    Ruben W M Van Vugt

    2014-08-01

    Full Text Available Schizophrenia is a complex mental disorder caused by an interplay between genetic and environmental factors, including early postnatal stressors. To explore this issue, we use two rat lines, apomorphine-susceptible (APO-SUS rats that display schizophrenia-relevant features and their phenotypic counterpart, apomorphine-unsusceptible (APO-UNSUS rats. These rat lines differ not only in their gnawing response to apomorphine, but also in their behavioral response to novelty (APO-SUS: high, APO-UNSUS: low. In this study, we examined the effects of early postnatal cross-fostering on maternal care and on the phenotypes of the cross-fostered APO-SUS and APO-UNSUS animals later in life. Cross-fostered APO-UNSUS animals showed decreased body weights as pups and decreased novelty-induced locomotor activity as adults (i.e., more extreme behavior, in accordance with the less appropriate maternal care provided by APO-SUS versus their own APO-UNSUS mothers (i.e., the APO-SUS mother displayed less non-arched-back nursing and more self-grooming, and was more away from its nest. In contrast, cross-fostered APO-SUS animals showed increased body weights as pups and reduced apomorphine-induced gnawing later in life (i.e., normalisation of their extreme behavior, in line with the more appropriate maternal care provided by APO-UNSUS relative to their own APO-SUS mothers (i.e., the APO-UNSUS mother displayed more non-arched-back nursing and similar self-grooming, and was not more away. Furthermore, we found that, in addition to arched-back nursing, non-arched-back nursing was an important feature of maternal care, and that cross-fostering APO-SUS mothers, but not cross-fostering APO-UNSUS mothers, displayed increased apomorphine-induced gnawing. Thus, cross-fostering not only causes early postnatal stress shaping the phenotypes of the cross-fostered animals later in life, but also affects the phenotypes of the cross-fostering mothers.

  10. Transplantation of primary cultured embryonic mesencephalic neural precursor cells for treating Parkinsonian rats

    Institute of Scientific and Technical Information of China (English)

    Li Fei; Chengchuan Jiang; Linyin Feng; Yaodong Ji; Zhongliang Ding

    2006-01-01

    BACKGROUND: Choosing proper donor cells is one of keys in experimental and clinical studies on cell replacement therapy (CRT) for treating Parkinson disease (PD). Embryonic mesencephalic precursor cells (MPCs) can stably differentiate into dopaminergic neuron after in vitro proliferated culture. As compared with embryonic stem cell and neural stem cell strains, cell composition of embryonic MPCs after primary culture is also the most close to that of embryonic mesencephalic ventral cell suspension without proliferated culture. Successful experience accumulated in the latter suggests that primary cultured embryonic MPCs might be the most potential donor cells in clinical application with CRT for treating PD so far.OBJECTIVE: To investigate the feasibility of primary cultured embryonic precursor cells cultured primarily as donor cells in CRT for treating PD in rats.DESIGN: A randomized and controlled trial taking SD rats as experimental animals.SETTING: Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University.MATERIALS: This experiment was carried out at the Institute of Neuroscience, Shanghai Institute for Biological Science, Chinese Academy of Sciences from July 2003 to June 2004. Totally 26 female SD rats,with body mass of 200 to 220 g, were provided by Shanghai Experimental Animal Center of Chinese Academy of Sciences.METHODS: Stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle were perfored to develop PD model rat. Among 26 SD rats, 20 rats achieved a more than 5 turns/min in apomorphine induced rotation test, reaching the standard of PD model rats. Immunohistochemical detection was performed on 1out of 20 model rats after execution, and the other 19 rats were randomly divided into control group (n=5),sham transplantation group (n=5)and cell grafted group (n=9). Primary cultured E12 MPC cell suspension (1.2×1011 L-1)were used as donor cells. 4 μL primary cultured E12 MPC cell suspension prepared freshly was injected

  11. Intracranial application of near-infrared light in a hemi-parkinsonian rat model: the impact on behavior and cell survival.

    Science.gov (United States)

    Reinhart, Florian; Massri, Nabil El; Chabrol, Claude; Cretallaz, Celine; Johnstone, Daniel M; Torres, Napoleon; Darlot, Fannie; Costecalde, Thomas; Stone, Jonathan; Mitrofanis, John; Benabid, Alim-Louis; Moro, Cécile

    2016-06-01

    OBJECT The authors of this study used a newly developed intracranial optical fiber device to deliver near-infrared light (NIr) to the midbrain of 6-hydroxydopamine (6-OHDA)-lesioned rats, a model of Parkinson's disease. The authors explored whether NIr had any impact on apomorphine-induced turning behavior and whether it was neuroprotective. METHODS Two NIr powers (333 nW and 0.16 mW), modes of delivery (pulse and continuous), and total doses (634 mJ and 304 J) were tested, together with the feasibility of a midbrain implant site, one considered for later use in primates. Following a striatal 6-OHDA injection, the NIr optical fiber device was implanted surgically into the midline midbrain area of Wistar rats. Animals were tested for apomorphine-induced rotations, and then, 23 days later, their brains were aldehyde fixed for routine immunohistochemical analysis. RESULTS The results showed that there was no evidence of tissue toxicity by NIr in the midbrain. After 6-OHDA lesion, regardless of mode of delivery or total dose, NIr reduced apomorphine-induced rotations at the stronger, but not at the weaker, power. The authors found that neuroprotection, as assessed by tyrosine hydroxylase expression in midbrain dopaminergic cells, could account for some, but not all, of the observed behavioral improvements; the groups that were associated with fewer rotations did not all necessarily have a greater number of surviving cells. There may have been other "symptomatic" elements contributing to behavioral improvements in these rats. CONCLUSIONS In summary, when delivered at the appropriate power, delivery mode, and dosage, NIr treatment provided both improved behavior and neuroprotection in 6-OHDA-lesioned rats. PMID:26613166

  12. Individual differences in drug dependence in rats: the role of genetic factors and life events.

    Science.gov (United States)

    Ellenbroek, Bart A; van der Kam, Elizabeth L; van der Elst, Martine C J; Cools, Alexander R

    2005-12-01

    Drug dependence and addiction is a chronic mental illness that has far reaching consequences for society in terms of economic loss, health costs and judicial problems. A crucial question in drug addiction, is what factors are involved in its aetiology, and especially what mediates the shit from use to abuse. As in most other mental illnesses, addiction can best be described using the so-called three hit model, which states that a disease results from an interaction between genetic factors, early lie events and late environmental factors. However, the precise nature of these factors still remains to be elucidated. This present review discusses the results from an animal model in which these three different hit are currently being investigated. The apomorphine susceptible (APO-SUS) and apomorphine unsusceptible (APO-UNSUS) rats, originally selected on the basis of their behavioural response to the dopaminergic agonist apomorphine, were recently found to be genetically different in the number of gene copies of a component of the gamma-secretase complex called Aph-1b. Whereas APO-UNSUS rats have three copies of the gene, APO-SUS rats have either 1 or 2 copies. In addition we have shown that these rats show differences in cocaine and alcohol self-administration, and that both early life events and late environmental factors can alter this self-administration behaviour. Thus, the data so far support the hypothesis that the APO-SUS and APO-UNSUS rats offer an interesting animal model for drug dependence in which genes and environment interact. We finally propose a theoretical model which can explain this gene-environment interaction. PMID:16253227

  13. Rodent neurotoxicity bioassays for screening contaminated Great Lakes fish

    Energy Technology Data Exchange (ETDEWEB)

    Beattie, M.K.; Hoffman, R. [Univ. of Minnesota, Duluth, MN (United States); Gerstenberger, S. [Univ. of Illinois, Urbana, IL (United States). Dept. of Veterinary Biosciences; Dellinger, J.A. [Medical Coll. of Wisconsin, Milwaukee, MI (United States). Dept. of Preventive Medicine

    1996-03-01

    Standard laboratory rat neurotoxicity protocols were used to study the consequences resulting from the consumption of walleye (Stizostedion vitreum), whitefish (Coregonus clupeaformis), and lake trout (Salvelinus namaycush) from Lake Superior (LS) and the consumption of carp (Cyprinus carpio) from Little Lake Butte des Morte (LLBM) near Oshkosh, Wisconsin, USA. Two 90-d subchronic studies are described, including a 45-d exposure to fish diets using male Sprague-Dawley hooded rats, and a 90-d exposure to fish diets using female rats of the same species. Behavioral alterations were tested using a battery of behavioral tests. In addition, pharmacologic challenges using apomorphine and D-amphetamine were administered to the rats to reveal latent neurotoxic effects. Cumulative fish consumption data were recorded daily, weight gain recorded weekly, and behavior data collected prior to exposure, and on days 7, 14, 55 {+-} 2, 85 {+-} 2. Motor activity data were collected on days 30 {+-} 2, 60 {+-} 2, and 90 {+-} 2 of the feeding protocols. Brain tissue from rodents fed these fish were subsequently analyzed for either mercury (Hg) or polychlorinated biphenyls (PCB). Mercury concentrations were increased in the brains of the walleye-fed rats, and PCB concentrations ranged from 0.5 nl/L to 10 nl/L in the brains of rats fed carp from LLBM, a Lake Michigan tributary. Adult male rats fed LLBM carp for 45 d exhibited the greatest behavior responses to the dopaminergic agonist apomorphine on the accelerating rotarod, although these differences were not significant. The 90-d exposure of LS walleye or Hg-spiked LS walleye resulted in behavior alterations on tactile startle response and second footsplay. D-Amphetamine challenge caused changes in tactile startle response, second footsplay, and accelerating rotarod performance after consuming walleye diets. Rats fed LLBM carp had altered behavioral responses to apomorphine on the accelerating rotarod.

  14. Pharmacological differences between the D-2 autoreceptor and the D-1 dopamine receptor in rabbit retina

    Energy Technology Data Exchange (ETDEWEB)

    Dubocovich, M.L.; Weiner, N.

    1985-06-01

    The effect of dopamine receptor agonists and antagonists was studied on the calcium-dependent release of (/sup 3/H)dopamine elicited by field stimulation at 3 Hz for a duration of 1 min (20 mA, 2 msec) from the rabbit retina in vitro and on adenylate cyclase activity in homogenates of rabbit retina. The relative order of potency of dopamine receptor agonists to inhibit the stimulation-evoked (/sup 3/H)dopamine release was pergolide greater than bromocriptine greater than apomorphine greater than LY 141865 greater than N,N-di-n-propyldopamine greater than or equal to dopamine. The relative order of potencies of dopamine receptor antagonists to increase (/sup 3/H)dopamine release was: S-sulpiride greater than or equal to domperidone greater than or equal to spiroperidol greater than metoclopramide greater than fluphenazine greater than or equal to R-sulpiride. alpha-Flupenthixol (0.01-1 microM) and (+)-butaclamol (0.01-1 microM) did not increase (/sup 3/H)dopamine overflow when added alone, but they antagonized the concentration-dependent inhibitory effect of apomorphine (0.1-10 microM). These results suggest that the dopamine inhibitory autoreceptor involved in the modulation of dopamine release from the rabbit retina possesses the pharmacological characteristics of a D-2 dopamine receptor. Maximal stimulation by 30 microM dopamine resulted in a 3-fold increase in adenylate cyclase activity with half-maximal stimulation occurring at a concentration of 2.46 microM. Apomorphine and pergolide elicited a partial stimulation of adenylate cyclase activity. However, at low concentrations both compounds were more potent than dopamine.

  15. Growth-hormone and somatostatin effects on (/sup 75/Se)selenomethionine uptake by the pancreas

    Energy Technology Data Exchange (ETDEWEB)

    Atkins, H.L.; Som, P.

    1979-06-01

    The imaging of the pancreas with (/sup 75/Se)selenomethionine has a low rate of reliability. This study was carried out in order to elucidate some factors that may be important in affecting the degree of uptake of the tracer by the pancreas. Studies were carried out in animals to observe the effects of growth-hormone (GH), somatostatin (SRIF), L-DOPA, and apomorphine administration on the distribution of (/sup 75/Se)selenomethionine. Intravenously administered GH significantly depressed pancreatic uptake of Se-75 in mice and dogs and depressed the pancreas-to-liver concentration ratio (P/L). The effect of i.p. GH in mice was to decrease the P/L ratio, but the decrease in pancreatic uptake was not statistically significant. There was also a greater effect of GH in dogs than in mice, with pancreatic uptake decreasing from 5.60 +- 2.17% to 1.24 +- 0.96% and the P/L from 4.78 +- 1.85 to 0.97 +- 0.73. L-DOPA and apomorphine produced effects similar to GH in mice. SRIF in small doses had little effect, but in larger doses it enhanced pancreatic uptake, although not affecting P/L. The results indicate that hypothalamic factors may be important in affecting the function of the exocrine pancreas. Both L-DOPA and apomorphine are known to stimulate GH production through hypothalamic-pituitary pathways. In addition to suppressing GH release, SRIF may have direct effects on the exocrine pancreas.

  16. Pharmacological evaluation of bee venom and melittin

    OpenAIRE

    Camila G. Dantas; Tássia L.G.M. Nunes; Tâmara L.G.M. Nunes; Ailma O. da Paixão; Francisco P. Reis; Waldecy de L. Júnior; Juliana C. Cardoso; Kátia P. Gramacho; Gomes, Margarete Z

    2014-01-01

    The objective of this study was to identify the pharmacological effects of bee venom and its major component, melittin, on the nervous system of mice. For the pharmacological analysis, mice were treated once with saline, 0.1 or 1.2 mg/kg of bee venom and 0.1 mg/kg of melittin, subcutaneously, 30 min before being submitted to behavioral tests: locomotor activity and grooming (open-field), catalepsy, anxiety (elevated plus-maze), depression (forced swimming test) and apomorphine-induced stereot...

  17. Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

    Science.gov (United States)

    Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza; Newman, Amy Hauck; Grundt, Peter; Rice, Kenner C; Husbands, Stephen M; Greedy, Benjamin M; Enguehard-Gueiffier, Cecile; Gueiffier, Alain; Chen, Jianyong; Wang, Shaomeng; Katz, Jonathan L; Grandy, David K; Sunahara, Roger K; Woods, James H

    2009-04-01

    Dopamine D(2)-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D(4) and D(3) receptors, respectively. The current studies were aimed at characterizing a series of D(2), D(3), and D(4) agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D(4) receptor (R) knockout (KO) mice. All D(3) agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D(4) agonists. Likewise, D(2), D(3), and D(4) antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D(3) antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D(2) antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D(4) antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D(3) receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D(4)RKO mice, effects that were inhibited by the D(3) antagonist, PG01037, in both wild-type and D(4)R KO mice. Together, these studies provide strong support that D(2)-like agonist-induced PE and yawning are differentially mediated by the D(3) (induction) and D(2) (inhibition) receptors. These studies fail to support a role for the D(4) receptor in the regulation of PE or

  18. Proerectile Effects of Dopamine D2-Like Agonists Are Mediated by the D3 Receptor in Rats and Mice

    OpenAIRE

    Collins, Gregory T; Truccone, Andrew; Haji-Abdi, Faiza; Newman, Amy Hauck; Grundt, Peter; Rice, Kenner C.; Husbands, Stephen M.; Greedy, Benjamin M.; Enguehard-Gueiffier, Cecile; Gueiffier, Alain; Chen, Jianyong; Wang, Shaomeng; Katz, Jonathan L.; Grandy, David K.; Sunahara, Roger K.

    2009-01-01

    Dopamine D2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D4 and D3 receptors, respectively. The current studies were aimed at characterizing a series of D2, D3, and D4 agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-...

  19. Dopamine D2-like receptor agonists induce penile erection in male rats: differential role of D2, D3 and D4 receptors in the paraventricular nucleus of the hypothalamus.

    Science.gov (United States)

    Sanna, Fabrizio; Succu, Salvatora; Hübner, Harald; Gmeiner, Peter; Argiolas, Antonio; Melis, Maria Rosaria

    2011-11-20

    Pramipexole, a dopamine D3/D2 receptor agonist, induces penile erection when administered subcutaneously (s.c.) or into the paraventricular nucleus of the hypothalamus of male rats, like apomorphine, a mixed D1/D2 receptor agonist, and PD 168,077, a D4 receptor agonist. A U-inverted dose-response curve was found with pramipexole and apomorphine, but not with PD 168,077 (0.025-0.5mg/kg s.c.). Pramipexole effect was abolished by L-741,626, a D2 receptor antagonist (2.5 and 5mg/kg s.c.) and raclopride, a D2/D3 receptor antagonist (0.025 and 0.1mg/kg s.c.), but not by SB277011A (2.5 and 10mg/kg s.c.) or FAUC 365 (1 and 2mg/kg s.c.), two D3 receptor antagonists, or L-745,870 (1 and 5mg/kg i.p.), a D4 receptor antagonist. Similar results were found with apomorphine (0.08mg/kg s.c.), although its effect was also partially reduced by L-745,870. In contrast, PD 168,077 effect was abolished by L-745,870, but not L-741,626, SB277011A, FAUC 365 or raclopride. Similar results were found when dopamine agonists (5-200ng/rat) and antagonists (1-5μg/rat) were injected into the paraventricular nucleus. However, no U-inverted dose-response curve was found with any of the three dopamine agonists injected into this nucleus. As pramipexole- and apomorphine-induced penile erection was reduced mainly by D2, but not D3 or D4 antagonists, D2 receptors are those that mediate the pro-erectile effect of these dopamine agonists. Although the selective stimulation of paraventricular D4 receptors induces penile erection, D4 receptors seem to play only a modest role in the pro-erectile effect of the above dopamine agonists. PMID:21784104

  20. Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-like effects of the M1/M4 preferring muscarinic receptor agonist xanomeline

    DEFF Research Database (Denmark)

    Dencker, Ditte; Wörtwein, Gitta; Weikop, Pia;

    2011-01-01

    Disturbances in central dopaminergic neurotransmission are believed to be centrally involved in the pathogenesis of schizophrenia. Central dopaminergic and cholinergic systems interact and the cholinergic muscarinic agonist xanomeline has shown antipsychotic effects in clinical studies. Preclinical...... xanomeline in amphetamine-induced hyperactivity and apomorphine-induced climbing. Interestingly, the antipsychotic-like effects of xanomeline in the two models were almost completely abolished in D1-M4-KO mice, suggesting that M(4) mAChRs colocalized with D(1) dopamine receptors are centrally involved in...

  1. Antipsychotic-Like Effect of Trimetazidine in a Rodent Model

    OpenAIRE

    Oytun Erbaş; Hüseyin Serdar Akseki; Betül Eliküçük; Dilek Taşkıran

    2013-01-01

    Trimetazidine (TMZ) has been used as an anti-ischemic agent for angina pectoris, chorioretinal disturbances, and vertigo. Also, it can induce extrapyramidal type adverse reaction such as parkinsonism, gait disorder, and tremor via blockade of D2 receptors. In the present study, we evaluated the effect of TMZ on novelty-induced rearing behavior and apomorphine-induced stereotypy behavior in male rats. Four groups of rat (n = 7) were administrated with TMZ (10 and 20 mg/kg, i.p.), chlorpromazin...

  2. Anchanling reduces pathology in a lactacystin- induced Parkinson's disease model

    Institute of Scientific and Technical Information of China (English)

    Yinghong Li; Zhengzhi Wu; Xiaowei Gao; Qingwei Zhu; Yu Jin; Anmin Wu; Andrew C. J. Huang

    2012-01-01

    A rat model of Parkinson's disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson's disease model rats, tyrosine hydroxylase expression was increased, α-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson's disease pathology possibly by enhancing degradation activity of the ubiquitin-proteasome system.

  3. Radioimmunological determination of arginine vasopressin (AVP) after stimulation and suppression of secretion. Radioimmunologische Bestimmung von Arginin-Vasopressin (AVP) nach Stimulation und Suppression der Sekretion

    Energy Technology Data Exchange (ETDEWEB)

    Boeltz, E.

    1982-12-21

    As proof of the proper functioning of the hypothalamus-hypophyseal system the AVP secretion pattern which results from the analysis of plasma concentration at certain time intervals and under stimulation or suppression conditions can be used. 10 healthy control persons showed during an oral glucose intolerance test (=suppression) a significant decline in the AVP plasma concentration and after stimulation with apomorphine a healthy control person showed a large increase in AVP concentration in plasma. Because of the for the patient very stressful examination the physiological osmoregulation should first be checked during the infusion of a 2.5% NaCl solution with a minimal increase of the AVP plasma concentration. (TRV).

  4. Morphine dependence and dopaminergic activity: tests of circling responses in rats with unilateral nigral lesions.

    OpenAIRE

    Halliwell, J. V.; Kumar, R.

    1980-01-01

    1 Rats with unilateral electrolytic lesions involving both parts of the substantia nigra show dose-related, ipsilateral circling responses to apomorphine which are stable over time. 2 In non-tolerant rats, morphine (up to 10 mg/kg) does not elicit any circling behaviour but as tolerance develops to morphine, initially 10 mg/kg daily and then 100 ng/kg daily for about 4 months, the rats show a progressive tendency to walk more towards the side of the lesion. This behaviour is qualitatively dif...

  5. Agentes dopaminérgicos e o tratamento da disfunção erétil

    Directory of Open Access Journals (Sweden)

    Neves Gilda

    2004-01-01

    Full Text Available The understanding of the scientific basis of the erectile function expanded rapidly the range of therapies for treating erectile dysfunction in recent years. This article reviews the role of dopamine on the erection mechanisms and its importance for new pro-erectile drug design. The ability of dopaminergic agents to elicit penile erection has been described since 1975 and successively confirmed by numerous studies. The development of apomorphine SL (dopaminergic non selective agonist to enhance erectile function represents a new pharmacological approach to the management of erectile dysfunction using CNS drugs. The search for selective D4 dopaminergic agents is being explored by some research groups and pharmaceutical companies.

  6. 紫外分光光度法测定盐酸阿扑吗啡片的含量均匀度

    Institute of Scientific and Technical Information of China (English)

    董伍爱; 马鲁豫

    2001-01-01

    @@ 盐酸阿扑吗啡片是盐酸阿扑吗啡(apomorphine hyarocheoride,AH)的单方制剂,近几年美国将其用于ED的治疗,正进行第三期临床试验.现对盐酸阿扑吗啡片进行定量研究,建立紫外分光光度法测定其含量均匀度,结果满意. 1 实验部分

  7. Psychoactive-drug response is affected by acute low-level microwave irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lai, H.; Horita, A.; Chou, C.K.; Guy, A.W.

    1983-01-01

    The effects of various psychoactive drugs were studied in rats exposed for 45 min in a circularly polarized, pulsed microwave field (2450 MHz; SAR 0.6 W/kg; 2-microseconds pulses, 500 pps). Apomorphine-induced hypothermia and stereotypy were enhanced by irradiation. Amphetamine-induced hyperthermia was attenuated while stereotypy was unaffected. Morphine-induced catalepsy and lethality were enhanced by irradiation at certain dosages of the drug. Since these drugs have different modes of action on central neural mechanisms and the effects of microwaves depend on the particular drug studied, these results show the complex nature of the effect of microwave irradiation on brain functions.

  8. Synthesis and psychotropic activity of functionally substituted diaziridines and bisdiaziridines

    Energy Technology Data Exchange (ETDEWEB)

    Kostyanovskii, R.G.; Shustov, G.V.; Nabiev, O.G.; Denisenko, S.N.; Sukhanova, S.A.; Lavretskaya, E.F.

    1987-04-01

    The authors examine the psychotropic activity of diaziridines which differ considerable in their structures and the C- and N-substituents. Diaziridines are monoamine oxidase inhibitors in the brain and, thus, are potential antidepressants. The acute toxicities and some pharmacological effects of diaziridines are shown. Mice were used in the experiments. The bisdiaziridines obtained differ in their /sup 1/H and /sup 13/C NMR spectra. The effect is presented of functionally substituted diaziridines on the effects of reserpine, 5-hydroxytryptophan, tryptamine, corazole, and apomorphine hypothermia.

  9. alpha. sub 2 -mediated effect of dopamine on the motility of the chicken esophagus

    Energy Technology Data Exchange (ETDEWEB)

    Sanchez, J.; Costa, G.; Benedito, S.; Garcia-Sacristan, L.R.A.; Orensanz, L. M. (Univ. Complutense de Madrid (Spain))

    1990-01-01

    Dopamine (DA), apomorphine and B-HT 933 produced dose related contractions on isolated longitudinal strips of chicken esophagus, whereas phenylephrine elicited no effect. DA induced contractions of myogenic origin, these contractions were insensitive to DA antagonists and were partially suppressed by yohimbine, which suggested an {alpha}{sub 2}-adrenergic implication in this DA effect. This hypothesis was further investigated by performing binding experiments, in which B-HT 933 displaced the binding of ({sup 3}H) DA to esophageal homogenates. The results suggest the participation of an {alpha}{sub 2} - adrenergic receptor in the contractile response elicited by DA in the isolated chicken esophagus.

  10. Stimulation of (/sup 3/H) spiroperidol binding after prolonged neuroleptic therapy by the cholecystokinin octapeptide analog cerulein

    Energy Technology Data Exchange (ETDEWEB)

    Vasar, E.E.; Allikmets, L.K.; Maimets, O.O.; Nurk, A.M.

    1985-06-01

    Evidence has recently been obtained that cholecystokinin and its analog cerulein have marked antipsychotic action on patients with schizophrenia who are resistant to neuroleptics; this is the basis for interest in this study of the effect of cerulein, a high-affinity analog of the octapeptide cholecystokinin, on binding of tritium-spiroperidol in vivo. Considering the apormorphine-like action of cerulein, this biochemical analysis was undertaken in the form of a comparative study with N-propyl-norapomorphine, a high-affinity analogy of apomorphine.

  11. New Drug of the Treatment for Parkinson's Complications——R-Apomor phine Hydrochloride%治疗严重帕金森(氏)病的新药——右旋盐酸阿扑吗啡

    Institute of Scientific and Technical Information of China (English)

    唐跃年; 陈颖; 孙朝荣; 胡松浩

    2007-01-01

    右旋盐酸阿扑吗啡(R-apomorphine hydrochloride,APH)其商品名为阿波金(Apokyn),由美国Mylanbeaek制药公司研制开发,用于治疗严重的帕金森(氏)病(PD)病人,并在2004年4月获得美国FDA批准上市;APH也是第1个用于治疗严重的PD急性发作病人的药物,其结构式见图1。

  12. Changes in sensitivity of brain dopamine and serotonin receptors during long-term treatment with carbidine

    Energy Technology Data Exchange (ETDEWEB)

    Zharkovskii, A.M.; Allikmets, L.K.; Chereshka, K.S.; Zharkovskaya, T.A.

    1986-04-01

    The authors study the state of the dopamine and serotonin receptors of the brain during chronic administration of carbidine to animals. Parts of the brain from two rats were pooled and binding of tritium-spiperone and tritium-LSD was determined. Statistical analysis of the data for apomorphine sterotypy was carried out and the Student's test was used for analysis of the remaining data. It is shown that after discontinuation of carbidine binding of tritium-spiperone and tritium-LSD in the cortex was reduced.

  13. 治疗严重帕金森(氏)病的新药——右旋盐酸阿扑吗啡

    Institute of Scientific and Technical Information of China (English)

    唐跃年; 陈颖; 孙朝荣; 胡松浩

    2007-01-01

    右旋盐酸阿扑吗啡(R-apomorphine hydrochloride,APH)其商品名为阿波金(Apokyn),由美国Mylan bertek制药公司研制开发,用于治疗严重的帕金森(氏)病(PD)病人,并在2004年4月获得美国FDA批准上市[1];APH也是第1个用于治疗严重的PD急性发作病人的药物[2-3],其结构式见图1.……

  14. [Oral therapy of erectile dysfunction].

    Science.gov (United States)

    Trummer, H

    2000-01-01

    Erectile disfunction (E. D.) is more common in older men but may affect younger men too. Diabetes mellitus, coronary heart disease and hypertension are often associated with E. D. The majority of the patients are treated medically for erectile dysfunction and, recently, oral therapy has become most important since Viagra has been approved. New phosphodiesterase blockers are in preclinical evaluation since then. Phentolamine and apomorphine will become available soon for the treatment of E. D. It is important to know about the etiology of E. D. as well as the mechanisms by which drugs may improve erection in order to decide which drug is appropriate for a particular patient. PMID:10746289

  15. Collective physician perspectives on non-oral medication approaches for the management of clinically relevant unresolved issues in Parkinson's disease

    DEFF Research Database (Denmark)

    Odin, P; Ray Chaudhuri, K; Slevin, J T;

    2015-01-01

    impairment or dementia, intrajejunal levodopa infusion is considered as both therapeutic and palliative in some countries. Falls are linked to cognitive decline and are likely to become more frequent with device-aided therapies. • Insufficient control of motor complications (or drug-resistant tremor in the...... case of DBS) are indications for device-aided therapies. Levodopa-carbidopa intestinal gel infusions or subcutaneous apomorphine pump may be considered for patients aged >70 years who have mild or moderate cognitive impairment, severe depression or other contraindications to DBS....

  16. Effects of microgram doses of haloperidol on open-field behavior in mice.

    Science.gov (United States)

    Conceição, I M; Frussa-Filho, R

    1996-04-01

    This study was designed to evaluate the effects of low doses of haloperidol on the open-field behavior of mice. A three-phase effect of haloperidol on the motor activity of mice was observed (depression, no effect, depression). This three-phase action was clear-cut in three experimental approaches (amphetamine-induced hyperactivity, and apomorphine- and bromocriptine-induced hypoactivity). A differential action of haloperidol on dopamine receptors mediating motor stimulation and motor depression was proposed. The present data indicate that considerably more attention should be paid to the novel behavioral and biochemical actions of neuroleptic drugs in the microgram dose range. PMID:8801585

  17. Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra

    International Nuclear Information System (INIS)

    This study examined the effects of continuously supplied dopamine delivered directly into the dopamine-deficient striatum. Rats received unilateral lesions of the substantia nigra by stereotaxic administration of 6-hydroxydopamine and were tested for apomorphine-induced rotational behavior and general activity. Osmotic mini-pumps were filled with dopamine in various concentrations, implanted subcutaneously and connected to a cannula implanted directly into the striatum. The system delivered solution at a rate of .5 μl/hr for two weeks. Dopamine in a dosage of 0.5 μg/per hour reduced apomorphine-induced rotational behavior by a mean of 52 +/- 5.8% (mean +/- SEM n=20) with a maximal individual decrease of 99%. There was no change in general activity or increase in stereotype behavior. Infusions of vehicle solutions did not decrease rotational behavior. Spread of the infused dopamine and its metabolites was estimated by adding 3H-dopamine to the pumps in tracer quantities. Radioactivity was highly concentrated at the infusion site and decreased rapidly within a few mm from the infusion site. Continuous infusion methods may eventually prove to be effective in the treatment of nigro-striatal degenerative disease. 12 references, 4 figures

  18. Psychotropic Activity of Sphaeranthus indicus Linn. In Experimental Animals

    Directory of Open Access Journals (Sweden)

    V J Galani

    2009-01-01

    Full Text Available Sphaeranthus indicus Linn. (Asteraceae is a branched herb with purple color flowers, distributed in wet places. The present study evaluated the neuropharmacological effects of the hydroalcoholic extract of S. indicus (SIE in rats and mice. Effect of SIE (100, 200 and 500 mg/kg, p.o. on spontaneous motor activity, pentobarbital-induced sleeping time, motor coordination, exploratory behaviour and apomorphine-induced stereotypy were investigated in mice. SIE (100, 200 and 500 mg/kg, p.o. induced catalepsy and effect of SIE on haloperidol induced catalepsy were studied in rats. The SIE showed significant reduction of spontaneous motor activity, exploratory behaviour and prolonged pentobarbital sleeping time in the mice. Neuroleptic potential of SIE was observed by the results in which SIE antagonized apomorphine-induced stereotypy in mice, produced catalepsy and potentiated haloperidol-induced catalepsy in rats. Further, SIE had no effect on motor-coordination as determined by the rota rod test. These results provide evidence that the hydroalcoholic extract of Sphaeranthus indicus may contain psychoactive substances that are sedative in nature with possible neuroleptic properties.

  19. Use of taste repellants and emetics to prevent accidental poisoning of dogs.

    Science.gov (United States)

    Houpt, K; Zgoda, J C; Stahlbaum, C C

    1984-08-01

    Twelve taste repellents and 3 oral emetics were tested. The taste repellents were capsaicin, capsicum, oleoresin, sucrose octaacetate, quinine tonic, quassia wood extract, vanillamide, horseradish extract, caffeine, pepperoni enhancer, acorn extract, and commercially available bitter and hot flavors. The emetics tested were: antimony potassium tartrate, apomorphine, and copper sulfate. Intake of a 20% sucrose solution by Beagles was significantly depressed by addition of vanillamide at concentrations greater than 0.001%, by capsicum and capsaicin at concentrations greater than 0.01%, and by horseradish extract, pepperoni enhancer, and a commercially available hot flavor at concentrations greater than 0.1%. Antimony potassium tartrate, when added to the 20% sucrose solution at a concentration of 0.1%, produced emesis as did apomorphine at a concentration of 0.005% and copper sulfate at 1%. When the emetic antimony potassium tartrate was combined with vanillamide in a 20% sucrose solution, intake was reduced to less than 20 ml, and vomiting occurred within 15 minutes. Capsaicin (0.02%) inhibited intake of ethylene glycol to less than the lethal dose in 5 dogs tested. Incorporation of such taste repellents and/or emetics into potentially poisonous substances would reduce accidental poisoning of animals and children. PMID:6476561

  20. EFFECTS OF ALCOHOL INTAKE ON PENILE STRUCTURE AND FUNCTION IN RATS

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective To investigate the effects of alcohol intake on penile structure and function in rats.Methods Thirty adult male Wistar rats were randomly divided into two groups: control group and alcohol intake group. They were administered with 2 mL of normal saline and 40% alcohol solution respectively through gastric tubes every day. Three months later, the animal model of alcohol intake was evaluated by modified Nayagida's method, and the effects of alcohol on the rats were studied by sexual behavior, the number of apomorphine-induced penile erection,level of testosterone in the sera, and the content of penile smooth muscle.Results The scores of animal model of alcohol intake evaluated by Nayagida's method were 0. 66 ± 2. 05 in the control group and 9. 26 ± 5.50 in the alcohol intake group (P < 0.05 ), which indicated that an animal model of alcohol intake was successfully established. Sexual behavior, the number of apomorphine-induced penile erection, testosterone level in the sera, and the content of penile smooth muscle of the alcohol intake group were all statistically different as compared with the control group ( P < 0. 05 ).Conclusion Alcohol intake induces sexual dysfunction in rats, which may be due to the decline of testosterone level in the sera and decline of penile smooth muscle.

  1. The dopamine D1 receptor agonist SKF-82958 effectively increases eye blinking count in common marmosets.

    Science.gov (United States)

    Kotani, Manato; Kiyoshi, Akihiko; Murai, Takeshi; Nakako, Tomokazu; Matsumoto, Kenji; Matsumoto, Atsushi; Ikejiri, Masaru; Ogi, Yuji; Ikeda, Kazuhito

    2016-03-01

    Eye blinking is a spontaneous behavior observed in all mammals, and has been used as a well-established clinical indicator for dopamine production in neuropsychiatric disorders, including Parkinson's disease and Tourette syndrome [1,2]. Pharmacological studies in humans and non-human primates have shown that dopamine agonists/antagonists increase/decrease eye blinking rate. Common marmosets (Callithrix jacchus) have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field due to their more developed prefrontal cortex than rodents, easy handling compare to other non-human primates, and requirement for small amounts of test drugs. In this study, we evaluated the effects of dopamine D1-4 receptors agonists on eye blinking in common marmosets. Our results show that the dopamine D1 receptor agonist SKF-82958 and the non-selective dopamine receptor agonist apomorphine significantly increased common marmosets eye blinking count, whereas the dopamine D2 agonist (+)-PHNO and the dopamine D3 receptor agonist (+)-PD-128907 produced somnolence in common marmosets resulting in a decrease in eye blinking count. The dopamine D4 receptor agonists PD-168077 and A-41297 had no effect on common marmosets' eye blinking count. Finally, the dopamine D1 receptor antagonist SCH 39166 completely blocked apomorphine-induced increase in eye blinking count. These results indicate that eye blinking in common marmosets may be a useful tool for in vivo screening of novel dopamine D1 receptor agonists as antipsychotics. PMID:26675887

  2. SYNTHESIS AND PHARMACOLOGICAL EFFECTS OF BUTADIENE AND CYCLOPENTADIENE ADDUCTS OF METHANDROSTENOLONE IN RATS

    Directory of Open Access Journals (Sweden)

    FAZEL SHAMSA

    2006-06-01

    Full Text Available In this study the reactivity of methandrostenolone or [(17b-17-hydroxy-17-methylandrosta-1, 4-diene-3-one], as a dienophil in a Diels-Alder type cycloaddition reaction was investigated. The purpose of this approach was to investigate whether the 1-dehydro position of methandrostenolone 1 undergoes a cycloaddition reaction with dienes, such as 1, 3 butadiene or cyclopentadiene, and to investigate the biological behavior of the reaction adducts, i.e, compound 3 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex 3’, 4-diene-3-one} and compound 4 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex (2’,5’ methylene 3’, 4-diene-3-one}, relative to compound 1. The results indicated that thedDiels-Alder reactionddid notpproceed under the usual circumstances of high pressure and temperature, but could proceed in the presence of a Lewis acid (AlCl3. The structures of compounds 3 and 4 were confirmed by spectroscopic methods. The androgenic behavior of compounds 3 and 4 in comparison to compound 1 in the apomorphine test indicated that both compounds were almost devoid of androgenic activity, but prevented apomorphine mediated penile erection in male rats in a similar manner as cyproterone acetate.

  3. Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease

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    Biggs Christopher S

    2007-07-01

    Full Text Available Abstract We have recently observed that the corticotrophin releasing hormone (CRF related peptide urocortin (UCN reverses key features of nigrostriatal damage in the hemiparkinsonian 6-hydroxydopamine lesioned rat. Here we have studied whether similar effects are also evident in the lipopolysaccaride (LPS neuroinflammatory paradigm of Parkinson's disease (PD. To do this we have measured restoration of normal motor behaviour, retention of nigral dopamine (DA and also tyrosine hydroxylase (TH activity. Fourteen days following intranigral injections of LPS and UCN, rats showed only modest circling after DA receptor stimulation with apomorphine, in contrast to those given LPS and vehicle where circling was pronounced. In separate experiments, rats received UCN seven days following LPS, and here apomorphine challenge caused near identical circling intensity to those that received LPS and UCN concomitantly. In a similar and consistent manner with the preservation of motor function, UCN 'protected' the nigra from both DA depletion and loss of TH activity, indicating preservation of DA cells. The effects of UCN were antagonised by the non-selective CRF receptor antagonist α-helical CRF and were not replicated by the selective CRF2 ligand UCN III. This suggests that UCN is acting via CRF1 receptors, which have been shown to be anti-inflammatory in the periphery. Our data therefore indicate that UCN is capable of maintaining adequate nigrostriatal function in vivo, via CRF1 receptors following a neuro-inflammatory challenge. This has potential therapeutic implications in PD.

  4. Impact of Duodopa on Quality of Life in Advanced Parkinson's Disease: A UK Case Series

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    T. Foltynie

    2013-01-01

    Full Text Available Treatment options in advanced Parkinson’s disease (PD include subcutaneous apomorphine, pallidal or subthalamic nucleus Deep Brain Stimulation (DBS, or levodopa/carbidopa intestinal gel (LCIG/Duodopa. In this study, we describe the outcome of 12 PD patients with PD related complications started on LCIG, with respect to their quality of life measured by a disease specific validated scale—the PDQ39, together with diaries recording time spent “On,” “Off,” “Dyskinetic,” or “Asleep.” At the time of latest follow up, improvements were observed in both the PDQ39 Summary index as well as diary reports of PD symptom control following introduction of LCIG, supporting its use in well selected patients. The use of a trial period of LCIG via naso-jejunal administration allows objective evaluation of improvement in PD symptom control in advance of the placement of the more invasive percutaneous jejunostomy procedure. The decision to embark on LCIG, apomorphine or DBS should be supported by input from centres with experience of all 3 approaches. Since LCIG is an expensive option, development of the most appropriate future commissioning of this therapy in the absence of Class 1 evidence requires careful scrutiny of the outcomes of its use in a broad range of published series.

  5. Antimigraine activity study of Moringa oleifera leaf juice

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    Kanchan P Upadhye

    2012-01-01

    Full Text Available Background: Migraine is characterized by a pulsating headache, usually restricted to one side, which comes in attacks lasting for 4-48 hours. Before the headache some of the patients also may experience visual disturbances called ′aura′. The attacks are also associated with nausea, vomiting and sensitivity to light and sound. Aim : The aim of the present investigation was to explore the antimigraine potential of alcoholic fraction of leaf juice of Moringa oleifera Lamm, which is traditionally used in the treatment of migraine. Materials and Methods: Three animal models, viz, Apomorphine induced climbing behavior; l-5-HTP induced syndrome and MK 801 induced hyperactivity were used to carry out the antimigraine activity studies. Statistical Analysis: The results were analyzed with ANOVA followed by Dunnett′s multiple comparison tests. P<0.05 is considered significant. Prism 5 was used for the statistical analysis. Results and Conclusion: Moringa oleifera significantly reduced the Apomorphine induced climbing behavior, l-5-HTP induced syndrome and MK 801 induced hyperactivity in a dose dependent manner. These results indicated that Moringa oleifera may be acting via dopaminergic and serotonergic receptors. It could be concluded that Moringa oleifera may be effectively used in the treatment or management of migraine.

  6. Interactive effects of morphine and dopaminergic compounds on spatial working memory in rhesus monkeys

    Institute of Scientific and Technical Information of China (English)

    Jian-Hong Wang; Joshua Dominie Rizak; Yan-Mei Chen; Liang Li; Xin-Tian Hu; Yuan-Ye Ma

    2013-01-01

    Opiates and dopamine (DA) play key roles in learning and memory in humans and animals.Although interactions between these neurotransmitters have been found,their functional roles remain to be fully elucidated,and their dysfunction may contribute to human diseases and addiction.Here we investigated the interactions of morphine and dopaminergic neurotransmitter systems with respect to learning and memory in rhesus monkeys by using the Wisconsin General Test Apparatus (WGTA) delayed-response task.Morphine and DA agonists (SKF-38393,apomorphine and bromocriptine) or DA antagonists (SKF-83566,haloperidol and sulpiride) were co-administered to the monkeys 30 min prior to the task.We found that dose-patterned co-administration of morphine with D1 or D2 antagonists or agonists reversed the impaired spatial working memory induced by morphine or the compounds alone.For example,morphine at 0.01 mg/kg impaired spatial working memory,while morphine (0.01 mg/kg) and apomorphine (0.01 or 0.06 mg/kg) co-treatment ameliorated this effect.Our findings suggest that the interactions between morphine and dopaminergic compounds influence spatial working memory in rhesus monkeys.A better understanding of these interactive relationships may provide insights into human addiction.

  7. Dopamine agonist activity of EMD 23,448

    Energy Technology Data Exchange (ETDEWEB)

    Martin, G.E.; Pettibone, D.J. (Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania (USA). Dept. of Pharmacology)

    1985-01-01

    EMD 23,448 was examined in tests of dopaminergic function and was found to be an atypical dopamine (DA) agonist. EMD 23,448 was a weak or inactive DA agonist when examined in tests of normal postsynaptic DA receptor function: production of stereotypy in the rat (ED/sub 50/ greater than sign 5.0 mg/kg.i.p.); production of emesis in beagles (minimum effective dose = 81..mu..g/kg i.v.); and, enhanced locomotor activity of the mouse (no excitation in doses <=50 mg/i.p.). Moreover, EMD 23,448 was relatively weak in competing for (/sup 3/H)-apomorphine binding to rat striatal membranes (Ki, 205 nM). On the other hand, this indolyl-3-butylamine did activate supersensitive postsynaptic DA receptors. Specifically, it elicited contralateral turning in rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra (ED/sub 50/ value = 0.9 mg/kg) and did elicit stereotypy in rats given chronic daily haloperidol treatments. EMD 23,448 also exerted pharmacological effects in tests designed to measure activation of dopamine autoreceptors. It inhibited the ..gamma..-butyrolactone-induced increase in striatal dopa levels (ED/sub 50/ = 1 mg/kg i.p.) and produced a dose-related fall in the locomotor activity of the mouse. The results are discussed and contrasted with data derived for apomorphine and the putatively selective autoreceptor agonist (+-)-3-PPP.

  8. The HDAC Inhibitor Phenylbutyrate Reverses Effects of Neonatal Ventral Hippocampal Lesion in Rats

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    Guy eSandner

    2011-01-01

    Full Text Available Recent evidence suggests that epigenetic mechanisms play a role in psychiatric diseases. In this study, we considered rats with neonatal ventral hippocampal lesions (NVHL that are currently used for modeling neurodevelopmental aspects of schizophrenia. Contribution of epigenetic regulation to the effects of the lesion was investigated, using a histone deacetylase (HDAC inhibitor. Lesioned or sham-operated rats were treated with the general HDAC inhibitor phenylbutyrate, which was injected daily from the day after surgery until adulthood. Changes in the volume of the lesion were monitored by magnetic resonance imaging (MRI. Anxiety was analyzed in the Plus Maze Test. Hypersensitivity of the dopaminergic system was evaluated by measuring the locomotor response to apomorphine. An associative conditioning test rewarded with food was used to evaluate learning abilities. The volume of the lesions expanded long after surgery, independently of the treatment, as assessed by MRI. Removal of the ventral hippocampus reduced anxiety, and this remained unchanged when animals were treated with phenylbutyrate. In contrast, NVHL rats’ hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment. Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition. The study provides evidence that chromatin remodeling may be useful for limiting behavioral consequences due to lesioning of the ventral hippocampus at an early age. This represents a novel approach for treating disorders resulting from insults occurring during brain development.

  9. Antipsychotic-Like Effect of Trimetazidine in a Rodent Model

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    Oytun Erbaş

    2013-01-01

    Full Text Available Trimetazidine (TMZ has been used as an anti-ischemic agent for angina pectoris, chorioretinal disturbances, and vertigo. Also, it can induce extrapyramidal type adverse reaction such as parkinsonism, gait disorder, and tremor via blockade of D2 receptors. In the present study, we evaluated the effect of TMZ on novelty-induced rearing behavior and apomorphine-induced stereotypy behavior in male rats. Four groups of rat ( were administrated with TMZ (10 and 20 mg/kg, i.p., chlorpromazine (1 mg/kg, i.p., or isotonic saline. One hour later, apomorphine (2 mg/kg, s.c. was administrated to each rat. Our results showed that both doses of TMZ significantly decreased the rearing behavior in rats, whereas the decrease with chlorpromazine was higher. TMZ also decreased the stereotypy scores in a dose-dependent manner. We concluded that TMZ has beneficial effects on rearing behavior and stereotypy, which are accepted to be indicators of antipsychotic effect. Taken together, with its antioxidative and cytoprotective properties, TMZ is worthy of being investigated for its anti-psychotic effects as a primary or an adjunctive drug.

  10. Novel protein-inhibitor interactions in site 3 of Ca(2+)-bound S100B as discovered by X-ray crystallography.

    Science.gov (United States)

    Cavalier, Michael C; Melville, Zephan; Aligholizadeh, Ehson; Raman, E Prabhu; Yu, Wenbo; Fang, Lei; Alasady, Milad; Pierce, Adam D; Wilder, Paul T; MacKerell, Alexander D; Weber, David J

    2016-06-01

    Structure-based drug discovery is under way to identify and develop small-molecule S100B inhibitors (SBiXs). Such inhibitors have therapeutic potential for treating malignant melanoma, since high levels of S100B downregulate wild-type p53 tumor suppressor function in this cancer. Computational and X-ray crystallographic studies of two S100B-SBiX complexes are described, and both compounds (apomorphine hydrochloride and ethidium bromide) occupy an area of the S100B hydrophobic cleft which is termed site 3. These data also reveal novel protein-inhibitor interactions which can be used in future drug-design studies to improve SBiX affinity and specificity. Of particular interest, apomorphine hydrochloride showed S100B-dependent killing in melanoma cell assays, although the efficacy exceeds its affinity for S100B and implicates possible off-target contributions. Because there are no structural data available for compounds occupying site 3 alone, these studies contribute towards the structure-based approach to targeting S100B by including interactions with residues in site 3 of S100B. PMID:27303795

  11. Characterization of actions of dopamine in the pituitary of the goldfish, Carassius auratus

    Energy Technology Data Exchange (ETDEWEB)

    Omeljaniuk, R.J.

    1988-01-01

    The dopamine receptor in the goldfish (Carassius auratus) pituitary and its involvement with inhibition of gonadotropin (GtH) and {alpha}-melanocyte stimulating hormone ({alpha}-MSH) release was studied. In vitro dopamine, in a dose-related manner, inhibited spontaneous GtH and {alpha}-MSH release from superfused fragments of pars distalis (PD) and neurointermediate lob (NIL), respectively; dopamine also inhibited sGnRH-A stimulation of GtH release. Thyrotropin releasing-hormone (TRH), in a dose-related manner, stimulated {alpha}-MSH release from NIL fragments; dopamine inhibited TRH action. The stereoisomers of apomorphine were equivalent in inhibiting GtH and {alpha}-MSH release from fragments treated with releasing factors. Domperidone, in a dose-related manner, antagonized dopamine action. ({sup 3}H)-Spiperone was used to radiolabel the goldfish pituitary dopamine receptor in vitro. The binding of ({sup 3}H)-spiperone had the characteristics of a receptor: tissue specificity, dependence on tissue quantity, reversibility, saturability, displaceability, specificity of binding with various drugs and a correlation of binding with biological effects were demonstrated. This is a low-affinity, high-capacity receptor which does not show binding stereoselectivity for apomorphine; domperidone binds avidly to this receptor. The NIL contains significantly greater numbers of this receptor compared to the PD.

  12. ROLE OF CHOLINERGIC SYSTEM ON THE CONSTRUCTION OF MEMORY AND ITS INTERACTION WITH DOPAMINERGIC SYSTEM

    Directory of Open Access Journals (Sweden)

    F. Z. Zangeneh

    2006-07-01

    Full Text Available The central cholinergic system has been associated with cognitive function and memory and acetylcholine plays an important role during the early stages of memory consolidation. In this study, after training mice were tested with one way active avoidance procedure and retention were tested at 4, 8, 12, 16 and 24 hours of training and compared with non-shocked mice, in which it took 24 hours, a suitable time for retention test. Low dose administration of arecoline and physostigmine pre-training, immediate post-training and before retrieval showed that muscarinic agonist arecoline can potentiated memory in post trained and retrieval phases and reversible cholinesterase inhibitor physostigmine potentiated memory only in retrieval phase. Scopolamine disrupted acetylcholine potentiation only in retrieval phase. In the second part of this study, the effect of dopaminergic system was investigated. Low dose of apomorphine and D2 agonist bromocriptine potentiated memory when administered immediately post-training, and D2 antagonist sulpiride impaired memory. When the cholinergic system was blocked by scopolamine immediately post-training, apomorphine and bromocriptine potentiated memory and sulpiride impaired it. In conclusion, these results suggest that, cholinergic system in retrieval phase is very critical and there was no interaction between the two systems in the post-training phase.

  13. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra

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    A. Harkavyi

    2013-01-01

    Full Text Available Glucagon-like peptide-1 receptor (GLP-1R activation by exendin-4 (EX-4 is effective in preclinical models of Parkinson’s disease (PD and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ and substantia nigra (SN. We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39 as well as the potential role of dopamine (DA D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39 or nafadotride (D3 antagonist and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39 and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39 or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39 or NAF, while in the SN the opposite profile was seen.

  14. Chronic intrastriatal dopamine infusions in rats with unilateral lesions of the substantia nigra

    Energy Technology Data Exchange (ETDEWEB)

    Hargraves, R.; Freed, W.J.

    1987-03-09

    This study examined the effects of continuously supplied dopamine delivered directly into the dopamine-deficient striatum. Rats received unilateral lesions of the substantia nigra by stereotaxic administration of 6-hydroxydopamine and were tested for apomorphine-induced rotational behavior and general activity. Osmotic mini-pumps were filled with dopamine in various concentrations, implanted subcutaneously and connected to a cannula implanted directly into the striatum. The system delivered solution at a rate of .5 ..mu..l/hr for two weeks. Dopamine in a dosage of 0.5 ..mu..g/per hour reduced apomorphine-induced rotational behavior by a mean of 52 +/- 5.8% (mean +/- SEM n=20) with a maximal individual decrease of 99%. There was no change in general activity or increase in stereotype behavior. Infusions of vehicle solutions did not decrease rotational behavior. Spread of the infused dopamine and its metabolites was estimated by adding /sup 3/H-dopamine to the pumps in tracer quantities. Radioactivity was highly concentrated at the infusion site and decreased rapidly within a few mm from the infusion site. Continuous infusion methods may eventually prove to be effective in the treatment of nigro-striatal degenerative disease. 12 references, 4 figures.

  15. Effects of cysteamine on dopamine-mediated behaviors: evidence for dopamine-somatostatin interactions in the striatum

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Iverson, M.T.; Radke, J.M.; Vincent, S.R.

    1986-06-01

    The effects of prior treatment with cysteamine, a drug which appears to deplete selectively the neuropeptide somatostatin, on apomorphine-induced stereotypy and amphetamine-induced locomotor activity and conditioned place preferences were investigated. Twelve hours following systemic cysteamine injections apomorphine-induced stereotypy was attenuated and striatal somatostatin levels were reduced by half. Systemic cysteamine also decreased the motor stimulant effects of amphetamine, without influencing the rewarding properties as determined by the conditioned place preference procedure. Direct injections of cysteamine into the nucleus accumbens also decreased the locomotor response to amphetamine, and produced a local reduction in somatostatin levels in the accumbens. Cysteamine did not appear to alter monoamine turnover in the striatum after either systemic or intra-accumbens injections. These results suggest that somatostatin in the nucleus accumbens and caudate-putamen modulates the motor, but not the reinforcing properties of dopaminergic drugs, possibly via an action postsynaptic to dopamine-releasing terminals. Furthermore, it is evident from these results that cysteamine is an important tool with which to study the central actions of somatostatin.

  16. Dopamine receptors on adrenal chromaffin cells modulate calcium uptake and catecholamine release

    Energy Technology Data Exchange (ETDEWEB)

    Bigornia, L.; Suozzo, M.; Ryan, K.A.; Napp, D.; Schneider, A.S.

    1988-10-01

    The presence of dopamine-containing cells in sympathetic ganglia, i.e., small, intensely fluorescent cells, has been known for some time. However, the role of dopamine as a peripheral neurotransmitter and its mechanism of action are not well understood. Previous studies have demonstrated the presence of D2 dopamine receptors on the surface of bovine adrenal chromaffin cells using radioligand binding methods and dopamine receptor inhibition of catecholamine release from perfused adrenal glands. In the present study, we provide evidence confirming a role of dopamine receptors as inhibitory modulators of adrenal catecholamine release from bovine chromaffin cell cultures and further show that the mechanism of modulation involves inhibition of stimulated calcium uptake. Apomorphine gave a dose-dependent inhibition (IC50 = 1 microM) of 45Ca2+ uptake stimulated by either nicotine (10 microM) or membrane depolarization with an elevated K+ level (60 mM). This inhibition was reversed by a series of specific (including stereospecific) dopamine receptor antagonists: haloperidol, spiperone, sulpiride, and (+)-butaclamol, but not (-)-butaclamol. In addition, the calcium channel agonist Bay K 8644 was used to stimulate uptake of 45Ca2+ into chromaffin cells, and this uptake was also inhibited by the dopamine receptor agonist apomorphine. The combined results suggest that dopamine receptors on adrenal chromaffin cells alter Ca2+ channel conductance, which, in turn, modulates catecholamine release.

  17. Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

    Directory of Open Access Journals (Sweden)

    Dayane Pessoa de Araújo

    2013-01-01

    Full Text Available This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg alone or associated with L-DOPA using an animal model of Parkinson’s disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

  18. Computational analysis of open loop handwriting movements in Parkinson's disease: a rapid method to detect dopamimetic effects.

    Science.gov (United States)

    Eichhorn, T E; Gasser, T; Mai, N; Marquardt, C; Arnold, G; Schwarz, J; Oertel, W H

    1996-05-01

    We used a computational analysis of open loop handwriting movements and a clinical rating scale for monitoring the effect of apomorphine in 16 patients with early untreated parkinsonism [subsequently L-DOPA responsive, probable Parkinson's disease (PD)], six patients with long-standing PD with L-DOPA associated motor fluctuations, and seven patients with known L-DOPA unresponsive parkinsonism. Subjects were instructed to write fluently concentric circles of approximately 12 mm in diameter. Movements were recorded for two periods of 3 s each, using a digitizing tablet. Mean peak velocity (Vmax) and mean peak acceleration (Amax) were determined. In addition, two sensitive indices describing the degree of automation of handwriting were derived: (a) NCV, calculated as the mean Number of Changes in direction of Velocity per half circle, and (b) NCA, the mean Number of Changes in the direction of Acceleration. Clinical rating was performed according to the Unified Parkinson's Disease Rating Scale part III (UPDRS III). After apomorphine injection, the patients with early untreated probable PD showed significant improvement of Vmax, Amax, NCV, NCA, and UPDRS III scores. Likewise, the patients with long-standing PD improved significantly in all kinematic parameters and UPDRS III scores. Patients with L-DOPA unresponsive parkinsonism failed to change significantly in any of the parameters tested. These observations suggest that the computer-assisted analysis of automated handwriting movements can be used as an objective quick method for quantifying dopamimetic effects on the kinematics of handwriting movements in parkinsonian patients. PMID:8723147

  19. Effects of (-)stepholidine in animal models for schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Bart A ELLENBROEK; Xue-xiang ZHANG; Guo-zhang JIN

    2006-01-01

    Aim: (-)Stepholidine (SPD) is an active ingredient of the Chinese herb Stephania intermedia, which binds to the dopamine D1 and D2 like receptors. Biochemical, electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D1 and a D2 antagonist, which could make SPD a unique antipsychotic drug. The present study aimed to investigate the antipsychotic properties of SPD in two animal models for schizophrenia. Methods: The effects of SPD, clozapine and haloperidol in increasing forelimb and hindlimb retraction time in the paw test and in reversing the apomorphine and MK801-induced disruption of prepulse inhibition was investigated. Results: In the paw test, clozapine and SPD increased the hindlimb retraction time, with only a marginal effect on the forelimb retraction time, whereas haloperidol potently increased both. In the prepulse inhibition paradigm, all three drugs reverse the apomorphine-induced disruption in prepulse inhibition, while none of the drugs could reverse the MK801-induced disruption. SPD even slightly, but significantly, potentiated the effects of MK801. Conclusion: The data show that SPD showed antipsychotic-like effects in both the prepulse inhibition paradigm and in the paw test. Moreover, the results of the paw test suggest that SPD has an atypical character with a relatively small potency to induce extrapyramidal side effects.

  20. The effects of opioid drugs on dopamine mediated locomotor activity in rats

    International Nuclear Information System (INIS)

    Opioid drugs influence various behavioural parameters including locomotor activity in experimental animals. The interaction between the opioid and dopaminergic systems is one possible explanation for the effect of opioid drugs on locomotor activity. In this study behavioural and biochemical assays were done to investigate the interaction between the opioid and dopaminergic systems. Behavioural studies were done by measurement of locomotor activity (LA) of rats after acute or chronic pretreatment with opioid and/or dopaminergic drugs. Biochemical studies were in the form of radioligand binding assays, the effect on the number (Bmax) and affinity (KD) of receptors was measured after chronic pretreatment with opioid and/or dopaminergic drugs. The opioid drugs used are morphine, nalbuphine and naloxone. Dopaminergic drugs used included: agonists-apomorphine and piribedil; antagonists-pimozide, haloperidol, chlorpromazine. In the acute situation increased LA was obtained with morphine and the DA agonists. A correlation between the behavioural and biochemical assays was found. Chronic pretreatment with morphine enhanced apomorphine induced LA, this supersensitivity was also measured as an increased receptor density (Bmax) of D2 receptors in the striatum. Chronic morphine pretreatment caused a decrease in morphine induced LA, while this subsensitivity was not apparent in the ligand binding assays - where no change in receptor number was observed. Chronic naloxone pretreatment enhanced morphine induced LA, as well as increased the Bmax of opioid receptors in the whole brain. It is concluded that an interaction between the opioid and dopaminergic systems does exist, and may account for the mechanism of action of the opioids

  1. Striatal binding of 2-amino-6,7-(/sup 3/H)dihydroxy-1,2,3,4-tetrahydronaphthalene to two dopaminergic sites distinguished by their low and high affinity for neuroleptics

    Energy Technology Data Exchange (ETDEWEB)

    List, S.J.; Wreggett, K.A.; Seeman, P.

    1982-07-01

    In order to develop more selective methods for labeling brain dopamine receptors, this study describes in detail the properties of 2-amino-6,7,-(/sup 3/H)dihydroxy-1,2,3,4,-tetrahydronaphthalene ((/sup 3/H) ADTN) binding to dopaminergic sites in rat, calf, and human brain. (/sup 3/H)ADTN labeled two distinct types of dopaminergic binding sites in the brain striatum of the rat, calf, and human. Very low concentrations of dopamine and dopaminergic catecholamines (with IC50 values of 1 to 10 nM) inhibited the binding of (/sup 3/H)ADTN to both sites. Neuroleptics, however, inhibited the binding of (/sup 3/H)ADTN in two distinctly separate concentration ranges, with IC50 values of 0.15 to 40 nM at one site and 100 and 50,000 nM at the other site. The site with high affinity for dopamine and low affinity for neuroleptics had binding properties that corresponded to those of the previously characterized D3 site). The (/sup 3/H)ADTN binding site with high affinity for neuroleptics demonstrated binding characteristics similar to a site labeled by /sup 3/H-Neuroleptics. (/sup 3/H)Apomorphine appeared to label the same two sites as (/sup 3/H)ADTN, while (/sub 3/H)dopamine labeled only the D3 site. Scatchard analysis of (/sup 3/H)ADTN or (/sub 3/H)apomorphine binding, under conditions for selective labeling of the low affinity neuroleptic site (D3) and the high affinity site for neuroleptics, detected a density of 70 fmol/mg of protein for each. The density of the D3 site in the calf striatum (170 fmol/mg of protein) was much greater than that of the high affinity neuroleptic site (50 fmol/mg). In the rat, the dissociation constant (KD) of (/sup 3/H)ADTN was 2 nM for both sites. (/sup 3/H)Apomorphine, however, had a higher affinity for the D3 site (KD.1.6 nM) than for the high affinity neuroleptic site (KD.4.2 nM).

  2. Therapeutic effect of human amniotic epithelial cell transplantation into the lateral ventricle of hemiparkinsonian rats

    Institute of Scientific and Technical Information of China (English)

    YANG Xin-xin; XUE Shou-ru; DONG Wan-li; Kong Yan

    2009-01-01

    Background Human amniotic epithelial cells (HAECs) are able to secrete biologically active neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3, both of which exhibit trophic activities on dopamine neurons.Previous study showed that when human amniotic epithelial cells were transplanted into the striatum of 6-hydroxydopamine (6-OHDA)-induced Parkinson disease rats, the cells could survive and exert functional effects. The purpose of this study was to investigate the survival and the differentiation of human amniotic epithelial cells after being transplanted into the lateral ventricle of Parkinson's disease (PD) rats, and to investigate the effects of grafts on healing PD in models.Methods The Parkinson's model was made with stereotactic microinjection of 6-hydroxydopamine (6-OHDA) into the striatum of a rat. The PD models were divided into two groups: the HAECs group and the normal saline (NS) group.Some untreated rats were taken as the control. The rotational asymmetry induced by apomorphine of the HAECs group and the NS group were measured post cell transplantation. The expression of nestin and vimentin in grafts were determined by immunohistology. Ten weeks after transplantation the density of tyrosine hydroxylase positive cells in the substantia nigra of the HAECs group, NS group and the untreated group was determined. The differentiation of grafts was determined by TH immunohistology. High performance liquid chromatography (HPLC) was used to determine monoamine neurotransmitter levels in the striatum.Results The rotational asymmetry induced by apomorphine of the HAECs group was ameliorated significantly compared to the NS group two weeks after transplantation (P <0.01). The grafts expressed nestin and vimentin five weeks after transplantation. TH immunohistochemistry indicated that the TH positive cells in the substantia nigra of the HAECs group increased significantly compared to the NS group (P<0.01). Tyrosine hydroxylase (TH) positive

  3. D3 receptor test in vitro predicts decreased cocaine self-administration in rats.

    Science.gov (United States)

    Caine, S B; Koob, G F; Parsons, L H; Everitt, B J; Schwartz, J C; Sokoloff, P

    1997-07-01

    The three dopamine agonists with highest reported D3 receptor selectivity in vitro, pramipexole, quinelorane and PD128,907, decreased self-administration of a high dose of cocaine in rats as a result of a leftward shift in the cocaine dose-effect function. In contrast the D3 preferring antagonist nafadotride increased cocaine self-administration. Moreover the relative potencies of these and other D2-like dopamine agonists (lisuride, 7-OH-DPAT, quinpirole, apomorphine, bromocriptine) to modulate cocaine self-administration were highly correlated with their relative potencies for increasing mitogenesis in vitro in cell lines expressing D3 but not D2 receptors. These results support the hypothesis that the D3 receptor may be an important target for pharmacotherapies for cocaine abuse and dependence. PMID:9243643

  4. Supersensitivity of GABAergic systems induced within rat substantia nigra and globus pallidus by haloperidol

    International Nuclear Information System (INIS)

    The supersensitivity was demonstrated by an increase in the responsiveness of individual neurons within these brain regions to microiontophoretically-applied GABA and by an up regulation of GABA binding sites. Rates received haloperidol for 30 days in their feed and were then withdrawn from treatment for 48 hrs. 3H-GABA binding was found to be significantly elevated with the SNR (55%) and GP (42%). Scatchard analysis of 3H-muscimol binding isotherms indicated that the number (Bmax) of high affinity binding sites within the GP was significantly increased (32%); within the SNR, significant increases were detected in the Bmax of both high (23%) and low (58%) affinity 3H-muscimol binding sites. After CHAL treatment, signs of dopaminergic supersensitivity within the basal ganglia were also observed. Spontaneous locomotor activity and apomorphine-induced stereotyped behavior were increased and specific 3H-spiroperidol binding was elevated within the striatum (60%) and GP (236%)

  5. [Neurochemical mechanisms of dorsal pallidum in antiadverse effects of anxiolytics of different models of anxiety].

    Science.gov (United States)

    Talaenko, A N; Krivobok, G K; Pankrat'ev, D V; Goncharenko, N V

    2005-07-01

    Microinjections of glutamine acid, serotonine and campiron into globus pallidus reveal antiadverse properties of ratsin in the test with avoiding "threatening situation" but not with "illuminated site" under the conditions of rats' free choice between light and dark sites. Dopamine, apomorphine, GABA, chlordiazepoxide, phenibut and indoter injected locally into this formation of basal ganglia do not affect the mechanisms of the involuntary movement, but counteract the conditions of anxiety in both models of behaviour. These results show different functional role of monoamino- and aminoacidergic systems of dorsal pallidum in operative regulation of behaviour with changing of aversive stimulus modality. Preliminary intraperitoneal injection of functional antagonists of investigated synoptotropic followed by microinjection of monoamines and amino acids into globus pallidus reveal selective involvement of neuromediator systems of dorsal pallidum into antiadverse anxiosedative and anxioselective actions. PMID:16206621

  6. Neurochemical mechanisms of the dorsal pallidum in the antiaversive effects of anxiolytics in various models of anxiety.

    Science.gov (United States)

    Talalaenko, A N; Krivobok, G K; Pankrat'ev, D V; Goncharenko, N V

    2006-09-01

    In conditions in which rats had a free choice between dark and light chambers, microinjections of glutamic acid, serotonin, and campiron into the globus pallidus showed that these agents have antiaversive properties in a threatening situation test but not in an illuminated area test. Dopamine, apomorphine, GABA, chlordiazepoxide, phenibut, and indoter injected locally into this formation of the basal ganglia had no effect on the mechanisms of voluntary movement but counteracted anxiety states in both behavioral models. These results provide evidence that the monoaminergic and aminoacidergic systems of the dorsal pallidum have different functional roles in the operative regulation of behavior for aversive stimuli of different modalities. Prior intraperitoneal administration of functional antagonists of these synaptotropic substances and subsequent microinjection of transmitter monoamines and amino acids and their agonists into the globus pallidus demonstrated the selective involvement of the neurotransmitter systems of the dorsal pallidum in the antiaversive effects of anxiosedative and anxioselective substances. PMID:16841156

  7. Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites

    International Nuclear Information System (INIS)

    Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors

  8. Hypothyroidism leads to increased dopamine receptor sensitivity and concentration

    International Nuclear Information System (INIS)

    Rats treated with iodine-131 were confirmed to be hypothyroid by their reduced baseline core body temperatures, reduced serum thyroxine concentrations and elevated serum thyroid stimulating hormone concentrations. When hypothyroid rats were compared to euthyroid controls they were more sensitive to the effects of apomorphine (1.0 mumol/kg) on stereotypy, operant responding and body temperature and showed a smaller reduction in locomotor activity after injection of haloperidol (0.25 mumol/kg). Receptor binding studies on striatal homogenates indicated that hypothyroid rats had increased concentrations of D2 dopamine receptors but there was no change in the affinity. It is concluded that hypothyroidism increases dopamine receptor sensitivity by increasing receptor concentration

  9. Antagonism of quercetin against tremor induced by unilateral striatal lesion of 6-OHDA in rats.

    Science.gov (United States)

    Mu, Xin; Yuan, Xia; Du, Li-Da; He, Guo-Rong; Du, Guan-Hua

    2016-01-01

    Quercetin, a flavonoid present in many plants, is reported to be effective in models of neurodegenerative diseases. The aim of the present study was to evaluate the anti-tremor effects of quercetin in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease. In rats, quercetin had no effect on apomorphine-induced rotations, but it could significantly attenuate muscle tremor of 6-OHDA lesioned rats. Interestingly, quercetin could decrease the burst frequency in a dose- and time-dependent manner. These results suggest that quercetin may have a protective effect on models to mimic muscle tremors of Parkinson's disease. This effect of quercetin may be associated with serotonergic system, but further study is needed. PMID:26217978

  10. Cytotoxic effects of catechols to glial and neuronal cells

    Directory of Open Access Journals (Sweden)

    Ramon Santos El-Bachá

    2015-04-01

    Full Text Available Catechols are compounds that autoxidises under physiological conditions leading to the formation of reactive oxygen species (ROS, semiquinones, and quinones. These molecules can be formed in organisms because of the metabolism of exogenous aromatic substances, such as benzene. However, there are several important endogenous catechols, which have physiological functions, such as catecholamines. Furthermore, several pharmacological agents are catechols, such as apomorphine, or can be metabolised to generate these compounds. In this presentation we will show that apomorphine can unspecifically bind to proteins during its autoxidation, a phenomenon that is inhibited by thiols. Brain endothelial cells and glial cells express xenobiotic-metabolising enzymes as components of the metabolic blood-brain barrier in an attempt to protect the central nervous system against drugs. Since UDP-glucuronosyltransferases (EC 2.4.1.17 are among these enzymes, we investigated the ability of brain microsomes to conjugate catechols with glucuronate. Despite the fact that 1-naphtol could be glucuronidated in the presence of brain cortex microsomes, the same was not observed for most of catechols that were tested. Therefore, this is not the main mechanism used to protect the brain against them. Indeed, catechols may inhibit other xenobiotic-metabolising enzymes. We showed that apomorphine inhibited the cytochrome P450-dependent dealkylation activity. The production of ROS and reactive quinones, as well as their effects on protein functions, seems to be involved in the cytotoxicity of catechols. Glial cells are more resistant than neuronal cells. Apomorphine was more toxic to rat neurons than to rat C6 glioma cells. 1,2-Dihydroxybenzene (catechol killed human GL-15 cells with an EC50 of 230 uM after 72 h, a effect that was significantly inhibited by superoxide dismutase (EC 1.15.1.1. Another mechanism that we found to be involved in catechol cytotoxicity is the inhibition

  11. Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist

    Energy Technology Data Exchange (ETDEWEB)

    Jaton, A.L.; Giger, R.K.A.; Vigouret, J.M.; Enz, A.; Frick, W.; Closse, A.; Markstein, R.

    1986-01-13

    The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by ..gamma..-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for /sup 3/H-dopamine and /sup 3/H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs. 29 references, 5 figures, 3 tables.

  12. Duration of drug action of dopamine D2 agonists in mice with 6-hydroxydopamine-induced lesions.

    Science.gov (United States)

    Tsuchioka, Akihiro; Oana, Fumiki; Suzuki, Takayuki; Yamauchi, Yuji; Ijiro, Tomoyuki; Kaidoh, Kouichi; Hiratochi, Masahiro

    2015-12-16

    Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans. PMID:26559726

  13. Unilateral Ibotenic Acid Lesions of the Prefrontal Cortex Reduce

    Directory of Open Access Journals (Sweden)

    Kuriyama,Shigeki

    2006-12-01

    Full Text Available Rats with 6-hydroxydopamine (6-OHDA-induced lesions of the substantia nigra are used as a model of Parkinson’s disease (PD, and these “lesioned” rats exhibit a rotational behavior when further injected with apomorphine (APO. We examined whether lesions in the prefrontal cortex (PFC could modify the rotational behavior in PD model rats. Rats initially received unilateral lesions of the substantia nigra by 6-OHDA injection, and then their rotational behavior was measured. Two PFC lesions were achieved by intracerebral infusions of ibotenic acid, followed by measurement of APOinduced rotation. Rotation was reduced by approximately 30オ after PFC injury. The PFC may have functional infl uences on the basal ganglia and may be involved in the pathophysiology of the rotational behavior of PD model rats.

  14. 左旋千金藤立定对D2受体的拮抗作用研究

    Institute of Scientific and Technical Information of China (English)

    刘大中; 尤春来; 蔡晓文

    2001-01-01

    利用阿扑吗啡(Apomorphine,APO)5mg·kg-1·d-1s.c.建立的哺乳期大鼠乳汁分泌低下模型,用以研究左旋千金藤立定(1-stepholidine,L-SPD)对抗APO所诱导的哺乳期大鼠泌乳素(pro-1actin,PRL)水平低下作用.实验结果表明,用APO所致哺乳期大鼠乳汁分泌低下模型研究进一步证实了L-SPD为D2受体阻断剂.

  15. Hypothyroidism leads to increased dopamine receptor sensitivity and concentration

    Energy Technology Data Exchange (ETDEWEB)

    Crocker, A.D.; Overstreet, D.H.; Crocker, J.M.

    1986-06-01

    Rats treated with iodine-131 were confirmed to be hypothyroid by their reduced baseline core body temperatures, reduced serum thyroxine concentrations and elevated serum thyroid stimulating hormone concentrations. When hypothyroid rats were compared to euthyroid controls they were more sensitive to the effects of apomorphine (1.0 mumol/kg) on stereotypy, operant responding and body temperature and showed a smaller reduction in locomotor activity after injection of haloperidol (0.25 mumol/kg). Receptor binding studies on striatal homogenates indicated that hypothyroid rats had increased concentrations of D2 dopamine receptors but there was no change in the affinity. It is concluded that hypothyroidism increases dopamine receptor sensitivity by increasing receptor concentration.

  16. Synthesis and pharmacological evaluation of piperidine (piperazine)-substituted benzoxazole derivatives as multi-target antipsychotics.

    Science.gov (United States)

    Huang, Ling; Zhang, Wenjun; Zhang, Xiaohua; Yin, Lei; Chen, Bangyin; Song, Jinchun

    2015-11-15

    The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment. PMID:26483200

  17. The thermal effect of microwaves during irradiation with low energy levels. I

    Energy Technology Data Exchange (ETDEWEB)

    Klein, M.J. (Centre d' Etudes et de Recherches de Medecine Aerospatiale, Division de Neurophysiologie Appliquee, Paris, France); Milhaud, C.L.

    1982-01-01

    The effect of a 30 min exposure to low energy microwaves (2.45 GHz, 2 and 5 mW/sq cm) was investigated using two classical hypothermia models of previsional animal psychopharmacology. Results show that hypothermia induced in mice by oxotremorine and by apomorphine reaches a maximum 30 min after the injections of the drugs. The microwave radiation produces a significant heating (1 degree C) in previously hypothermic mice, while the same radiation levels do not influence the rectal temperature of the control animals. These results indicate that the mice are able to control the amount of calories introduced by low level microwave radiation since this heating can only be observed after a pharmacological inhibition of the thermoregulatory mechanisms. In addition, it is found that low level microwaves do not modify the permeability of the blood-brain barrier.

  18. Presence of dopamine D-2 receptors in human tumoral cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Sokoloff, P.; Riou, J.F.; Martres, M.P.; Schwartz, J.C. (Centre Paul Broca, Paris (France))

    1989-07-31

    ({sup 125}I) Iodosulpride binding was examined on eight human cell lines derived from lung, breast and digestive tract carcinomas, neuroblastomas and leukemia. Specific binding was detected in five of these cell lines. In the richest cell line N417, derived from small cell lung carcinoma, ({sup 125}I) iodosulpride bound with a high affinity (Kd = 1.3 nM) to an apparently homogeneous population of binding site (Bmax = 1,606 sites per cell). These sites displayed a typical D-2 specificity, established with several dopaminergic agonists and antagonists selective of either D-1 or D-2 receptor subtypes. In addition, dopamine, apomorphine and RU 24926 distinguished high- and low-affinity sites, suggesting that the binding sites are associated with a G-protein. The biological significance and the possible diagnostic implication of the presence of D-2 receptors on these cell lines are discussed.

  19. Intrastriatal Gene Transfer of Vascular Endothelial Growth Factor Rescues Dopaminergic Neurons in a Rat Parkinson's Disease Model

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    To examine the ability of intrastriatal gene transfer of vascular endothelial growth factor 165 mediated by adenoviral vector to rescue dopaminergic neurons in a rat model of Parkinson's disease (PD), we constructed recombinant replication-deficent adenoviral vectors carrying the gene of VEGF165 (Ad-VEGF), and injected Ad-VEGF (or Ad-LacZ and PBS as controls) into the striatum of rats 7 days after the lesion by 6-hydroxydopamine. The rat rotational behavior analysis and tyrosine hydroxylase (TH) immunohistochemistry were performed to assess the change of dopaminergic neurons. Our results showed that the rats receiving Ad-VEGF injection displayed a significant improvement in apomorphine-induced rotational behavior and a significant preservation of TH-positive neurons and fibers compared with control animals. It is concluded that intrastriatal gene transfer by Ad-VEGF may rescue the dopaminergic neurons from degeneration in a rat model of PD.

  20. Clinical spectrum of impulse control disorders in Parkinson's disease.

    Science.gov (United States)

    Weintraub, Daniel; David, Anthony S; Evans, Andrew H; Grant, Jon E; Stacy, Mark

    2015-02-01

    Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored closely for development of ICDs as part of routine clinical care. PMID:25370355

  1. Sex differences in the effects of perinatal anoxia on dopamine function in rats.

    Science.gov (United States)

    Laplante, François; Brake, Wayne G; Chehab, Sara L; Sullivan, Ron M

    2012-01-01

    Birth complications involving reduced oxygen to the fetus pose risks for neurodevelopmental disorders like schizophrenia and ADHD, which involve central dopamine (DA) dysfunction and also show gender differences in incidence or severity. Here, we examine possible sex differences in the long-term consequences of perinatal anoxia in the rat, on central DA systems and DA-mediated behaviour. As adults, sensorimotor gating (prepulse inhibition, PPI) was differentially affected by anoxia in males and females, tending to be impaired only in males. Apomorphine-induced suppression of PPI was especially pronounced in males. Anoxia caused increases in amygdala DA levels in both sexes. However, sex-specific changes in DA and metabolite levels in prefrontal cortex and nucleus accumbens were found, suggesting a possible basis for some of the observed gender biases in certain neurodevelopmental disorders, sensitive to birth hypoxia. PMID:22061835

  2. A porcine model of progressive Parkinson disease established by chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication

    DEFF Research Database (Denmark)

    Nielsen, M S; Glud, Andreas Nørgaard; Møller, Arne;

    2009-01-01

    for continuous intramuscular MPTP delivery (2-24 mg MPTP/day). Six pigs served as normal controls. During 11 weeks the general behavior and motor performance of the animals were observed and scored. All animals underwent digital gait analysis preoperatively, 4 and 11 weeks postoperatively using an......-related decrease in gait velocity for the intoxicated animals. This decrease could be reversed completely with apomorphine. For dosages of 2-12 mg MPTP/day, the symptoms failed to progress from the initial state of mild Parkinsonism, and some recovery was observed. Animals receiving 18 mg/day progressed to...... moderate parkinsonism, whereas animals receiving 24 mg/day had their pumps turned off after 11 days due to severe PD symptoms. Histopathological examination showed increased nigral neuron loss with increased MPTP dosages. HPLC showed decreased striatal dopamine levels at daily MPTP dosages of 12 mg or...

  3. Dose-dependent neuroprotective effect of ciliary neurotrophic factor delivered via tetracycline-regulated lentiviral vectors in the quinolinic acid rat model of Huntington's disease.

    Science.gov (United States)

    Régulier, E; Pereira de Almeida, L; Sommer, B; Aebischer, P; Déglon, N

    2002-11-01

    The ability to regulate gene expression constitutes a prerequisite for the development of gene therapy strategies aimed at the treatment of neurologic disorders. In the present work, we used tetracycline (Tet)-regulated lentiviral vectors to investigate the dose-dependent neuroprotective effect of human ciliary neurotrophic factor (CNTF) in the quinolinic acid (QA) model of Huntington's disease (HD). The Tet system was split in two lentiviruses, the first one containing the CNTF or green fluorescent protein (GFP) cDNAs under the control of the Tet-response element (TRE) and a second vector encoding the transactivator (tTA). Preliminary coinfection study demonstrated that 63.8% +/- 2.0% of infected cells contain at least two viral copies. Adult rats were then injected with CNTF- and GFP-expressing viral vectors followed 3 weeks later by an intrastriatal administration of QA. A significant reduction of apomorphine-induced rotations was observed in the CNTF-on group. In contrast, GFP-treated animals or CNTF-off rats displayed an ipsilateral turning behavior in response to apomorphine. A selective sparing of DARPP-32-, choline acetyltransferase (ChAT)-, and NADPH-d-positive neurons was observed in the striatum of CNTF-on rats compared to GFP animals and CNTF-off group. Enzyme-linked immunosorbent assay (ELISA) performed on striatal samples of rats sacrificed at the same time point indicated that this neuroprotective effect was associated with the production of 15.5 +/- 4.7 ng CNTF per milligram of protein whereas the residual CNTF expression in the off state (0.54 +/- 0.02 ng/mg of protein) was not sufficient to protect against QA toxicity. These results establish the proof of principle of neurotrophic factor dosing for neurodegenerative diseases and demonstrate the feasibility of lentiviral-mediated tetracycline-regulated gene transfer in the brain. PMID:12427308

  4. Characterizing the spontaneous blink generator: an animal model.

    Science.gov (United States)

    Kaminer, Jaime; Powers, Alice S; Horn, Kyle G; Hui, Channing; Evinger, Craig

    2011-08-01

    Although spontaneous blinking is one of the most frequent human movements, little is known about its neural basis. We developed a rat model of spontaneous blinking to identify and better characterize the spontaneous blink generator. We monitored spontaneous blinking for 55 min periods in normal conditions and after the induction of mild dry eye or dopaminergic drug challenges. The normal spontaneous blink rate was 5.3 ± 0.3 blinks/min. Dry eye or 1 mg/kg apomorphine significantly increased and 0.1 mg/kg haloperidol significantly decreased the blink rate. Additional analyses revealed a consistent temporal organization to spontaneous blinking with a median 750 s period that was independent of the spontaneous blink rate. Dry eye and dopaminergic challenges significantly modified the regularity of the normal pattern of episodes of frequent blinking interspersed with intervals having few blinks. Dry eye and apomorphine enhanced the regularity of this pattern, whereas haloperidol reduced its regularity. The simplest explanation for our data is that the spinal trigeminal complex is a critical element in the generation of spontaneous blinks, incorporating reflex blinks from dry eye and indirect basal ganglia inputs into the blink generator. Although human subjects exhibited a higher average blink rate (17.6 ± 2.4) than rats, the temporal pattern of spontaneous blinking was qualitatively similar for both species. These data demonstrate that rats are an appropriate model for investigating the neural basis of human spontaneous blinking and suggest that the spinal trigeminal complex is a major element in the spontaneous blink generator. PMID:21813686

  5. Acute administration of dopaminergic drugs has differential effects on locomotion in larval zebrafish.

    Science.gov (United States)

    Irons, T D; Kelly, P E; Hunter, D L; Macphail, R C; Padilla, S

    2013-02-01

    Altered dopaminergic signaling causes behavioral changes in mammals. In general, dopaminergic receptor agonists increase locomotor activity, while antagonists decrease locomotor activity. In order to determine if zebrafish (a model organism becoming popular in pharmacology and toxicology) respond similarly, the acute effects of drugs known to target dopaminergic receptors in mammals were assessed in zebrafish larvae. Larvae were maintained in 96-well microtiter plates (1 larva/well). Non-lethal concentrations (0.2-50 μM) of dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (butaclamol, SCH-23390, and haloperidol) were administered at 6 days post-fertilization (dpf). An initial experiment identified the time of peak effect of each drug (20-260 min post-dosing, depending on the drug). Locomotor activity was then assessed for 70 min in alternating light and dark at the time of peak effect for each drug to delineate dose-dependent effects. All drugs altered larval locomotion in a dose-dependent manner. Both the D1- and D2-like selective agonists (SKF-38393 and quinpirole, respectively) increased activity, while the selective antagonists (SCH-23390 and haloperidol, respectively) decreased activity. Both selective antagonists also blunted the response of the larvae to changes in lighting conditions at higher doses. The nonselective drugs had biphasic effects on locomotor activity: apomorphine increased activity at the low dose and at high doses, while butaclamol increased activity at low to intermediate doses, and decreased activity at high doses. This study demonstrates that (1) larval zebrafish locomotion can be altered by dopamine receptor agonists and antagonists, (2) receptor agonists and antagonists generally have opposite effects, and (3) drugs that target dopaminergic receptors in mammals appear, in general, to elicit similar locomotor responses in zebrafish larvae. PMID:23274813

  6. Dopaminergic profile of new heterocyclic N-phenylpiperazine derivatives

    Directory of Open Access Journals (Sweden)

    G. Neves

    2003-05-01

    Full Text Available Dopamine constitutes about 80% of the content of central catecholamines and has a crucial role in the etiology of several neuropsychiatric disorders, including Parkinson's disease, depression and schizophrenia. Several dopaminergic drugs are used to treat these pathologies, but many problems are attributed to these therapies. Within this context, the search for new more efficient dopaminergic agents with less adverse effects represents a vast research field. The aim of the present study was to report the structural design of two N-phenylpiperazine derivatives, compound 4: 1-[1-(4-chlorophenyl-1H-4-pyrazolylmethyl]-4-phenylhexahydropyrazine and compound 5: 1-[1-(4-chlorophenyl-1H-1,2,3-triazol-4-ylmethyl]-4-phenylhexahydropyrazine, planned to be dopamine ligands, and their dopaminergic action profile. The two compounds were assayed (dose range of 15-40 mg/kg in three experimental models: 1 blockade of amphetamine (30 mg/kg, ip-induced stereotypy in rats; 2 the catalepsy test in mice, and 3 apomorphine (1 mg/kg, ip-induced hypothermia in mice. Both derivatives induced cataleptic behavior (40 mg/kg, ip and a hypothermic response (30 mg/kg, ip which was not prevented by haloperidol (0.5 mg/kg, ip. Compound 5 (30 mg/kg, ip also presented a synergistic hypothermic effect with apomorphine (1 mg/kg, ip. Only compound 4 (30 mg/kg, ip significantly blocked the amphetamine-induced stereotypy in rats. The N-phenylpiperazine derivatives 4 and 5 seem to have a peculiar profile of action on dopaminergic functions. On the basis of the results of catalepsy and amphetamine-induced stereotypy, the compounds demonstrated an inhibitory effect on dopaminergic behaviors. However, their hypothermic effect is compatible with the stimulation of dopaminergic function which seems not to be mediated by D2/D3 receptors.

  7. Direct Comparison of Rat- and Human-Derived Ganglionic Eminence Tissue Grafts on Motor Function.

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    Lelos, Mariah J; Roberton, Victoria H; Vinh, Ngoc-Nga; Harrison, Carl; Eriksen, Peter; Torres, Eduardo M; Clinch, Susanne P; Rosser, Anne E; Dunnett, Stephen B

    2016-01-01

    Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products. PMID:26727032

  8. Dopamine receptors participate in acquisition and consolidation of latent learning of spatial information in zebrafish (Danio rerio).

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    Naderi, Mohammad; Jamwal, Ankur; Ferrari, Maud C O; Niyogi, Som; Chivers, Douglas P

    2016-06-01

    There is growing appreciation that various aspects of learning and memory are strongly influenced by dopamine neurotransmission, and that zebrafish hold particular promise in the study of neurotransmitter systems. In this study, we sought to investigate the effect of dopamine receptors on acquisition and consolidation of memory in zebrafish using a latent learning paradigm. To this end, fish were subjected to a 30 min training trial each day for 16 days during which fish were allowed to freely explore a complex maze with the left or right path blocked and without the presence of a reward. During 16 days fish were treated with dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (SCH-23390 and eticlopride) before or after training trials. To assess cognitive performance of fish, a subsequent probe trial was performed on day 17 while all paths leading to a reward chamber were open and the maze now contained stimulus fish as a reward. Pre- and post-training exposure to apomorphine, SKF-38393, and quinpirole significantly impaired learning and memory in fish. In contrast, fish exposed to eticlopride before and after training exhibited improved performance in a latent learning task. Administration of SCH-23390 before training did not affect zebrafish learning ability, but produced significant memory enhancement when given after training trials. Taken together, these findings are the first indications that D1 and D2 receptors are critically involved in acquisition and consolidation of latent learning in zebrafish, with a more prominent role for D2 receptors. The current study opens the door to future studies to investigate the involvement of dopamine receptors in various aspects of cognitive processes. PMID:26772761

  9. Transplantation of Deprenyl-Induced Tyrosine Hydroxylase-Positive Cells Improves 6-OHDA-Lesion Rat Model of Parkinson’s Disease: Behavioral and Immunohistochemical Evaluation

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    Leili Hosseinpour

    2013-01-01

    Full Text Available Objective: There is longstanding experimental and clinical evidence that supports the idea that replacement of dopaminergic (DAergic neurons can ameliorate functional disabilities of Parkinson’s disease (PD. The purpose of the present study is to examine the efficacy of transplantation of rat bone marrow stromal cell (BMSCs-derived tyrosine hydroxylase-positive (TH+ cells induced by deprenyl into 6-hydroxydopamine (6-OHDA-lesioned rat models, using behavioral tests and immunohistochemical evaluations.Materials and Methods: In this experimental study, undifferentiated BrdU-labeled BMSCs were incubated in serum-free medium that contained 10-8 M deprenyl for 24 hours. Afterwards, BMSCs were cultured for 48 hours in α-minimal essential medium (α-MEM supplemented with 10% FBS, then differentiated into TH+ neurons. We randomly divided 24 hemiparkinsonian rats as follows: group 1 (control received only medium, while groups 2 and 3 were injected with 2×105 BMSCs and deprenyl-treated cells in 4 μl medium. Injections were made into the injured strata of the rats. Rotational behavior in response to apomorphine was tested before transplantation and at 2, 4, and 6 weeks post-graft. Animals were then sacrificed, and the brains were extracted for immunohistochemical and electron microscopic studies.Results: Apomorphine-induced rotation analysis indicated that animals with grafted cells in groups 2 and 3 exhibited significantly less rotational behavior than those in the control group at 2, 4, and 6 weeks after transplantation. Immunohistochemical analysis demonstrated that BrdU-labeled cells expressed specific neuronal markers, such as NF 200 and TH, at the implantation site. The presence of TH+ cells in conjunction with the reduction in rotation might show the capacity of grafted cells to release dopamine. Ultrastructural analysis revealed the presence of immature neurons and astrocyte-like cells at the graft site.Conclusion: TH+ neurons induced by

  10. Microglial cells are involved in the susceptibility of NADPH oxidase knockout mice to 6-hydroxy-dopamine-induced neurodegeneration.

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    Marina S Hernandes

    Full Text Available We explored the impact of Nox-2 in modulating inflammatory-mediated microglial responses in the 6-hydroxydopamine (6-OHDA-induced Parkinson's disease (PD model. Nox1 and Nox2 gene expression were found to increase in striatum, whereas a marked increase of Nox2 expression was observed in substantia nigra (SN of wild-type (wt mice after PD induction. Gp91(phox-/- 6-OHDA-lesioned mice exhibited a significant reduction in the apomorphine-induced rotational behavior, when compared to wt mice. Immunolabeling assays indicated that striatal 6-OHDA injections reduced the number of dopaminergic (DA neurons in the SN of wt mice. In gp91(phox-/- 6-OHDA-lesioned mice the DA degeneration was negligible, suggesting an involvement of Nox in 6-OHDA-mediated SN degeneration. Gp91(phox-/- 6-OHDA-lesioned mice treated with minocycline, a tetracycline derivative that exerts multiple anti-inflammatory effects, including microglial inhibition, exhibited increased apomorphine-induced rotational behavior and degeneration of DA neurons after 6-OHDA injections. The same treatment also increased TNF-α release and potentiated NF-κB activation in the SN of gp91(phox-/--lesioned mice. Our results demonstrate for the first time that inhibition of microglial cells increases the susceptibility of gp91(phox-/- 6-OHDA lesioned mice to develop PD. Blockade of microglia leads to NF-κB activation and TNF-α release into the SN of gp91(phox-/- 6-OHDA lesioned mice, a likely mechanism whereby gp91(phox-/- 6-OHDA lesioned mice may be more susceptible to develop PD after microglial cell inhibition. Nox2 adds an essential level of regulation to signaling pathways underlying the inflammatory response after PD induction.

  11. Binding of (/sup 125/I)-N-(p-aminophenethyl)spiroperidol to the D-2 dopamine receptor in the neurointermediate lobe of the rat pituitary gland: a thermodynamic study

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    Agui, T.; Amlaiky, N.; Caron, M.G.; Kebabian, J.W.

    1988-02-01

    The novel iodinated ligand (/sup 125/I)-N-(p-aminophenethyl)spiroperidol ((/sup 125/I)NAPS) was used to identify the D-2 dopamine receptor in the intermediate lobe of the rat pituitary gland. The binding of (/sup 125/I)NAPS was of high affinity and saturable, given that the dissociation constant and the maximal binding were 34.7 +/- 4.8 pM and 21.1 +/- 2.5 fmol/mg of protein, respectively. The ability of dopaminergic agonists and antagonists to compete with (/sup 125/I)NAPS varied markedly with incubation temperature. The marked decrease of the molar potency associated with increasing incubation temperature in the competitive displacement curve suggested that the binding of five agonists, dopamine, (-)-apomorphine, (-)-n-propylnorapomorphine, N-0434, and LY-171555, to the D-2 dopamine receptor was enthalpy-driven, with a negative change in entropy. In contrast, the binding of three antagonists, fluphenazine, (+)-butaclamol, and domperidone, was entropy-driven, with positive change in entropy, suggesting less temperature-sensitive change in the molar potency. Several molecules gave unanticipated results; the molar potency of two dopamine agonists, bromocriptine and lisuride, was much less temperature-sensitive than the other agonists used in this study. The thermodynamic parameters for the atypical agonists indicated entropy-driven binding. Conversely, the molar potency of (+)-apomorphine, a dopamine receptor antagonist, was markedly affected by incubation temperature, indicating enthalpy-driven binding. Another antagonist, YM-09151-2, was affected by the inclusion of sodium chloride in the assay system: in the absence of sodium chloride, the drug was relatively weak and displayed enthalpy-driven binding; in the presence of sodium chloride, its molar potency was increased and its binding manner turned into entropy-driven.

  12. Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

    Science.gov (United States)

    Ek, Fredrik; Malo, Marcus; Åberg Andersson, Madelene; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per; Olsson, Roger

    2016-05-18

    Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID

  13. The neurosteroidogenic enzyme 5α-reductase modulates the role of D1 dopamine receptors in rat sensorimotor gating.

    Science.gov (United States)

    Frau, Roberto; Mosher, Laura J; Bini, Valentina; Pillolla, Giuliano; Pes, Romina; Saba, Pierluigi; Fanni, Silvia; Devoto, Paola; Bortolato, Marco

    2016-01-01

    Neurosteroids exert diverse modulatory actions on dopamine neurotransmission and signaling. We previously documented that the enzyme 5α-reductase, which catalyzes the main rate-limiting step in neurosteroid synthesis, is required for the behavioral responses of Sprague-Dawley rats to non-selective dopaminergic agonists, such as the D1-D2 receptor agonist apomorphine. Specifically, systemic and intra-accumbal administrations of the 5α-reductase inhibitor finasteride countered apomorphine-induced deficits of sensorimotor gating, as measured by the prepulse inhibition (PPI) of the startle reflex; the classes of dopamine receptors involved in these effects, however, remain unknown. Prior rodent studies have revealed that the contributions of dopamine receptors to PPI regulation vary depending on the genetic background; thus, we analyzed the effect of finasteride on the PPI deficits induced by selective dopamine receptor agonists in Long-Evans (a strain exhibiting PPI deficits in response to both D1 and D2 receptor agonists) and Sprague-Dawley rats (which display PPI reductions following treatment with D2, and D3, but not D1 receptor agonists). In Long-Evans rats, finasteride opposed the PPI deficits induced by activation of D1, but not D2 receptors; conversely, in Sprague-Dawley rats, finasteride prevented the reductions in %PPI and accumbal dopamine extracellular levels caused by selective stimulation of D3, but not D2 receptors; however, the effects on %PPI were not confirmed by analyses on absolute PPI values. Our findings suggest that 5α-reductase modulates the effects of D1, but not D2 receptor agonists on sensorimotor gating. These data may help elucidate the role of neurosteroids in neuropsychiatric disorders featuring PPI deficits, including schizophrenia and Tourette syndrome. PMID:26415119

  14. Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

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    V. Rizelio

    2010-01-01

    Full Text Available The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN promoted by N-methyl-D-aspartate (NMDA would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA injection into the medial forebrain bundle (MFB. Initially, 16 mg 6-OHDA (6-OHDA group or vehicle (artificial cerebrospinal fluid - aCSF; Sham group was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

  15. CART modulates the effects of levodopa in rat model of Parkinson's disease.

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    Upadhya, Manoj A; Shelkar, Gajanan P; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2016-03-15

    Parkinson's disease (PD) is an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of substantia nigra (SN). The neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to closely interact with the dopamine system and regulate psychomotor activity. We screened the effectiveness of CART in reversing the symptoms of PD in a rat model. PD like condition was induced by administering 6-hydroxydopamine (6-OHDA) directly in the SN of the right side. Fifteen days later, intraperitoneal (IP) treatment with apomorphine hydrochloride to these rats, resulted in contralateral rotations in the rotation test chamber suggesting induction of PD-like symptoms. This action of apomorphine was significantly attenuated by intracerebroventricular (ICV) treatment with CART and potentiated by CART antibody. IP treatment with levodopa also produced contralateral rotation in PD induced rats, and showed anti-Parkinson-like action. Prior treatment with CART via ICV route potentiated the anti-Parkinsonian effects of levodopa, while CART antibody produced opposite effects. CART treatment per se, to PD induced rats produced ipsilateral rotations, suggesting that the peptide may promote the endogenous release of dopamine from intact neurons. While CART-immunoreactivity in arcuate nucleus, paraventricular nucleus, striatum, substantia nigra, ventral tegmental area and locus coeruleus was reduced in the PD induced rats, levodopa treatment restored the expression of CART-immunoreactivity in these nuclei. These results suggest that endogenous CART might closely interact with the dopamine containing SN-striatal pathway which is known to profoundly influence the motor system. The study underscores the importance of CART as a potential therapeutic agent in the treatment of PD. PMID:26771081

  16. The melanin-concentrating hormone (MCH system modulates behaviors associated with psychiatric disorders.

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    Shinjae Chung

    Full Text Available Deficits in sensorimotor gating measured by prepulse inhibition (PPI of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin-concentrating hormone (MCH system has been shown to modulate dopamine-related responses. Its receptor (MCH1R is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders.

  17. Amniotic fluid stem cells with low γ-interferon response showed behavioral improvement in Parkinsonism rat model.

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    Yu-Jen Chang

    Full Text Available Amniotic fluid stem cells (AFSCs are multipotent stem cells that may be used in transplantation medicine. In this study, AFSCs established from amniocentesis were characterized on the basis of surface marker expression and differentiation potential. To further investigate the properties of AFSCs for translational applications, we examined the cell surface expression of human leukocyte antigens (HLA of these cells and estimated the therapeutic effect of AFSCs in parkinsonian rats. The expression profiles of HLA-II and transcription factors were compared between AFSCs and bone marrow-derived mesenchymal stem cells (BMMSCs following treatment with γ-IFN. We found that stimulation of AFSCs with γ-IFN prompted only a slight increase in the expression of HLA-Ia and HLA-E, and the rare HLA-II expression could also be observed in most AFSCs samples. Consequently, the expression of CIITA and RFX5 was weakly induced by γ-IFN stimulation of AFSCs compared to that of BMMSCs. In the transplantation test, Sprague Dawley rats with 6-hydroxydopamine lesioning of the substantia nigra were used as a parkinsonian-animal model. Following the negative γ-IFN response AFSCs injection, apomorphine-induced rotation was reduced by 75% in AFSCs engrafted parkinsonian rats but was increased by 53% in the control group after 12-weeks post-transplantation. The implanted AFSCs were viable, and were able to migrate into the brain's circuitry and express specific proteins of dopamine neurons, such as tyrosine hydroxylase and dopamine transporter. In conclusion, the relative insensitivity AFSCs to γ-IFN implies that AFSCs might have immune-tolerance in γ-IFN inflammatory conditions. Furthermore, the effective improvement of AFSCs transplantation for apomorphine-induced rotation paves the way for the clinical application in parkinsonian therapy.

  18. Combinatorial topography and cell-type specific regulation of the ERK pathway by dopaminergic agonists in the mouse striatum.

    Science.gov (United States)

    Gangarossa, Giuseppe; Perroy, Julie; Valjent, Emmanuel

    2013-03-01

    Therapeutic agents and drugs of abuse regulate the extracellular signal-regulated kinase (ERK) cascade signaling in the medium-sized spiny neurons (MSNs) of the striatum. However, whether this regulation is associated with specific cortical and thalamic inputs has never been studied. We used Drd2-EGFP BAC-transgenic mice to undertake a topographical and cell-type specific analysis of ERK phosphorylation and two of its downstream targets histone H3 and ribosomal protein S6 (rS6) in the dorsal striatum following injection of SKF81297 (D1R-like agonist), quinpirole (D2R-like agonist) or apomorphine (non selective DA receptor agonist). In striatal areas receiving inputs from the cingulate/prelimbic, visual and auditory cortex, SKF81297 treatment increased phosphorylation of ERK, histone H3 and rS6 selectively in EGFP-negative MSNs of Drd2-EGFP mice. In contrast, no regulation was found in striatal region predominantly targeted by the sensorimotor and motor cortex. Apomorphine slightly enhanced ERK and rS6, but not histone H3 phosphorylation. This regulation occurred exclusively in EGFP-negative neurons mostly in striatal sectors receiving connections from the insular, visual and auditory cortex. Quinpirole administration inhibited basal ERK activation but did not change histone H3 and rS6 phosphorylation throughout the rostrocaudal axis of the dorsal striatum. This anatomo-functional study indicates that D1R and D2R agonists produce a unique topography and cell-type specific regulation of the ERK cascade signaling in the mouse striatum, and that those patterns are closely associated with particular cortical and thalamic inputs. This work evidences the need of a precise identification of the striatal areas under study to further understand striatal plasticity. PMID:22453353

  19. Postnatal manganese exposure does not alter dopamine autoreceptor sensitivity in adult and adolescent male rats.

    Science.gov (United States)

    McDougall, Sanders A; Mohd-Yusof, Alena; Kaplan, Graham J; Abdulla, Zuhair I; Lee, Ryan J; Crawford, Cynthia A

    2013-04-15

    Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as a persistent increase in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12 mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired. PMID:23458069

  20. Improvement of Parkinsonian behavior with co-grafts of Schwann cells and neural stem cells in the rat

    Institute of Scientific and Technical Information of China (English)

    Ying Xia; Chengchuan Jiang; Zhongliang Ding; Yang Wang; Bin Xu; Linyin Feng

    2008-01-01

    BACKGROUND: Due to the lack of autograft transplant rejection, Schwann cells (SCs) can promote the proliferation of embryonic stem cells and the induction of dopaminergic neurons. Mesencephalic stem cells can be induced to produce dopaminergic neurons. The therapeutic effects of co-grafts of SCs and neural stem cells (NSCs) deserves further study and verification in Parkinsonian animal models.OBJECTIVE: To investigate the effects of Schwann cells and mesencephalic NSC co-grafts in Parkinsonian animal models on animal behavior and histology.DESIGN: Randomized controlled experiment.SETTING: Fudan University; Institute of Neuroscience, Chinese Academy of Sciences.MATERIALS: The following animals were obtained from the Experimental Animal Center, Shanghai Institute for Biological Science, Chinese Academy of Sciences: 5 Sprague-Dawley rats, embryonic day (E) 13–16; 16 neonatal Sprague-Dawley rats, postnatal day 1–3; and 18 adult SD rats of both genders. Animal experimentation met animal ethical approval.METHODS: The experiment was performed at the Department of Anatomy, Histology and Embryology, Shanghai Medical Center, Fudan University from September 2005 to January 2007. The mesencephalic NSCs were obtained from the brains of SD rats at E 13–16, and SCs were harvested from the sciatic nerves of neonatal rats at day 1–3. Hemiparkinsonian rats (n =18) were selected for transplantation after estimating rotational behavior in response to apomorphine and were randomly assigned to three groups: control group, NSC group, and co-graft group. There were 6 rats in each group. Either phosphate buffered saline (PBS), NSCs, or SCs plus NSCs were transplanted into the right neostriatum of Parkinsonian rats, respectively.MAIN OUTCOME MEASURES: ① Rotational behavior was induced by apomorphine (0.05 mg/kg, I.p.) 2, 4, 6, 8, and 10 weeks after transplantation, and the number of rotations were counted. ② Differentiation and survival of dopaminergic neurons in the right

  1. Increased expression of gap junction protein connexin 36 in the striatum of rat with levodopa-induced dyskinesia%左旋多巴诱发异动症大鼠纹状体缝隙连接蛋白CX36表达增强

    Institute of Scientific and Technical Information of China (English)

    王海雷; 陈先文; 高冕; 王烈成

    2013-01-01

    Objective: To observe the expression of connexin 36 (CX36) in the brain of levodopa-induced dyskinesia (LID) rat model, and explore the role of gap junction in the pathogenesis of LID. Methods: Hemi-parkinsonism (PD) and LID rat models were made. The experimental animals were divided into three groups; LID group, PD group and normal control group, respectively. Each group was divided into two subgroups (carbenoxolone and saline groups). Then, the apomorphine induced abnormal involuntary movement ( AIM) and rotational behavior in responese to gap junction blocker carbenoxolone given by intraperitoneal injection were assessed . After the behavior testing, the rats were executed and processed for examining CX36 expression in the striatum and cortex by immunohistochemistry. Results: Carbenoxolone injected intraperitoneally showed no significant effects on apomorphine-induced AIM in LID rats and on apomorphine-induced rotational behavior in PD rats (P>0.05). The expression of CX36 in striatum and motor cortex of LID rats was significantly increased compared with PD model or the normal control rats (P < 0. 05 ). Compared with the normal control group, CX36 expression in these brain regions in the PD model group was also elevated (P <0. 05). Conclusion: The expression of connexin 36 in the striatum and cerebral motor cortex were increased in LID rats, gap junction dysfunction may play a role in the pathogenesis of LID.%目的:观察左旋多巴诱发异动症(LID)大鼠模型缝隙连接蛋白36(CX36)表达,初步探讨缝隙连接在LID形成机制中的作用.方法:制备帕金森病(PD)和LID大鼠模型,将实验动物分3组:LID模型组、PD未治疗组、正常对照组.各组大鼠分2亚组(缝隙连接阻断剂处理组和生理盐水对照组),观察系统途径给予缝隙连接阻断剂甘珀酸(carbenoxolone)对各组大鼠不自主运动行为的影响.利用免疫组化法检测各组大鼠脑皮层运动区和纹状体区CX36表达并进行分析比较.

  2. D1 dopamine receptor activity of anti-parkinsonian drugs.

    Science.gov (United States)

    Fici, G J; Wu, H; VonVoigtlander, P F; Sethy, V H

    1997-01-01

    Clinical and preclinical investigations suggest that stimulation of D1 dopamine receptors may be responsible for dyskinesias induced by dopamine agonist treatment of Parkinson's Disease (PD), and that these dyskinesias may be decreased by treatment with a D1 antagonist (clozapine). Therefore, the effects of dopamine agonists and antagonists have been investigated in a primary cerebellar granule cell model of cAMP formation that seems to be highly responsive to the D1 receptors. SKF 38393, lisuride, apomorphine, pergolide, dopamine, bromocriptine and 7-OH-DPAT showed concentration-dependent increases in cAMP formation, with EC50s (in microM) of 0.013, 0.053, 0.25, 1.04, 2.18, 50.9 and 54.4, respectively. SKF 38393, apomorphine, dopamine and pergolide had similar intrinsic activity (100%), while the intrinsic activities of 7-OH-DPAT, bromocriptine and lisuride were 28.0%, 20.7% and 17.2%, respectively. SCH 23390, a selective D1 dopamine receptor antagonist, blocked an increase in cAMP formation produced by EC50 concentrations of all of the dopamine agonists investigated in this study. Clozapine concentration-dependently blocked pergolide-induced increases in cAMP and was approximately 1700-fold less potent than SCH 23390 (IC50: 0.97 microM and 0.56 nM, respectively). U-95666A (1-1000 microM), selective for the D2 receptors, showed no significant effect on cAMP, while pramipexole (0.1-100 microM), a D3 preferring agonist, did not elevate cAMP. These data suggest that primary cerebellar granule cell cultures are an excellent model for measuring D1 dopamine receptor-mediated changes in cellular cAMP. The results are discussed with reference to the relationship between the D1 receptor-stimulated increase in cAMP formation and the induction of dyskinesia in humans by these anti-parkinsonian drugs. PMID:9126882

  3. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor.

    Science.gov (United States)

    Newman-Tancredi, Adrian; Cussac, Didier; Audinot, Valérie; Nicolas, Jean-Paul; De Ceuninck, Frédéric; Boutin, Jean-A; Millan, Mark J

    2002-11-01

    The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D(2SHORT(S)), hD(2LONG(L)), hD(3), and hD(4.4) receptors and at halpha(2A)-, halpha(2B)-, halpha(2C)-, and halpha(1A)-adrenoceptors (ARs). As determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D(2)-like" sites. However, at hD(2S) receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E(max)100%); TL99, talipexole, and apomorphine were highly efficacious (79-92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40-55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD(2L) receptors, with terguride and roxindole acting as antagonists. At hD(3) receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD(4) receptors, highest efficacies (approximately 70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD(2S) versus hD(2L) sites were highly correlated (r = 0.79), they correlated only modestly to hD(3)/hD(4) sites (r = 0.44-0.59). In [(35)S]GTPgammaS studies of halpha(2A)-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at halpha(2B)- and halpha(2C)-ARs. Using [(3)H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at halpha(1A)-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist

  4. A gene therapy of experimental parkinsonism monkeys with intra-striatums implantation of AAV-TH with CT guiding

    International Nuclear Information System (INIS)

    Objective: To observe the transfection ability to neuron and the therapy effect of adeno-associated virus vector (AAV) mediated intracerebral expressing of human tyrosine hydroxylase (TH) in the Rhesus monkey of Parkinson disease with CT guiding. Methods: Six Rhesus monkeys were induced into hemi-parkinsonism models by infusion of MPTP into right internal carotid artery. Under the guidance of CT and stereotactic apparatus, the recombinant adeno-associated virus vectors-human tyrosine hydroxylase were injected into the right caudate nucleus of 5 PD monkeys. The motor ability of the PD model was evaluated for 6 months after implantation. The content of DA, DOPAC, and HVA in the caudate nucleus was assayed with HPLC, and the expression of the tyrosine hydroxylase gene was detected with immunohistochemistry and RT-PCR. Results: The method of stereotactic puncture guided with CT had the features of real-time operating, fine location, and mini-trauma. The motor ability of all five models was all ameliorated after stereotactical injection of AAV-hTH vectors from two weeks up to six months. One PD monkey did not show any twist in response to apomorphine test. The frequency of twirl in the other 4 PD monkeys in response to apomorphine test was decreased by 42%-70% compared with that preoperatively. The contents of DA and DA metabolites in the lesion caudate nucleus were increased. Many TH positive cells in the implantation sites of caudate nucleus were shown by immunohistochemistry, which was different from the contralateral caudate nucleus. TH-mRNA was found in the treated side of caudate nucleus with RT-PCR, but no positive detection in the untreated side of caudate nucleus or in other sites in the brain. The negative results of RT-PCR were also shown in samples of the heart, liver, kidney tissue, or right side caudate nucleus of the uninjected monkey. Conclusion: Under the guidance of CT and stereotactic apparatus, the AAV-hTH vector can be injected accurately into the

  5. PET Imaging of Serotonin Transporters With 4-[(18)F]-ADAM in a Parkinsonian Rat Model With Porcine Neural Xenografts.

    Science.gov (United States)

    Chiu, Chuang-Hsin; Li, I-Hsun; Weng, Shao-Ju; Huang, Yuahn-Sieh; Wu, Shinn-Chih; Chou, Ta-Kai; Huang, Wen-Sheng; Liao, Mei-Hsiu; Shiue, Chyng-Yann; Cheng, Cheng-Yi; Ma, Kuo-Hsing

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Apart from effective strategies to halt the underlying neuronal degeneration, cell replacement now offers novel prospects for PD therapy. Porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. This study was undertaken to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation in a PD rat model using animal positron emission tomography (PET) coupled with 4-[(18)F]-ADAM, a serotonin transporter (SERT) imaging agent. The parkinsonian rat was induced by injecting 6-hydroxydopamine into the medial forebrain bundle (MFB) of the right nigrostriatal pathway. The apomorphine-induced rotation behavioral test and 4-[(18)F]-ADAM/animal PET scanning were carried out following 6-OHDA lesioning. At the second week following 6-OHDA lesioning, the parkinsonian rat rotates substantially on apomorphine-induced contralateral turning. In addition, the mean striatal-specific uptake ratio (SUR) of 4-[(18)F]-ADAM decreased by 44%. After transplantation, the number of drug-induced rotations decreased markedly, and the mean SUR of 4-[(18)F]-ADAM and the level of SERT immunoreactivity (SERT-ir) in striatum were partially restored. The mean SUR level was restored to 71% compared to that for the contralateral intact side, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery at the fourth week postgraft. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat

  6. Effect of Passive Smoking on the Rotational Behavior and Striatal Dopamine Content of 6-hydroxydopamine-induced Rat Model of Parkinson Disease%被动吸烟对帕金森病大鼠旋转行为和纹状体多巴胺含量的影响

    Institute of Scientific and Technical Information of China (English)

    董宁; 孙圣刚; 陈吉相; 王涛

    2001-01-01

    目的 观察被动吸烟对帕金森病(PD)大鼠的影响,以验证流行病学研究的结论,为PD研究提供一条新的线索。方法 用6-羟基多巴胺(6-OHDA)立体定向注入大鼠一侧黑质致密部和中脑被盖腹侧区建立偏侧PD模型,观察术前4周开始给予的被动吸烟(持续6周)和术后2周对成功模型给予的被动吸烟(持续2周)对阿朴吗啡诱发的旋转行为及纹状体DA含量的影响。结果 术前4周开始被动吸烟的大鼠旋转行为有减少趋势,受损侧纹状体DA含量较对照组升高。术后2周,成功模型给予的被动吸烟对PD大鼠的旋转行为及纹状体DA含量均无影响。结论 被动吸烟可减轻6-OHDA对黑质DA能神经元的损伤。%Objective To observe the effect of passive smoking on therotational behavior and striatal dopamine content of the rat Parkinson disease (PD) model. Methods Creating the PD rat model by unilaterally injecting 6-hydroxydopamine(6-OHDA) into the substantia nigra pars compacta(SNpc) and the ventral tegmental area(VTA), the effects of passive smoking on the apomorphine-induced rotation behavior and the dopamine content of striatum beginning four weeks before the operation(lasting six weeks) or two weeks after the operation(lasting two weeks) in the successful models were observed. Results Rats received passive smoking beginning four weeks before the operation had a tendency to decrease the apomorphine-induced rotation behavior. The dopamine content of the striatum was elevated as compared to the control group. Passive smoking beginning two weeks after the operation in the successful models did not alter either the rotation behavior or the DA content of striatum. Conclusions Passive smoking can partially protect DA neurons of substantia nigra from the damage of 6-OHDA.

  7. Determination of four central nervous system drugs by capillary electrophoresis with contactless conductivity detection%毛细管电泳非接触电导法测定4种中枢神经系统用药

    Institute of Scientific and Technical Information of China (English)

    朱妍; 葛淑丽; 汪雪; 舒露; 王清江; 何品刚; 方禹之

    2013-01-01

    运用毛细管电泳非接触式电导检测方法对4种中枢神经系统用药-盐酸阿扑吗啡、氢溴酸加兰他敏、富马酸喹硫平、氯氮平的分离进行了研究.考察了电泳介质的种类、浓度、分离电压、进样时间对分离效果的影响,在10 mmol/L三羟基氨基甲烷(Tris)-8 mmol/L柠檬酸(Cit)-20%甲醇的运行缓冲液中,激发电压为60V,激发频率为600kHz,4种药物在15 min内得到了分离.4种药物的线性范围分别为0.97 ~ 15.6 mg/L;0.97~15.6 mg/L;0.48~15.6 mg/L和0.97~250 mg/L,检测限为0.32,0.32,0.16和0.32 mg/L.%A new method has been built for simultaneous determination of apomorphine hydrochloride, galanthamine hydrobromide, quetiapine fumarate and clozapine in tablet by capillary electrophoresis with contactless conductivity detection. The effects of some important factors such as the concentration of running buffer, separation voltage, injection time and additives were investigated. With optimized buffer of 10 mmol/L Tris-8 mmol/L Cit-20%methanol, the samples were well separated and detected at the excitation voltage of 60V and frequency of 600kHz. The linear ranges of apomorphine, galanthamine, quetiapine and clozapine were 0. 97 ~ 15. 6 mg/L; 0. 97 ~ 15. 6 mg/L; 0. 48 ~ 15. 6 mg/L and 0. 97 -250 mg/L, respectively. The detection limit were 0. 32, 0. 32,0. 16 and 0. 32 mg/L.

  8. Pre-synaptic histamine H₃ receptors modulate glutamatergic transmission in rat globus pallidus.

    Science.gov (United States)

    Osorio-Espinoza, A; Alatorre, A; Ramos-Jiménez, J; Garduño-Torres, B; García-Ramírez, M; Querejeta, E; Arias-Montaño, J-A

    2011-03-10

    The globus pallidus, a neuronal nucleus involved in the control of motor behavior, expresses high levels of histamine H(3) receptors (H(3)Rs) most likely located on the synaptic afferents to the nucleus. In this work we studied the effect of the activation of rat pallidal H(3)Rs on depolarization-evoked neurotransmitter release from slices, neuronal firing rate in vivo and turning behavior. Perfusion of globus pallidus slices with the selective H(3)R agonist immepip had no effect on the release of [(3)H]-GABA ([(3)H]-γ-aminobutyric acid) or [(3)H]-dopamine evoked by depolarization with high (20 mM) K(+), but significantly reduced [(3)H]-d-aspartate release (-44.8 ± 2.6% and -63.7 ± 6.2% at 30 and 100 nM, respectively). The effect of 30 nM immepip was blocked by 10 μM of the selective H(3)R antagonist A-331440 (4'-[3-[(3(R)-dimethylamino-1-pyrrolidinyl]propoxy]-[1,1-biphenyl]-4'-carbonitrile). Intra-pallidal injection of immepip (0.1 μl, 100 μM) decreased spontaneous neuronal firing rate in anaesthetized rats (peak inhibition 68.8±10.3%), and this effect was reversed in a partial and transitory manner by A-331440 (0.1 μl, 1 mM). In free-moving rats the infusion of immepip (0.5 μl; 10, 50 and 100 μM) into the globus pallidus induced dose-related ipsilateral turning following systemic apomorphine (0.5 mg/kg, s.c.). Turning behavior induced by immepip (0.5 μl, 50 μM) and apomorphine was partially prevented by the local injection of A-331440 (0.5 μl, 1 mM) and was not additive to the turning evoked by the intra-pallidal injection of antagonists at ionotropic glutamate receptors (0.5 μl, 1 mM each of AP-5, dl-2-amino-5-phosphonovaleric acid, and CNQX, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione). These results indicate that pre-synaptic H(3)Rs modulate glutamatergic transmission in rat globus pallidus and thus participate in the control of movement by basal ganglia. PMID:21195747

  9. Prenatal manipulation of the serotonergic system: Biochemical, pharmacological and behavioral effects

    International Nuclear Information System (INIS)

    Rat pups were exposed in utero to pharmacological agents that stimulated or diminished serotonergic activity in vivo. Dams received 5-Methoxytryptamine 1mg/kg, from day 12 of gestation to birth, or parachlorophenylalanine, the serotonin synthesis inhibitor, from day 7 to 17 of gestation. Both groups of offspring showed significant reductions in the specific high affinity uptake of 3H-5-HT into brainstem and forebrain areas on postnatal days 1, 15, and 30, indicating reduced outgrowth of serotonin. At 15 days of age, both groups of treated offspring showed deficits in activity and in performing behaviors that required inhibition, but these deficits were no longer apparent on Day 30. Dose response experiments for 5-MT produced a dual effect: enhanced uptake in forebrain and inhibition of uptake in brainstem and forebrain on postnatal days 1, 15 and 30. Prenatal 5-MT caused deficits in avoidance and activity. Prenatal exposure to PAT, the 5-HT1a agonist caused reduced uptake in brainstem, while exposure to TFMPP (the 5-HT1b agonist) produced enhanced uptake in forebrain, as did the high dose of 5-MT. Sensitivity of the pharmacological response to acute 5-MT, 1 mg/kg, and apomorphine, 5 mg/kg was measured in an activity test

  10. New oral agents for erectile dysfunction: what is changing in our practice?

    Institute of Scientific and Technical Information of China (English)

    Antonio Aversa; Andrea Fabbri

    2001-01-01

    Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i. e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.

  11. Effects of selective dopaminergic compounds on a delay-discounting task.

    Science.gov (United States)

    Koffarnus, Mikhail N; Newman, Amy H; Grundt, Peter; Rice, Kenner C; Woods, James H

    2011-08-01

    Impulsivity is widely regarded as a multidimensional trait that encompasses two or more distinct patterns of behavior, and dopaminergic systems are implicated in the expression of impulsive behavior in both humans and animal subjects. Impulsive choice, or the tendency to choose rewards associated with relatively little or no delay, has been extensively studied in humans and animal subjects using delay-discounting tasks. Here, delay-discounting procedures were used to assess the effects of receptor-selective dopaminergic agonists, antagonists, and dopamine transporter ligands on choices of immediate versus delayed sucrose pellets. The effects of d-amphetamine, GBR 12909, apomorphine, SKF 81297, sumanirole, pramipexole, ABT-724, SCH 23390, L-741,626, PG01037, and L-745,870 were assessed in 24 Sprague-Dawley rats. The only drugs to affect impulsive choice selectively without altering undelayed choice were the D1-like antagonist, SCH 23390 (0.01 mg/kg), and the D4 partial agonist, ABT-724 (3.2 mg/kg), which both increased impulsive choice. The shared effects of these compounds may be explained by their localization within the prefrontal cortex on different groups of neurons. None of the selective agonists and antagonists tested reduced impulsive choice, so further research is needed to determine if direct dopaminergic agonists or antagonists may be therapeutically useful in the treatment of impulse-control disorders. PMID:21694584

  12. Anxiolytic effects of dopamine receptor ligands: I. Involvement of dopamine autoreceptors.

    Science.gov (United States)

    Bartoszyk, G D

    1998-01-01

    The anxiolytic-like properties of dopamine agonists and antagonists with different receptor profiles were investigated in the ultrasonic vocalization test in rats after subcutaneous administration. Only dopamine D2 receptor agonists inhibited ultrasonic vocalization with the following ED50 values: apomorphine (0.07 mg/kg), quinelorane (0.01 mg/kg), quinpirole (0.04 mg/kg), pramipexole (0.09 mg/kg), roxindole (0.04 mg/kg), talipexole (0.04 mg/kg), (+/-)-7-OH-DPAT (0.05 mg/kg), (+/-)-PPHT (0.03 mg/kg), (-)-TNPA (0.06 mg/kg), PD128907 (0.13 mg/kg). The D2 antagonists haloperidol, mazapertine, raclopride, remoxipride, L745870, U99194A, U101958 and S(-)-DS121, the partial agonists PD143188 and preclamol, the selective D1 agonist R(+)-SKF38393 and the D1 antagonist SCH23390, and the uptake inhibitors GBR12909, GBR12935 and indatraline lacked significant inhibitory effects on ultrasonic vocalization. Because at least some of the D2 receptor agonists investigated have selectivity for dopamine autoreceptors, it is speculated that the dopamine autoreceptor may be a target for the development of new antianxiety drugs. PMID:9472724

  13. Anticompulsive Activity of a New Pyrazolo[C]Pyridine Derivative GIZh-72 under Conditions of Unpredictable Chronic Mild Stress.

    Science.gov (United States)

    Kudryashov, N V; Kalinina, T S; Zhmurenko, L A; Voronina, T A

    2016-07-01

    Anticompulsive activity of a novel compound GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]Pyridine-3-on, chloral hydrate) in a dose of 20 mg/kg (single, subchronic, and chronic administration) in comparison with fluvoxamine (25 mg/kg) was studied in the marble burying test in the model of unpredictable chronic mild stress on BALB/c mice. GIZh-72 produced an anticompulsive effect that increased with increasing treatment duration under stress conditions in contrast to fluvoxamine that induced inversion of this effect after long-term administration. Neuroleptic activity of GIZh-72 in doses of 20 and 40 mg/kg was studied on the model of apomorphine-induced climbing in C57Bl/6 mice. In contrast to haloperidol (0.5 mg/kg), GIZh-72 exhibited no neuroleptic properties. Our results indicate that GIZh-72 holds much promise for pharmacotherapy of obsessive-compulsive disorder. PMID:27502699

  14. Effects of arachidonic acid and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine on prolactin secretion from anterior pituitary cells

    International Nuclear Information System (INIS)

    The role of two lipids, arachidonic acid and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, as modulators or prolactin secretion has been examined. Stimulators of phospholipase A2 activity, melittin and mastoparan, were found to increase prolactin release. Melittin also caused release of previously incorporated 3H-arachidonic acid and this effect was associated with loss of radiolabel from the phospholipid fraction. Exogenous arachidonic acid also stimulated prolactin secretion. Conversely, inhibitors of phospholipase A2 activity, dibromoacetophenone and U10029A, decreased basal and stimulated prolactin release. Prolactin release could also be lowered by ETYA, BW755C and NDGA, inhibitors of arachidonic acid metabolism. In the second series of experiments the effects of the biologically active phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor, PAF) on prolactin release were examined. PAF is an ether-linked phospholipid known to stimulate granule release in a variety of cell types including both inflammatory and noninflammatory cells. PAF increased release of prolactin from dispersed rat anterior pituitary cells; stimulation was not due to cell lysis. PAF-induced prolactin release could be blocked by the dopaminergic agonists apomorphine and bromocriptine as well as by two PAF receptor antagonists, SRI 63-072 and L-652-731

  15. LASSBio-579, a prototype antipsychotic drug, and clozapine are effective in novel object recognition task, a recognition memory model.

    Science.gov (United States)

    Antonio, Camila B; Betti, Andresa H; Herzfeldt, Vivian; Barreiro, Eliezer J; Fraga, Carlos A M; Rates, Stela M K

    2016-06-01

    Previous studies on the N-phenylpiperazine derivative LASSBio-579 have suggested that LASSBio-579 has an atypical antipsychotic profile. It binds to D2, D4 and 5-HT1A receptors and is effective in animal models of schizophrenia symptoms (prepulse inhibition disruption, apomorphine-induced climbing and amphetamine-induced stereotypy). In the current study, we evaluated the effect of LASSBio-579, clozapine (atypical antipsychotic) and haloperidol (typical antipsychotic) in the novel object recognition task, a recognition memory model with translational value. Haloperidol (0.01 mg/kg, orally) impaired the ability of the animals (CF1 mice) to recognize the novel object on short-term and long-term memory tasks, whereas LASSBio-579 (5 mg/kg, orally) and clozapine (1 mg/kg, orally) did not. In another set of experiments, animals previously treated with ketamine (10 mg/kg, intraperitoneally) or vehicle (saline 1 ml/100 g, intraperitoneally) received LASSBio-579, clozapine or haloperidol at different time-points: 1 h before training (encoding/consolidation); immediately after training (consolidation); or 1 h before long-term memory testing (retrieval). LASSBio-579 and clozapine protected against the long-term memory impairment induced by ketamine when administered at the stages of encoding, consolidation and retrieval of memory. These findings point to the potential of LASSBio-579 for treating cognitive symptoms of schizophrenia and other disorders. PMID:26513177

  16. Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson’s disease

    Institute of Scientific and Technical Information of China (English)

    Ping Gu; Zhongxia Zhang; Dongsheng Cui; Yanyong Wang; Lin Ma; Yuan Geng; Mingwei Wang

    2012-01-01

    In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson’s disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2’-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson’s disease. Immunohistochemical staining showed that, 5-bromo-2’-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson’s disease.

  17. Fetal Mesencephalic Neuron Transplantation and Tyrosine Hydroxylase Gene Therapy for Monkey and Rat Models of Parkinsonism Induced By MPTP or 6OHDA

    Institute of Scientific and Technical Information of China (English)

    Shengdi Chen; Yingchun Zhao; Huizhen Yu; Zhenguo Liu; Lei Cao; hongcheng Zheng; Xingyuan Liu; Zhihua Jiang; Changfu Zhou

    2000-01-01

    @@The intracerebral transplantation and gene therapy may provide putative therapeutic approach to Parkinson′s disease. In the present study, implant of fetal mesencephalic dopamine neuron into I-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkey model and in vivo and ex vivo tyrosine hydroxylase(TH) gene therapy for 6-hydroxydopamine(6-OHDA)-induced hemiparkinsonian rat model were investigated. The monkey model of hemiparkinsonism induced by unilateral administration of MPTP into the common carotid artery of three rhesus monkeys. The cell suspensions of substantia nigra obtained from human fetus of 11-12 weeks of gestation were injected stereotaxically into the caudate nucleus or substantia nigra of the lesioned side. The recipients were immunosuppressed by taking cyclosporine A for one month following the implant procedure. Apomorphine(APO)-induced motor asymmetry was significantly improved during the period of 18 weeks after graft. TH immunostaining assay demonstrated the surviving and sprouting of TH-immunoreactive cell bodies in the caudate nucleus for almost one year.

  18. Dopaminergic receptors in rat dura mater: pharmacological characteristics.

    Science.gov (United States)

    Cavallotti, C; Frati, A; Cavallotti, D; Tranquilli Leali, F M

    2004-03-01

    1. The location and distribution of dopaminergic receptors in rat dura mater was studied by examining several dural zones (vascular, perivascular, intervascular) in different cranial and spinal regions. 2. The pharmacological characteristics and anatomical distribution of dopamine D1- and D2-like receptors sites were investigated using combined pharmacological techniques and immunofluorescent microscopy. 3. Samples of rat dura mater were obtained from 10 adult Wistar rats. On frozen slices, dopaminergic D1 and D2 receptors were stained immunohistochemically using monoclonal antibodies. 4. Inhibition studies were performed using fluorescent and non-fluorescent agonists or antagonists to define the pharmacological specificity of the immunostaining. 5. The greater sensitivity to displacement by amisulpride, bromocryptine, domperidone, haloperidol, raclopride and l-sulpiride than to displacement by N-propyl-nor-apomorphine, quinpirole and clozapine suggests that the immunofluorescent sites observed in these experiments are likely to belong to the dopamine D2 receptor subtype. 6. Our observations provide evidence of the presence of D1 and D2 receptors in the wall of meningeal vessels. The dopaminergic receptors are located in the adventitia, media and intima of dural arteries. Furthermore, the density of receptors is higher in close proximity to arteries and decreases passing from the vascular to the perivascular and intervascular zones. 7. In the rat dura mater, dopamine regulates the meningeal blood vessels and, through this action, dopamine and its receptors can play an important role in the pathogenesis of cephalalgia. PMID:15008964

  19. Influence of simvastatin on dopaminergic neurons of lipopolysaccharide—induced rat model of Parkinson’s disease

    Institute of Scientific and Technical Information of China (English)

    Tan; Wang; Xue-Bin; Cao; Xiao-Wu; Chen; Pei-Pei; Huang; Tian; Zhang; Zhi-Bin; Chen; Bei-Sha; Tang

    2015-01-01

    Objective::To investigate the neuroprotective effects of simvastatin on lipopolysaccharide(LPS)-indueed rat model of Parkinson’s disease(PD) and the mechanisms involved.Methods:Hemiparkinsonian rat models were induced by stereotaxieal injection of LPS in the right substantia nigra compacts.After 2 weeks of simvastatin treatment,rotational behavior test was performed after the intraperitoneal injection of apomorphine.Expression of tyroxine hydroxylase(TH) and glial fibrillan acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum,and the level of TNF-α was evaluated using enzyme-linked immunosorbent assay.Results:Comparing with untreated group,behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment.The TH positive cell count in substantia nigra and striatum were significantly increased(P<0.05) and TNF- α expression was significantly decreased(P<0.05) in simvastatin group compared to untreated group.Conclusions:Simvastatin could effectively inhibit the activation of astrocytes,reduce TNF-α expression,and exert anti-inflammatory effects,and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.

  20. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Directory of Open Access Journals (Sweden)

    Haeseung Lee

    Full Text Available An in silico chemical genomics approach is developed to predict drug repositioning (DR candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity.

  1. Antipsychotic-like effects of zolpidem in Wistar rats.

    Science.gov (United States)

    Mierzejewski, Pawel; Kolaczkowski, Marcin; Marcinkowska, Monika; Wesolowska, Anna; Samochowiec, Jerzy; Pawlowski, Maciej; Bienkowski, Przemyslaw

    2016-02-15

    Aside from their use in the treatment of anxiety disorders and insomnia, benzodiazepines and other GABAA receptor positive modulators are widely used as add-on treatments in schizophrenic and non-schizophrenic psychoses. However, there is relatively little direct clinical or pre-clinical evidence for antipsychotic effects of GABAergic medications. Previous studies have indicated that zolpidem, a GABAergic drug acting preferentially at α1-containing GABAA receptors, may produce catalepsy through interactions with dopaminergic neurotransmission. The aim of the present study was to investigate effects of zolpidem in experimental models of antipsychotic activity and extrapyramidal side effects in Wistar rats. Effects of zolpidem were compared with that of a classic benzodiazepine drug, diazepam and a second-generation antipsychotic medication, risperidone. High doses of risperidone (10.0mg/kg, i.p.) and zolpidem (10.0mg/kg, i.p.), but not diazepam, induced relatively short-lasting cataleptic responses in the bar test. Zolpidem and risperidone, but not diazepam, produced some antipsychotic-like effects at doses, which produced no catalepsy and did not inhibit spontaneous locomotor activity and apomorphine-induced stereotypies. The present results tend to indicate that zolpidem exerts some neuroleptic-like effects at doses, which do not produce motor side effects. Our findings may provide further rationale for the development of new subtype-selective GABAA receptor modulators for the treatment of psychotic symptoms. PMID:26825544

  2. Non-Oral Drug Delivery Strategies: From Early Diagnosis to Advanced Treatments

    Directory of Open Access Journals (Sweden)

    Claudia Trenkwalder

    2015-08-01

    Full Text Available This educational symposium, sponsored by Britannia Pharmaceuticals Limited, was held during the 1st Congress of the European Academy of Neurology (EAN, which took place from 20th-23rd June 2015 in Berlin, Germany. The symposium reviewed the role of non-oral drug delivery strategies in patients with Parkinson’s disease (PD and how they can overcome problems that occur with the gastrointestinal (GI route of administration in many patients. GI dysfunction is recognised as a common problem in PD and may in fact be a preclinical marker of the disease. It can affect the absorption of oral medication resulting in OFF periods and unreliable control of motor symptoms, which in turn can have a negative impact on quality of life (QoL. Delayed time-to-ON (TTO after an oral levodopa dose and dose failures are known to be significant contributors to total OFF time. Results of the recently completed AM-IMPAKT trial in patients with morning akinesia due to a delay in the onset of oral levodopa effect demonstrate that apomorphine intermittent injection (penject is able to provide rapid and effective resolution of such complications, restoring patients to the ON state quickly and allowing them to get on with their daily activities.

  3. Photoaffinity ligand for dopamine D2 receptors: azidoclebopride

    Energy Technology Data Exchange (ETDEWEB)

    Niznik, H.B.; Guan, J.H.; Neumeyer, J.L.; Seeman, P.

    1985-02-01

    In order to label D2 dopamine receptors selectively and covalently by means of a photosensitive compound, azidoclebopride was synthesized directly from clebopride. The dissociation constant (KD) of clebopride for the D2 dopamine receptor (canine brain striatum) was 1.5 nM, while that for azidoclebopride was 21 nM. The affinities of both clebopride and azidoclebopride were markedly reduced in the absence of sodium chloride. In the presence of ultraviolet light, azidoclebopride inactivated D2 dopamine receptors irreversibly, as indicated by the inability of the receptors to bind (/sup 3/H)spiperone. Maximal photoinactivation of about 60% of the D2 dopamine receptors occurred at 1 microM azidoclebopride; 30% of the receptors were inactivated at 80 nM azidoclebopride (pseudo-IC50). Dopamine agonists selectively protected the D2 receptors from being inactivated by azidoclebopride, the order of potency being (-)-N-n-propylnorapomorphine greater than apomorphine greater than (+/-)-6,7-dihydroxy-2-aminotetralin greater than (+)-N-n-propylnorapomorphine greater than dopamine greater than noradrenaline greater than serotonin. Similarly, dopaminergic antagonists prevented the photoinactivation of D2 receptors by azidoclebopride with the following order of potency: spiperone greater than (+)-butaclamol greater than haloperidol greater than clebopride greater than (-)-sulpiride greater than (-)-butaclamol.

  4. The Antagonist Effects of L-tetrahydropalmatine on Low Prolactin Level Model of Lactational Rats%左旋四氢巴马汀对大鼠催乳素水平低下模型的拮抗作用

    Institute of Scientific and Technical Information of China (English)

    韩蕾; 尤春来; 周晓辉

    2002-01-01

    研究左旋四氢巴马汀(L-tetrahydropalmatine,L-THP)对哺乳期催乳素(Prolactin,PRL)水平低下模型大鼠中枢多巴胺(Dopamine,DA)D2受体的拮抗作用.通过对哺乳期大鼠皮下注射阿扑吗啡(Apomorphine,APO)2.5mg·kg-1·d-1和5.0mg·kg-1·d-1,以确定用APO建立哺乳期大鼠PRL水平低下模型的有效剂量.并在此模型基础上研究L-THP对APO诱导的哺乳期大鼠PRL水平低下的拮抗作用.结果表明,皮下注射APO 5.0mg·kg-1·d-1可显著降低哺乳期大鼠血清PRL水平,抑制仔鼠体重增长,可造成哺乳期大鼠PRL水平低下模型.L-THP 60mg·kg-1·d-1可显著性提高哺乳期大鼠血清PRL水平,促进仔鼠体重增长.L-THP可能是D2受体拮抗剂.

  5. Bindings of /sup 3/H-prazosin and /sup 3/H-yohimbine to alpha adrenoceptors in the guinea-pig stomach

    Energy Technology Data Exchange (ETDEWEB)

    Taniguchi, T.; Nishikawa, H.

    1988-01-01

    Alpha adrenoceptor subtypes have been investigated by radioligand binding study in guinea-pig stomach using /sup 3/H-prazosin and /sup 3/H-yohimbine. The specific /sup 3/H-prazosin binding to guinea-pig stomach was saturable and of high affinity with a Bmax of 33 fmol/mg protein. Specific /sup 3/H-yohimbine binding to the tissue was also saturable and of high affinity with a Bmax of 150 fmol/mg protein. Adrenergic drugs competed for /sup 3/H-prazosin binding in order of prazosin > phentolamine > methoxamine > norepinephrine > clonidine > epinephrine > yohimbine. These drugs competed for /sup 3/H-yohimbine binding in order of yohimbine > phentolamine > clonidine > epinephrine > norepinephrine > prazosin > methoxamine. They also examined whether dopamine receptors exist in guinea-pig stomach, using radioligand binding study. Specific binding of /sup 3/H-spiperone, /sup 3/H-apomorphine, /sup 3/H-dopamine and /sup 3/H-domperidone was not detectable in the stomach. Dopaminergic drugs such as dopamine, haloperidol, domperidone and sulpiride competed for /sup 3/H-prazosin binding in order of haloperidol > domperidone > dopamine > sulpiride. Metoclopramide, sulpiride and dopamine competed for /sup 3/H-yohimbine binding in order of metoclopramide > sulpiride > dopamine.

  6. Recent advances in drug therapy for myopia%近视眼药物治疗研究进展

    Institute of Scientific and Technical Information of China (English)

    许瑶; 曾骏文

    2013-01-01

    本文回顾了最近国内外近视眼药物治疗的相关研究,从常见药物治疗和针对脉络膜新生血管的治疗两方面作了介绍,并为未来的治疗方向提出了一些设想.本文主要介绍了阿托品、哌仑西平、阿扑吗啡、7-甲基黄嘌呤等传统药物的新用法,同时也阐述了光动力疗法、单抗类药物用于近视治疗的最新研究进展.%This article reviews about recent advances of studies on drug therapy for myopia,introducing the common drug therapies and therapies for choroidal neovascularization.This article proposes some ideas of future treatment for myopia.This review introduces the new usage of some traditional drugs including atropine,pirenzepine,apomorphine,7-methylxanthine,and reviews the latest advances in studies on photodynamic therapy and monoclonal antibody drugs therapy for myopia.

  7. Protective Effect of Oral Hesperetin Against Unilateral Striatal 6-Hydroxydopamine Damage in the Rat.

    Science.gov (United States)

    Kiasalari, Zahra; Khalili, Mohsen; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease (PD) is a neurodegenerative disorder due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNC). PD finally leads to incapacitating symptoms including motor and cognitive deficits. This study was undertaken to assess protective effect of the flavanone hesperetin against striatal 6-hydroxydopamine lesion and to explore in more detail some underlying mechanisms including apoptosis, inflammation and oxidative stress. In this research study, intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats received hesperetin (50 mg/kg/day) for 1 week. Hesperetin reduced apomorphine-induced rotational asymmetry and decreased the latency to initiate and the total time on the narrow beam task. It also attenuated striatal malondialdehyde and enhanced striatal catalase activity and GSH content, lowered striatal level of glial fibrillary acidic protein as an index of astrogliosis and increased Bcl2 with no significant change of the nuclear factor NF-kB as a marker of inflammation. Hesperetin treatment was also capable to mitigate nigral DNA fragmentation as an index of apoptosis and to prevent loss of SNC dopaminergic neurons. This study indicated the protective effect of hesperetin in an early model of PD via attenuation of apoptosis, astrogliosis marker and oxidative stress and it may be helpful as an adjuvant therapy for management of PD at its early stages. PMID:26700436

  8. The overview of the therapeutic strategy for motor complications of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    LIU Zhen-guo

    2013-08-01

    Full Text Available Currently, levodopa remains to be the most effective agent to improve motor symptoms in Parkinson's disease (PD. However, the chronic use is associated with the emergence of motor fluctuations, which has been one of the most troublesome dilemmas in PD's treatment. A plenty of clinical studies evidenced some risk factors would contribute to the emergence of the motor complications. Therefore, a better understanding of these risk factors may help to draw up the preventive strategies to target "at risk" populations before the onset of motor complications. Therapeutic strategies using different types and timing of dopaminergic therapy may influence the emergence of motor complications. Unfortunately, the traditional oral treatments for motor complications are only partially effective, rarely abolishing motor complications. The clinical improvement might be achieved with invasive strategies via subcutaneous or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation (DBS of the subthalamic nucleus, especially at late stage of PD. Besides, targeting transmitter systems beyond the dopamine system is another interesting approach for the motor complications of PD. However, clinical trail evidence regarding the medicine has been inconsistent. The treatment of motor complications is a long-term project, and the strategies should be modified to solve the demands at different stages.

  9. [Application of levodopa/carbidopa intestinal gel in advanced Parkinson's disease].

    Science.gov (United States)

    Toth, Adrián; Nagy, Helga; Wacha, Judit; Bereczki, Dániel; Takáts, Annamária

    2015-12-01

    Parkinson's disease is the second most common neurodegenerative disorder around the world. Levodopa has remained the "gold standard" of the therapy even several decades after its introduction. Chronic levodopa treatment is associated with the development of motor complications in most patients. Advanced Parkinson's disease is characterized by these complications: motor and non-motor fluctuation and disturbing dyskinesia. Continuous dopaminergic stimulation might reduce these complications. In advanced Parkinson's disease levodopa is still effective. In the treatment of this stage there are several advanced or device-aided therapies: apomorphine pump, deep brain stimulation and levodopa/carbidopa intestinal gel. Levodopa/carbidopa intestinal gel is an aqueous gel that can be delivered to the jejunum via a percutaneous gastrojejunostomy tube which is connected to an infusion pump dosing the levodopa gel continuously to the place of absorption. Levodopa/carbidopa gel infusion can be used as monotherapy, can be tested, can be used individually and this therapy is reversible. Several clinical trials demonstrated that levodopa/carbidopa intestinal gel therapy is of long-term benefit, improves the quality of life of the patients and can reduce motor fluctuation and dyskinesia. PMID:26727723

  10. Action of (D-ProU)-US -casomorphin/sub 1-5/ on processes of synaptic transmission. [Use of TH-spiperone for binding studies

    Energy Technology Data Exchange (ETDEWEB)

    Kammerer, E.; Koch, S.; Roque, D.M.L.

    1985-01-01

    The peptide (D-ProU)-US -casomorphin/sub 1-5/ is a potent and long acting analgesic. Furthermore it is able to antagonize apomorphine-induced behavioral patterns, which are preferentially used as screening methods to detect dopaminolytic or neuroleptic properties. Because all of these tests do not exclude interaction of drugs with transmission systems other than the dopaminergic, biochemical studies were undertaken to estimate possible influences of the opioid peptide on processes of dopaminergic, serotonergic, and cholinergic transmission systems. In lower concentrations (D-ProU)-US -casomorphin/sub 1-5/ enhances the potassium-stimulated release of acetylcholine from hippocampal slices and the basal overflow of dopamine from striatal slices. In high concentrations an augmentation of the potassium evoked release of dopamine and a reduction of the binding of (TH)spiperone on dopaminergic and serotonergic striatal receptors could be observed. These biochemical findings are discussed with regard to the behavioral patterns induced by this opioid peptide. (author).

  11. Pentoxifylline Neuroprotective Effects Are Possibly Related to Its Anti-Inflammatory and TNF-Alpha Inhibitory Properties, in the 6-OHDA Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Kelly Rose Tavares Neves

    2015-01-01

    Full Text Available Pentoxifylline (PTX is a phosphodiesterase inhibitor with anti-TNF-alpha activity, associated with its anti-inflammatory action. Considering Parkinson’s disease (PD as a neuroinflammatory disorder, the objectives were to evaluate PTX neuroprotective properties, in a model of PD. Male Wistar rats, divided into sham-operated (SO, untreated 6-OHDA, and 6-OHDA treated with PTX (10, 25, and 50 mg/kg groups, received a unilateral 6-OHDA injection, except the SO group administered with saline. Treatments started 24 h after surgery and continued for 15 days when the animals were submitted to apomorphine-induced rotations, open field, and forced swimming tests. At the next day, they were euthanized and their striata processed for neurochemical (DA and DOPAC determinations, histological, and immunohistochemical (Fluoro-Jade, TH, DAT, OX-42, TNF-alpha, COX-2, and iNOS studies. PTX reversed the behavioral changes observed in the untreated 6-OHDA animals. Furthermore, PTX partially reversed the decrease in DA contents and improved neuronal viability. In addition, decreases in immunostaining for TH and dopamine transporter (DAT were reversed. The untreated 6-OHDA group showed intense OX-42, TNF-alpha, COX-2, and iNOS immunoreactivities, which were attenuated by PTX. In conclusion, we demonstrated a neuroprotective effect of PTX, possibly related to its anti-inflammatory and antioxidant actions, indicating its potential as an adjunct treatment for PD.

  12. Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Kiasalari, Zahra; Baluchnejadmojarad, Tourandokht; Roghani, Mehrdad

    2016-05-01

    Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre-surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor α with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress. PMID:26119304

  13. 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.

  14. Pyrroloquinoline quinone-conferred neuroprotection in rotenone models of Parkinson's disease.

    Science.gov (United States)

    Qin, Jiaojiao; Wu, Meilong; Yu, Shu; Gao, Xiaorong; Zhang, Jingjing; Dong, Xingyue; Ji, Jinyan; Zhang, Yuxi; Zhou, Lin; Zhang, Qi; Ding, Fei

    2015-11-01

    Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has proven to protect neurons against glutamate-induced damage both in vitro and in vivo. This study was aimed to investigate the possible neuroprotective effects of PQQ in rotenone-induced Parkinson's disease (PD) model. Pre-treatment with PQQ prevented cultured SH-SY5Y cells from rotenone-induced apoptosis, accompanied by modulation of apoptosis-related proteins (Bcl-2, Bax and Smac), restoration of the mitochondrial membrane potential, inhibition of intracellular reactive oxygen species (ROS) production, suppression of tyrosine residues nitration, and dopamine redistribution. PQQ also exerted protective effects in an in vivo PD model, which was created by rotenone injection into the medial forebrain bundle of rats. Co-injection with PQQ and rotenone improved the apomorphine-evoked rotation, decreased neuronal loss, increased the ROS-scavenging ability, regulated intracellular expressions of mitochondrial complex subunits (Ndufs1-4), tyrosine hydroxylase, and vesicular monoamine transporter 2. Taken together, our results collectively suggest that PQQ confers neuroprotection in rotenone-induced PD model probably through complex and multifaceted mechanisms, at least involving oxidative stress, mitochondrial integrity, and dopamine functions. PMID:26276080

  15. Animal models of deep brain stimulation%脑深部电刺激猴帕金森病模型的建立

    Institute of Scientific and Technical Information of China (English)

    曹依群; 周晓平; 胡小吾; 姜秀峰

    2005-01-01

    目的通过猴偏侧帕金森病(Parkinson disease,PD)模型丘脑底核(subthalamic nucleus,STN)脑深部电刺激(deep brain stimulation,DBS)系统的植入,对脑深部电刺激动物模型的制备进行了探讨.方法2只猴偏侧PD模型,按照猴脑立体定向图谱,在右侧STN植入脑深部刺激电极,并同期皮下植入脉冲发生器.术后行头颅X线平片和MRI检查,给予慢性高频电刺激,观察运动症状改善.结果2只偏侧猴PD模型成功的同期植入DBS系统,术后的症状观察和阿朴吗啡(apomorphine,APO)诱发旋转实验,证实STN慢性高频电刺激有效地缓解了猴PD样症状.结论通过立体定向技术同期将DBS系统植入动物体内,可以有效的建立DBS动物模型,为DBS在神经疾病的应用研究提供了良好的实验模型.

  16. Stereoselectivity of presynaptic autoreceptors modulating dopamine release

    Energy Technology Data Exchange (ETDEWEB)

    Arbilla, S.; Langer, S.Z. (Department of Biology, Laboratoires d' Etudes et de Recherches Synthelabo, Paris, France)

    1981-12-17

    The effects of the (R)- and (S)-enantiomers of sulpiride and butaclamol were studied on the spontaneous and field stimulation-evoked release of total radioactivity from slices of rabbit caudate nucleus prelabelled with (/sup 3/H)dopamine. (S)-Sulpiride in concentrations ranging from 0.01-1..mu..M enhanced the electrically evoked release of (/sup 3/H)dopamine while (R)-sulpiride was 10 times less potent than (S)-sulpiride. Exposure to (S)-butaclamol (0.1-1 ..mu..M) but not to (R)-butaclamol (0.1-10..mu..M) enhanced the field-stimulated release of (/sup 3/H)dopamine. The facilitatory effects of (S)- and (R)-sulpiride and (S)-butaclamol on the stimulated release of the labelled neurotransmitter were observed under conditions in which these drugs did not modify the spontaneous outflow of radioactivity. Only the active enantiomers of sulpiride and butaclamol antagonized the inhibition by apomorphine (1..mu..M) of the stimulated release of (/sup 3/H)dopamine. Our results indicate that the presynaptic inhibitory dopamine autoreceptors modulating the stimulation-evoked release of (/sup 3/H)dopamine in the caudate nucleus are, like the classical postsynaptic dopamine receptors, chemically stereoselective.

  17. 香烟烟雾对老龄鼠性功能的影响

    Institute of Scientific and Technical Information of China (English)

    焦广宇; 朱孝娟; 等

    2002-01-01

    目的 探讨香烟烟雾对不同月龄大鼠阴茎勃起功能的影响及其与阴茎组织一氧化氮合酶(NOS)活性的关系。方法 观察香烟烟雾对阿朴吗啡Apomorphine(APO)诱导的大鼠阴茎勃起能力的影响,测定阴茎组织NOS活性。结果 阴茎勃起能力及NOS活性呈年龄依赖性下降(P<0.01)。吸烟组阴茎NO活性降低(p<0.01),4月龄大鼠勃起能力变化不大(P<0.05),但10月龄及16月龄大鼠勃起能力显著下降(P<0.05)。结论 香烟烟雾对低龄鼠性功能影响不大,但对老龄鼠影响可能与阴茎NOS活性降低有关。

  18. Impact of Overactive Bladder Syndrome on Female Sexual Function

    Directory of Open Access Journals (Sweden)

    Serdar Toksöz

    2015-12-01

    Full Text Available The etiology of female sexual dysfunction includes psychological, physiological and iatrogenic causes. Physiological and iatrogenic causes are abdominal surgery, menopause, smoking, spinal cord injuries and some antipsychotic, antihypertensive, and antidepressant drugs. When assessing sexual function, sexual function questionnaires, such as the Female Sexual Function Index, and the Sexual Function Questionnaire are used. The prevalence of female sexual dysfunction is 43% and it has been reported to increase depending on menopause and age. Estrogen, estrogen + testosterone and tibolone, PDE5, apomorphine, bupropion and flibanserin are used in the treatment of female sexual dysfunction. Overactive bladder is a disease affecting the quality of life and is characterized by urgency, frequency, nocturia and urge incontinence with especially filling phase of the bladder resulting from loss of detrusor muscle inhibition. The prevalence of overactive bladder in women in the United States has been reported to be 16.9%. Lower urinary tract symptoms and overactive bladder syndrome are not known how to cause female sexual dysfunction. Menopause and partner status were the most important predictors for female sexual dysfunction. It has been reported that overactive bladder syndrome and urinary incontinence provide prediction of development of female sexual dysfunction. Shame, fear of incontinence, and urinary incontinence as well as urge sensation during sexual intercourse in individuals with overactive bladder syndrome have been reported to be the main factors causing female sexual dysfunction. Pathophysiological relationship between the two disorders has not been elucidated and further clinical and experimental studies are needed in this regard.

  19. ( sup 125 I)(+)FISCH: A new CNS D-1 dopamine receptor imaging ligand

    Energy Technology Data Exchange (ETDEWEB)

    Billings, J.; Kung, M.P.; Chumpradit, S.; Pan, S.; Kung, H.F. (Univ. of Pennsylvania, Philadelphia (USA))

    1989-01-01

    Radiolabeling and in vitro and in vivo evaluation of an iodinated benzazepine: ({sup 125}I)FISCH 7-Chloro-8-hydroxy-1-(4{prime}-iodophenyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, as a potential imaging agent for CNS D-1 dopamine receptors in animals, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats. The striatum/cerebellum ratio was 2.50 at 60 min after the injection. The regional distribution in rat brain, as measured by ex vivo autoradiography, displayed highest uptake in the regions of the striatal complex and the substantia nigra, regions known to have a high concentration of D-1 dopamine receptors. Furthermore, this localized regional cerebral distribution was blocked by pretreatment with SCH-23390, a selective D-1 dopamine receptor antagonist. The in vitro binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 {plus minus} 0.15 nM. Competition data (in vitro) showed the following rank order of potency: SCH-23390 > ({plus minus})IBZP >> apomorphine > WB 4101 > ketanserin {approximately} spiperone. The preliminary data suggest that this analog of SCH-23390 shows similar selectivity for the CNS D-1 receptor.

  20. Penile erectile dysfunction after brachial plexus root avulsion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Guo Fu; Xuejia Li; Liqiang Gu; Bengang Qin; Li Jiang; Xijun Huang; Qinsen Lu; Dechun Zhang; Xiaolin Liu; Jiakai Zhu; Jianwen Zheng

    2014-01-01

    Our previous studies have demonstrated that some male patients suffering from brachial plexus injury, particularly brachial plexus root avulsion, show erectile dysfunction to varying degrees. However, the underlying mechanism remains poorly understood. In this study, we evaluated the erectile function after establishing brachial plexus root avulsion models with or without spinal cord injury in rats. After these models were established, we administered apomorphine (via a sub-cutaneous injection in the neck) to observe changes in erectile function. Rats subjected to simple brachial plexus root avulsion or those subjected to brachial plexus root avulsion combined with spinal cord injury had signiifcantly fewer erections than those subjected to the sham operation. Expression of neuronal nitric oxide synthase did not change in brachial plexus root avulsion rats. However, neuronal nitric oxide synthase expression was signiifcantly decreased in brachial plexus root avulsion + spinal cord injury rats. These ifndings suggest that a decrease in neuronal nitric oxide synthase expression in the penis may play a role in erectile dysfunction caused by the combi-nation of brachial plexus root avulsion and spinal cord injury.

  1. Regulation of dopamine synthesis and release in striatal and prefrontal cortical brain slices

    Energy Technology Data Exchange (ETDEWEB)

    Wolf, M.E.

    1986-01-01

    Brain slices were used to investigate the role of nerve terminal autoreceptors in modulating dopamine (DA) synthesis and release in striatum and prefrontal cortex. Accumulation of dihydroxyphenylalanine (DOPA) was used as an index of tyrosine hydroxylation in vitro. Nomifensine, a DA uptake blocker, inhibited DOPA synthesis in striatal but not prefrontal slices. This effect was reversed by the DA antagonist sulpiride, suggesting it involved activation of DA receptors by elevated synaptic levels of DA. The autoreceptor-selective agonist EMD-23-448 also inhibited striatal but not prefrontal DOPA synthesis. DOPA synthesis was stimulated in both brain regions by elevated K/sup +/, however only striatal synthesis could be further enhanced by sulpiride. DA release was measured by following the efflux of radioactivity from brain slices prelabeled with (/sup 3/H)-DA. EMD-23-448 and apomorphine inhibited, while sulpiride enhanced, the K/sup +/-evoked overflow of radioactivity from both striatal and prefrontal cortical slices. These findings suggest that striatal DA nerve terminals possess autoreceptors which modulate tyrosine hydroxylation as well as autoreceptors which modulate release. Alternatively, one site may be coupled to both functions through distinct transduction mechanisms. In contrast, autoreceptors on prefrontal cortical terminals appear to regulate DA release but not DA synthesis.

  2. NADPH Oxidase and the Degeneration of Dopaminergic Neurons in Parkinsonian Mice

    Directory of Open Access Journals (Sweden)

    Marina S. Hernandes

    2013-01-01

    Full Text Available Several lines of investigation have implicated oxidative stress in Parkinson’s disease (PD pathogenesis, but the mechanisms involved are still unclear. In this study, we characterized the involvement of NADPH oxidase (Nox, a multisubunit enzyme that catalyzes the reduction of oxygen, in the 6-hydroxydopamine- (6-OHDA- induced PD mice model and compared for the first time the effects of this neurotoxin in mice lacking gp91phox-/-, the catalytic subunit of Nox2, and pharmacological inhibition of Nox with apocynin. Six-OHDA induced increased protein expression of p47phox, a Nox subunit, in striatum. gp91phox-/- mice appear to be completely protected from dopaminergic cell loss, whereas the apocynin treatment conferred only a limited neuroprotection. Wt mice treated with apocynin and gp91phox-/- mice both exhibited ameliorated apomorphine-induced rotational behavior. The microglial activation observed within the striatum and the substantia nigra pars compacta (SNpc of 6-OHDA-injected Wt mice was prevented by apocynin treatment and was not detected in gp91phox-/- mice. Apocynin was not able to attenuate astrocyte activation in SN. The results support a role for Nox2 in the 6-OHDA-induced degeneration of dopaminergic neurons and glial cell activation in the nigrostriatal pathway and reveal that no comparable 6-OHDA effects were observed between apocynin-treated and gp91phox-/- mice groups.

  3. In vivo binding in rat brain and radiopharmaceutical preparation of radioiodinated HEAT, an alpha-1 adrenoceptor ligand

    Energy Technology Data Exchange (ETDEWEB)

    Couch, M.W.; Greer, D.M.; Thonoor, C.M.; Williams, C.M.

    1988-03-01

    In vivo binding of (/sup 125/I)-2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl tetralone) ((/sup 125/I)HEAT) to alpha-1 adrenoceptors in the rat brain was determined over 4 hr. Uptake in the thalamus and frontal cortex was approximately 0.1% injected dose per gram tissue. Thalamus/cerebellum ratios of 10:1 and frontal cortex/cerebellum ratios of 5:1 were found at 4 hr. Pretreatment with prazosin, an alpha-1 antagonist, completely inhibited the accumulation of (/sup 125/I)HEAT in thalamus and frontal cortex; yet uptake of radioactivity was not significantly affected by antagonists and agonists for other receptors classes (propranolol, beta-1; apomorphine, D-1; spiperone, D-2). Binding of (/sup 125/I)HEAT is saturable. At 4 hr, (/sup 125/I)HEAT or (/sup 123/I)HEAT was shown to be the only radioactive material in rat thalamus and frontal cortex. Iodine-123 HEAT and (/sup 125/I)HEAT were synthesized as radiopharmaceuticals within 3 hr in 99% radiochemical purity.

  4. Adenosine AA Receptor Antagonists Do Not Disrupt Rodent Prepulse Inhibition: An Improved Side Effect Profile in the Treatment of Parkinson's Disease

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    Carina J. Bleickardt

    2012-01-01

    Full Text Available Parkinson's disease (PD is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A2A receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A2A antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI, a model of psychosis. Dopamine receptor agonists pramipexole (0.3–3 mg/kg, pergolide (0.3–3 mg/kg, and apomorphine (0.3–3 mg/kg significantly disrupted PPI; ropinirole (1–30 mg/kg had no effect; L-dopa (100–300 mg/kg disrupted rat but not mouse PPI. SCH 412348 (0.3–3 mg/kg did not disrupt rodent PPI; istradefylline (0.1–1 mg/kg marginally disrupted mouse but not rat PPI. These results suggest that A2A antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.

  5. 姜朴组合物对呕吐的作用%The Antiemitic Effect of Zingiber and Magnolia Officinalis Composition

    Institute of Scientific and Technical Information of China (English)

    赵成健; 毛晓宇; 丁波; 石振艳; 张芳; 岳旺; 李晓玲

    2014-01-01

    目的:研究生姜与厚朴组合物对呕吐的作用。方法:在顺铂、硫酸铜、阿扑吗啡所致水貂呕吐模型观察生姜与厚朴组合物的止呕效果。结果:生姜与厚朴组合物对于顺铂、硫酸铜、阿扑吗啡所致水貂的呕吐反应均有对抗作用(P<0.01)。结论:生姜与厚朴组合物可抑制呕吐反应,是天然、低毒的药物。%Objective:To study the antiemitic effect of Zingiber and Magnolia officinalis composition. Method:The antiemetic effects of the composition were examined by cisplatin,copper sulfate and apomorphine-induced mink vomiting models.Result:The composition could reduce vomiting of the three models(P<0.01). Conclusion:Zingiber and Magnolia officinalis composition can reduce vomiting,it’s the natural and low toxic drug.

  6. AB096. Taurine supplementation improves erectile function in rats with streptozotocin-induced type 1 diabetes via amelioration of penile fibrosis and endothelial dysfunction

    Science.gov (United States)

    Ruan, Yajun; Li, Mingchao; Wang, Tao; Yang, Jun; Rao, Ke; Wang, Shaogang; Yang, Weimin; Liu, Jihong; Ye, Zhangqun

    2016-01-01

    Objective For patients with diabetes, erectile dysfunction (ED) is common and greatly affects quality of life. However, these patients often exhibit a poor response to first-line oral phosphodiesterase type 5 inhibitors. The aim of this study was to investigate whether taurine, a sulfur-containing amino acid, affects diabetic ED (DED). Methods Type 1 diabetes mellitus was induced in male rats using streptozotocin. After 12 weeks, an apomorphine test was conducted to confirm DED. Only rats with DED were administered taurine or vehicle for four weeks. Age-matched nondiabetic rats were administered saline intraperitoneally for four weeks. Erectile function was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum also were analyzed. Results Erectile function was significantly reduced in the diabetic rats compared with in the nondiabetic rats, and was ameliorated in the diabetic rats treated with taurine. The corpus cavernosum of the rats with DED exhibited severe fibrosis and decreased smooth muscle content. Deposition of extracellular matrix proteins was increased in the diabetic rats, while expression of endothelial nitric oxide synthase/cyclic guanosine monophosphate/nitric oxide pathway–related proteins was reduced. Taurine supplementation restored erectile response as well as histologic and molecular alterations. Conclusions Taurine supplementation improves erectile function in rats with DED probably by potential antifibrotic activity. This finding provides evidence for a potential new therapy for DED.

  7. Larval zebrafish model for FDA-approved drug repositioning for tobacco dependence treatment.

    Directory of Open Access Journals (Sweden)

    Margot A Cousin

    Full Text Available Cigarette smoking remains the most preventable cause of death and excess health care costs in the United States, and is a leading cause of death among alcoholics. Long-term tobacco abstinence rates are low, and pharmacotherapeutic options are limited. Repositioning medications approved by the U.S. Food and Drug Administration (FDA may efficiently provide clinicians with new treatment options. We developed a drug-repositioning paradigm using larval zebrafish locomotion and established predictive clinical validity using FDA-approved smoking cessation therapeutics. We evaluated 39 physician-vetted medications for nicotine-induced locomotor activation blockade. We further evaluated candidate medications for altered ethanol response, as well as in combination with varenicline for nicotine-response attenuation. Six medications specifically inhibited the nicotine response. Among this set, apomorphine and topiramate blocked both nicotine and ethanol responses. Both positively interact with varenicline in the Bliss Independence test, indicating potential synergistic interactions suggesting these are candidates for translation into Phase II clinical trials for smoking cessation.

  8. Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine-1,3,4-oxadiazoles derivatives as atypical antipsychotics.

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    Yin Chen

    Full Text Available BACKGROUND: It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D(2 and D(3, serotonin 5-HT(1A and 5-HT(2A receptors with low affinity for the serotonin 5-HT(2C and H(1 receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. METHODOLOGY/PRINCIPAL FINDINGS: A series of 2-substituted-5-thiopropylpiperazine (piperidine -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D(2, 5-HT(1A and 5-HT(2A receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D(2, 5-HT(1A and 5-HT(2A receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D(3 receptor, and low affinity for serotonin 5-HT(2C and H(1 receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. CONCLUSIONS/SIGNIFICANCE: Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.

  9. Evidence that 5-hydroxytryptamine/sub 3/ receptors mediate cytotoxic drug and radiation-evoked emesis

    Energy Technology Data Exchange (ETDEWEB)

    Miner, W.D.; Sanger, G.J.; Turner, D.H.

    1987-08-01

    The involvement of 5-hydroxytryptamine (5-HT) 5-HT/sub 3/ receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT/sub 3/ receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT/sub 3/ receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT/sub 3/ receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.

  10. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures.

    Science.gov (United States)

    Lee, Haeseung; Kang, Seungmin; Kim, Wankyu

    2016-01-01

    An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug's mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity. PMID:26954019

  11. Emesis, radiation exposure, and local cerebral blood flow in the ferret

    Energy Technology Data Exchange (ETDEWEB)

    Tuor, U.I.; Kondysar, M.H.; Harding, R.K.

    1988-06-01

    We examined the sensitivity of the ferret to emetic stimuli and the effect of radiation exposure near the time of emesis on local cerebral blood flow. Ferrets vomited following the administration of either apomorphine (approx 45% of the ferrets tested) or peptide YY (approx 36% of those tested). Exposure to radiation was a very potent emetic stimulus, but vomiting could be prevented by restraint of the hindquarters of the ferret. Local cerebral blood flow was measured using a quantitative autoradiographic technique and with the exception of several regions in the telencephalon and cerebellum, local cerebral blood flow in the ferret was similar to that in the rat. In animals with whole-body exposure to moderate levels of radiation (4 Gy of /sup 137/Cs), mean arterial blood pressure was similar to that in the control group. However, 15-25 min following irradiation there was a general reduction of local cerebral blood flow ranging from 7 to 33% of that in control animals. These cerebral blood flow changes likely correspond to a reduced activation of the central nervous system.

  12. Progesterone Exerts a Neuromodulatory Effect on Turning Behavior of Hemiparkinsonian Male Rats: Expression of 3α-Hydroxysteroid Oxidoreductase and Allopregnanolone as Suggestive of GABAA Receptors Involvement

    Directory of Open Access Journals (Sweden)

    Roberto Yunes

    2015-01-01

    Full Text Available There is a growing amount of evidence for a neuroprotective role of progesterone and its neuroactive metabolite, allopregnanolone, in animal models of neurodegenerative diseases. By using a model of hemiparkinsonism in male rats, injection of the neurotoxic 6-OHDA in left striatum, we studied progesterone’s effects on rotational behavior induced by amphetamine or apomorphine. Also, in order to find potential explanatory mechanisms, we studied expression and activity of nigrostriatal 3α-hydroxysteroid oxidoreductase, the enzyme that catalyzes progesterone to its active metabolite allopregnanolone. Coherently, we tested allopregnanolone for a possible neuromodulatory effect on rotational behavior. Also, since allopregnanolone is known as a GABAA modulator, we finally examined the action of GABAA antagonist bicuculline. We found that progesterone, in addition to an apparent neuroprotective effect, also increased ipsilateral expression and activity of 3α-hydroxysteroid oxidoreductase. It was interesting to note that ipsilateral administration of allopregnanolone reversed a clear sign of motor neurodegeneration, that is, contralateral rotational behavior. A possible GABAA involvement modulated by allopregnanolone was shown by the blocking effect of bicuculline. Our results suggest that early administration of progesterone possibly activates genomic mechanisms that promote neuroprotection subchronically. This, in turn, could be partially mediated by fast, nongenomic, actions of allopregnanolone acting as an acute modulator of GABAergic transmission.

  13. Prenatal manipulation of the serotonergic system: Biochemical, pharmacological and behavioral effects

    Energy Technology Data Exchange (ETDEWEB)

    Shemer, A.V.

    1988-01-01

    Rat pups were exposed in utero to pharmacological agents that stimulated or diminished serotonergic activity in vivo. Dams received 5-Methoxytryptamine 1mg/kg, from day 12 of gestation to birth, or parachlorophenylalanine, the serotonin synthesis inhibitor, from day 7 to 17 of gestation. Both groups of offspring showed significant reductions in the specific high affinity uptake of {sup 3}H-5-HT into brainstem and forebrain areas on postnatal days 1, 15, and 30, indicating reduced outgrowth of serotonin. At 15 days of age, both groups of treated offspring showed deficits in activity and in performing behaviors that required inhibition, but these deficits were no longer apparent on Day 30. Dose response experiments for 5-MT produced a dual effect: enhanced uptake in forebrain and inhibition of uptake in brainstem and forebrain on postnatal days 1, 15 and 30. Prenatal 5-MT caused deficits in avoidance and activity. Prenatal exposure to PAT, the 5-HT{sub 1a} agonist caused reduced uptake in brainstem, while exposure to TFMPP (the 5-HT{sub 1b} agonist) produced enhanced uptake in forebrain, as did the high dose of 5-MT. Sensitivity of the pharmacological response to acute 5-MT, 1 mg/kg, and apomorphine, 5 mg/kg was measured in an activity test.

  14. Identification of potential drugs for Parkinson's disease based on a sub-pathway method.

    Science.gov (United States)

    Sun, Ai-Guo; Lin, Ai-Qi; Huang, Shao-Yue; Huo, Di; Cong, Chao-Hua

    2016-01-01

    Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in ageing individuals. Current therapeutic regimen suffers from general side effects and a poor efficiency for PD symptoms. The need for development new therapeutic agents for PD is urgent. Here, we aimed to explore the metabolic mechanism of PD and identified potential novel agents for PD by a sub-pathway-based method. By using the GSE7621 microarray data from the GEO database, we first identified the 1226 differentially expressed genes (DEGs) between PD and normal samples. Then we identified 19 significant enriched metabolic sub-pathways, which may involve in development of PD. Finally, by an integrated analysis of PD-involved sub-pathways and drug-affected sub-pathways, we identified 49 novel small molecular drugs capable to target the PD-involved sub-pathways. Our method could not only identify existing drug (apomorphine) for PD, but also predict potentially novel agents (ketoconazole and astemizole), which might have therapeutic effects via targeting some key enzymes in arachidonic acid metabolism. These candidate agents identified by our approach may provide insights into a novel therapy approach for PD. PMID:25405535

  15. /sup 125/I-spiperone: a novel ligand for D/sub 2/ dopamine receptors

    Energy Technology Data Exchange (ETDEWEB)

    Gundlach, A.L.; Largent, B.L.; Synder, S.H.

    1984-11-05

    /sup 125/I-Spiperone binds with high affinity K/sub D/ 0.3 nM) to a single specific site (B/sub max/ 34 pmole/g wet weight) in homogenates of rat corpus striatum. Specific binding is about 40-60 percent of total binding and is displaced stereo-specifically by butaclamol and clopenthixol. Neuroleptic drugs of various classes are potent inhibitors of /sup 125/I-spiperone binding (/sub i/'s 1-10 nM). Selective dopamine antagonists such as sulpiride (K/sub i/ 50 nM) and dopamine agonists such as apomorphine (K/sub i/ 200 nM) are also potent inhibitors. The drugs specificity of /sup 125/I-spiperone binding correlates well with that of /sup 3/H-spiperone binding, providing good evidence that /sup 125/I-spiperone labels D/sub 2/ dopamine receptors in striatal membranes. /sup 125/I-Spiperone, with its high specific activity (2200 Ci/mmol) may prove to be a useful ligand in studies examining D/sub 2/ dopamine receptors in soluble preparations and by autoradiography. Furthermore iodinated spiperone may be useful in radioreceptor assays of neuroleptic drug levels and, in a /sup 123/I-labeled form for imaging of dopamine receptors, in vivo, using single photon tomography. 18 references, 4 figures, 1 table.

  16. Conditioned taste aversion in rats exposed to 2450 MHz CW microwaves

    Energy Technology Data Exchange (ETDEWEB)

    Williams, W.; Michaelson, S.M.

    1978-01-01

    The ability of 2450 MHz CW microwaves to induce an aversive response to saccharin was investigated in rats subjected to the following exposure parameters: incident power densities of 10 to 65 mW/cm/sup 2/ for 10 minutes; 20 mW/cm/sup 2/ for 2 hours; and 65 mW/cm/sup 2/ continuously for 1 hour. Sham-irradiated controls were tested simultaneously. Core body temperatures were measured using a rectal probe before and after microwave exposure. Only those animals irradiated continuously at 65 mW/cm/sup 2/ for 1 hour responded with a significantly reduced saccharin intake. The aversive response correlated with a rise of core body temperature to 39.8/sup 0/C or higher. While taste aversions following administration of apomorphine are considered to be the result of gastrointestinal disturbances, such disturbance does not appear to be the primary cause for microwave-induced aversion. More likely, it appears that exposure to certain levels of microwave irradiation induces a stress that is hyperthermic in nature. What effect this hyperthermic condition has on gastrointestinal and biochemical processes cannot be assessed at this time. It appears, however, that when core body temperature is raised to approximately 40/sub 0/C or higher for one hour or more, the physiological and behavioral temperature regulating mechanisms of the animal become sufficiently stressed to produce the observed taste aversion.

  17. Combined MSC-Secreted Factors and Neural Stem Cell Transplantation Promote Functional Recovery of PD Rats.

    Science.gov (United States)

    Yao, Yuan; Huang, Chen; Gu, Ping; Wen, Tieqiao

    2016-01-01

    Stem cell transplantation has enormous potential for the treatment of neurodegenerative disorders like Parkinson's disease (PD). Mesenchymal stem cells (MSCs) have attracted much attention because they can secrete a wide variety of cellular factors that promote cell growth. In this study, we prepared a conditioned medium (CM) using lyophilized MSC culture medium that contained the secretome of MSCs and applied this CM to the culture of neural stem cells (CM-NSCs) for the transplantation of PD model rats. Quantitative real-time PCR, Western blot, and immunocytochemistry were used to identify cell differentiation and expression of dopaminergic neuron-specific genes in vitro. Behavioral tests including rotational behavior and MWM training tests were also performed to assess the recovery. Our results indicated that combined treatment of CM and neural stem cell transplantation can significantly reduce apomorphine-induced rotational asymmetry and improve spatial learning ability. The CM-NSCs were able to differentiate into dopaminergic neurons in the ventral tegmental area (VTA) and medial forebrain bundle (MFB), and migrated around the lesion site. They showed a higher activity than untreated NSCs in cell survival, migration, and behavior improvement in the dopa-deficit rat model. These findings suggest that the neural stem cells treated with conditioned medium possess a great potential as a graft candidate for the treatment of Parkinson's disease. PMID:26607204

  18. Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity.

    Science.gov (United States)

    Jiang, Weijun; Xiong, Lei; Bin Yang; Li, Weiwei; Zhang, Jing; Zhou, Qing; Wu, Qiuyue; Li, Tianfu; Zhang, Cui; Zhang, Mingchao; Xia, Xinyi

    2016-01-01

    To investigate the effect of hyperhomocysteinaemia (HHCy) on penile erectile function in a rat model, a methionine-rich diet was used in which erectile function, the reproductive system, and nitric oxide synthase were characterized. The intracavernous pressure, apomorphine experiments, measurement of oxidative stress, hematoxylin and eosin staining, immunohistochemistry analysis, reverse transcription-polymerase chain reactions and measurement of endothelial nitric oxide synthase activity were utilized. Our results showed that erections in the middle-dose, high-dose, and interference (INF) groups were significantly lower than the control (P < 0.05). INF group, being fed with vitamins B and folic acid, demonstrated markedly improved penile erections compared with the middle-dose group (P < 0.05). HHCy-induced eNOS and phospho-eNOS protein expression was reduced and the antioxidant effect was markedly impaired. The data of the present data provide evidence that HHCy is a vascular risk factor for erectile dysfunction by impairing cavernosa endothelial nitric oxide synthase activity. Intake of vitamins B can alleviate this abnormality. PMID:27221552

  19. Treatment of Parkinson's disease with aporphines. Possible role of growth hormone

    Energy Technology Data Exchange (ETDEWEB)

    Cotzias, G.C.; Papavasiliou, P.S.; Tolosa, E.S.; Mendez, J.S.; Bell-Midura, M.

    1976-03-11

    To avoid the main drawbacks of prolonged treatment with levodopa (involuntary movements and the ''on-off'' phenomenon), we administered apomorphine by mouth to 14 patients with Parkinson's disease. This treatment caused azotemia, which we circumvented by switching to N-propylnoraporphine, whose nephrotoxic dose (80 mg six times per day) was larger than its therapeutic dose (10 to 15 mg six times per day). Slowly increasing doses induced significant improvement (P less than 0.005) in all 24 patients studied, transitory mental aberrations in seven, and release of growth hormone in three patients tested. In patients previously on prolonged levodopa administration, the dyskinesia and ''on-off'' phenomenon were almost identical with N-propylnoraporphine, but both drawbacks were reduced or abolished in six patients by coadministration of ..cap alpha..-methyldopa hydrazine plus levodopa. This coadministration seemed to abolish tachyphylaxis. We conclude that N-propylnoraporphine is very useful in the treatment of Parkinson's disease.

  20. Neuroprotective effects of protocatechuic aldehyde against neurotoxin-induced cellular and animal models of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Xin Zhao

    Full Text Available Protocatechuic aldehyde (PAL has been reported to bind to DJ-1, a key protein involved in Parkinson's disease (PD, and exerts potential neuroprotective effects via DJ-1 in SH-SY5Y cells. In this study, we investigated the neuroprotective pharmacological effects of PAL against neurotoxin-induced cell and animal models of PD. In cellular models of PD, PAL markedly increased cell viability rates, mitochondrial oxidation-reduction activity and mitochondrial membrane potential, and reduced intracellular ROS levels to prevent neurotoxicity in PC12 cells. In animal models of PD, PAL reduced the apomorphine injection, caused turning in 6-OHDA treated rats, and increased the motor coordination and stride decreases in MPTP treated mice. Meanwhile, in an MPTP mouse model, PAL prevented a decrease of the contents of dopamine (DA and its metabolites in the striatum and TH-positive dopaminergic neuron loss in the substantia nigra (SN. In addition, PAL increased the protein expression of DJ-1 and reduced the level of α-synuclein in the SN of MPTP lesioned mice. PAL also increased the spine density in hippocampal CA1 neurons. The current study demonstrates that PAL can efficiently protect dopaminergic neurons against neurotoxin injury in vitro and in vivo, and that the potential mechanisms may be related to its effects in increasing DJ-1, decreasing α-synuclein and its growth-promoting effect on spine density.

  1. Mesenchymal stem cells that located in the electromagnetic fields improves rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Majid Jadidi

    2016-07-01

    Full Text Available Objective(s: The main characteristic of mesenchymal stem cells (MSCs is their ability to produce other cell types. Electromagnetic field (EMF stimulates differentiation of MSCs into other cells. In this study, we investigated whether EMF can effect on the differentiation of MSCs into dopaminergic (DA neurons. Materials and Methods: An EMF with a frequency of 50 Hz and two intensities of 40 and 400 µT 1hr/day was generated around the cells for a week. Afterwards, these cells were injected into the left ventricle of Parkinsonian rats. The rats survived for 2 weeks, and then sampling was performed. Results: The injected cells differentiated into DA neurons and sporadically settled in the substantia nigra pars compacta (SNpc. Transplanted rats exhibited significant partial correction apomorphine-induced rotational behavior compared to Parkinsonian rats (5.0±0.1 vs 7.57±0.08. Results demonstrated that endogenous serum and brain derived neurotrophic factor (BDNF were altered in all experimental groups. The greatest increase was in group of 400 µT EMF in comparison with Parkinsonian rats (398±15 vs. 312±11.79 pg ⁄ mg. Current study have shown that 6-Hydroxydopamine can cause severe loss of dopaminergic neurons (68±6.58, but injected MSCs that exposed to 40 and 400 µT EMF increased dopaminergic neurons in SNpc ( 108±2.33  & 126±3.89 (P

  2. Supersensitivity of GABAergic systems induced within rat substantia nigra and globus pallidus by haloperidol

    Energy Technology Data Exchange (ETDEWEB)

    Frey, J.J.M.

    1986-01-01

    The supersensitivity was demonstrated by an increase in the responsiveness of individual neurons within these brain regions to microiontophoretically-applied GABA and by an up regulation of GABA binding sites. Rates received haloperidol for 30 days in their feed and were then withdrawn from treatment for 48 hrs. {sup 3}H-GABA binding was found to be significantly elevated with the SN{sub R} (55%) and GP (42%). Scatchard analysis of {sup 3}H-muscimol binding isotherms indicated that the number (B{sub max}) of high affinity binding sites within the GP was significantly increased (32%); within the SN{sub R}, significant increases were detected in the B{sub max} of both high (23%) and low (58%) affinity {sup 3}H-muscimol binding sites. After CHAL treatment, signs of dopaminergic supersensitivity within the basal ganglia were also observed. Spontaneous locomotor activity and apomorphine-induced stereotyped behavior were increased and specific {sup 3}H-spiroperidol binding was elevated within the striatum (60%) and GP (236%).

  3. Subtle Cardiovascular Dysfunction in the Unilateral 6-Hydroxydopamine-Lesioned Rat

    Directory of Open Access Journals (Sweden)

    K. Slack

    2010-01-01

    Full Text Available The present study evaluated whether the unilateral 6-hydroxydopamine (6-OHDA model of Parkinson's disease produces autonomic deficits. Autonomic parameters were assessed by implanting a small radiofrequency telemetry device which measured heart rate variability (HRV, diurnal rhythms of heart rate (HR, core body temperature (cBT and locomotor activity (LA. Rats then received 6-OHDA lesion or sham surgery. 6-OHDA lesioned rats exhibited head and body axis biases, defective sensorimotor function (“disengage” test, and prominent apomorphine rotation (all P<.05 versus controls. Diurnal rhythm of HR was lower for 6-OHDA lesioned rats (n=8 versus controls (n=6; P<.05. Whilst HR decreased similarly in both groups during the day, there was a greater decrease in HR for the 6-OHDA lesioned rats at night (by 38 b.p.m. relative to 17 b.p.m. for controls. LA and cBT did not differ between surgery groups. This study indicates the unilateral 6-OHDA model of PD shows subtle signs of cardiovascular autonomic dysfunction.

  4. Photoaffinity labelling of high affinity dopamine binding proteins

    Energy Technology Data Exchange (ETDEWEB)

    Ross, G.M.; McCarry, B.E.; Mishra, R.K.

    1986-03-01

    A photoactive analogue of the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) has been synthesized and used to photoaffinity label dopamine binding proteins prepared from bovine caudate nucleus. N-(3-)N'-4-azidobenzamidol)-aminopropyl)-aminopropyl)-ADTN (AzB-AP-ADTN) was incubated with caudate membranes and irradiated with UV light. Membranes were then repeatedly washed by centrifugation to remove excess photolabel. A binding assay, using (/sup 3/H)-SCH 23390 (a D/sub 1/ specific antagonist), was then performed to evaluate the loss of receptor density in the photolyzed preparation. AzB-AP-ADTN irreversibly blocked (/sup 3/H)-SCH 23390 binding in a dose-dependent manner. Scatchard analysis revealed a decrease in the B/sub max/, with no significant change in the K/sub d/, of (/sup 3/H)-SCH 23390 binding. Compounds which compete for D/sub 1/ receptor binding (such as dopamine, SKF 38393 or apomorphine), proteted the SCH 23390 binding site from inactivation. This data would suggest that the novel photoaffinity ligand, AzB-AP-ADTN, can covalently label the D/sub 1/ (adenylate cyclase linked) dopamine receptor.

  5. Effects of pharmacological block of GABAA receptors on pallidal neurons in normal and parkinsonian state

    Directory of Open Access Journals (Sweden)

    Yan Xue

    2010-02-01

    Full Text Available The globus pallidus plays a central integrative role in the basal ganglia circuitry. Morphological studies have revealed a high level of GABA and GABAA receptors in the globus pallidus. To further investigate the effects of endogenous GABAA neurotransmission in the globus pallidus of normal and parkinsonian rats, in vivo extracellular recording and behavioral tests were performed in the present studies. In normal rats, micro-pressure ejection of GABAA receptor antagonist gabazine (0.1 mM increased the spontaneous firing rate of pallidal neurons by 28.3%. Furthermore, in 6-hydroxydopamine parkinsonian rats, gabazine increased the firing rate by 46.0% on the lesioned side, which was significantly greater than that on the unlesioned side (21.5%, P<0.05, as well as that in normal rats (P<0.05. In the behaving rats, unilateral microinjection of gabazine (0.1 mM evoked consistent contralateral rotation in normal rats, and significantly potentiated the number of apomorphine-induced contralateral rotations in parkinsonian rats. The present electrophysiological and behavioral findings may provide a rational for further investigations into the potential of pallidal endogenous GABAA neurotransmission in the treatment of Parkinson’s disease.

  6. Effects of arachidonic acid and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine on prolactin secretion from anterior pituitary cells

    Energy Technology Data Exchange (ETDEWEB)

    Camoratto, A.M.

    1988-01-01

    The role of two lipids, arachidonic acid and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, as modulators or prolactin secretion has been examined. Stimulators of phospholipase A{sub 2} activity, melittin and mastoparan, were found to increase prolactin release. Melittin also caused release of previously incorporated {sup 3}H-arachidonic acid and this effect was associated with loss of radiolabel from the phospholipid fraction. Exogenous arachidonic acid also stimulated prolactin secretion. Conversely, inhibitors of phospholipase A{sub 2} activity, dibromoacetophenone and U10029A, decreased basal and stimulated prolactin release. Prolactin release could also be lowered by ETYA, BW755C and NDGA, inhibitors of arachidonic acid metabolism. In the second series of experiments the effects of the biologically active phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor, PAF) on prolactin release were examined. PAF is an ether-linked phospholipid known to stimulate granule release in a variety of cell types including both inflammatory and noninflammatory cells. PAF increased release of prolactin from dispersed rat anterior pituitary cells; stimulation was not due to cell lysis. PAF-induced prolactin release could be blocked by the dopaminergic agonists apomorphine and bromocriptine as well as by two PAF receptor antagonists, SRI 63-072 and L-652-731.

  7. Effects of gene silencing of Fas-associated death domain on apoptosis-related proteins in rat models of parkinsonism%Fas相关死亡结构域蛋白基因沉默对帕金森病模型鼠黑质凋亡相关蛋白的影响

    Institute of Scientific and Technical Information of China (English)

    栗永生; 薛莉; 韩珣; 谢安木

    2012-01-01

    Objective To investigate the effects of gene silencing of Fas-associated death domain (FADD) with synthetic small interfering RNA (siRNA) on apomorphine-induced contralateral rotation,and the expression of Fas and caspase-8 in rat models of parkinsonism. Methods Sprague-Dawley rats were randomly divided into 5 groups:control group,Parkinson' s disease (PD) group,FADD siRNA group,FADD siRNA positive control group and FADD siRNA negative control group. Synthetic FADD siRNA sequences,siRNA positive sequences or siRNA negative sequences were infused into right substantianigra of midbrain using RNA interference and stereotactic techniques before parkinsonian rat model establishment.Apomorphine-induced contralateral rotations of the rats were observed after the injection.The protein and mRNA expression levels of FADD,Fas and caspase-8 were measured by Western blot and RT-PCR.Results In the control group,no rotation was observed after injecting apomorphine; however,in the rest groups,the number of rats respectively was 12 (12/14),3 (3/13),4 (4/15) and 11 ( 11/14 ) in apomorphine-induced contralateral rotation,which had significant statistical differences ( x2 = 18.56,P =0.000).In parkinsonian substantia nigra,marked increases in the protein and mRNA levels of FADD,Fas and caspase-8 were observed,compared with control group.Furthermore,compared with PD group,FADD protein and mRNA levels were strongly suppressed by administration of FADD siRNA in FADD siRNA group. FADD siRNA administration also resulted in great attenuation of 6-hydroxydopamine-induced increases in expression and activation of caspase-8.However,no decrease in expression of Fas was observed in FADD siRNA group and FADD siRNA positive control group,compared with PD group.Conclusion Our results suggest that death receptor signaling pathway plays a critical role in the pathogenesis of PD.FADD siRNA is effective against this pathway and it may,at least in part,provide a potential neuroprotective effect

  8. Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Gallagher, G.; Brown, A.; Szabo, S.

    1987-03-01

    Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.

  9. 纹状体内单侧注射6-羟多巴制备小鼠帕金森病模型%Preparation of mouse Parkinson's disease model by unilateral injection of 6-hydroxydopamine into striatum

    Institute of Scientific and Technical Information of China (English)

    付爱玲; 王逸麟

    2011-01-01

    Aim Until now. there is no data that show mouse microinjection 6-hydroxydopamine ( 6-OHDA ) for Parkinson ' s disease ( PD ) model in our country. Here a mouse PD model was suggested by injection 6-OHDA into unilateral striatum.Methods The right striatum of mice was injected 6-OHDA, the Apomorphine- and Amphetamine-induced rotation behaviors were measured. and the tyrosine hvdroxvlase ( TH ) activity of cortex,left and right striatum were assayed by radioassay method. Results and Conclusion The results indicate that mouse injected 6-OHDA into striatum can be used to induce acute PD animal model. the successful rate was 95% , and the period is about four weeks.%探讨小鼠纹状体内注射6-OHDA制作PD模型可行性.方法 将6-OHDA注射入小鼠单侧纹状体内,使用阿朴吗啡和安非他命诱发的动物单侧旋转进行行为学检测,同位素法检测皮层、左右纹状体内多巴胺能神经元标志酶酪氨酸羟化酶(tyrosine hydroxylase,TH)的活性.结果 与结论小鼠纹状体内注射6-OHDA后,可成功制作急性PD模型,成功率为95%,模型持续时间大约4周.

  10. Experimental study on dopaminergic neurons in mesencephalic ventral tegmental area of parkinson disease rats%帕金森病模型大鼠中脑腹侧被盖区多巴胺能神经元改变的实验研究

    Institute of Scientific and Technical Information of China (English)

    陈晓宇; 张荣宜; 沈韶辉; 齐威琴; 韩卉

    2006-01-01

    目的:探讨帕金森病(Parkinson's disease,PD)大鼠模型中脑腹侧被盖区(ventral tegmental area,VTA)多巴胺能神经元的改变.方法:应用6-羟基多巴胺(6-hydroxydopamine,6-OHDA)注射右侧黑质致密区(substantia nigra compacta,SNc)制作PD大鼠模型,进行阿朴吗啡(apomorphine,APO)诱发行为学观察、电镜、尼氏染色观察中脑VTA神经元的改变、酪氨酸羟化酶(tyrosine hydroxylase,TH)免疫组织化学ABC观察其DA能神经元的改变并进行图像分析.结果:APO诱发PD大鼠模型异常旋转行为,尼氏染色见PD大鼠中脑VTA有神经细胞肿胀、坏死等变化,VTA TH阳性神经元数量减少,形态学改变.结论:中脑VTA DA能神经参与PD模型大鼠的改变;APO能诱导6-OHDA PD模型大鼠的旋转行为,其强弱可能与TH+神经元数量直接相关.

  11. Review: management of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Pedrosa DJ

    2013-03-01

    Full Text Available David J Pedrosa, Lars Timmermann Department of Neurology, University Hospital Cologne, Cologne, Germany Abstract: Parkinson's disease (PD is one of the most frequent neurological diseases. Despite the modern imaging and nuclear techniques which help to diagnose it in a very early stage and lead to a better discrimination of similar diseases, PD has remained a clinical diagnosis. The increasing number of available treatment options makes the disease management often complicated even when the presence of PD seems undoubted. In addition, nonmotor symptoms and side effects of some therapies constitute some pitfalls already in the preclinical state or at the beginnings of the disease, especially with the progressive effect on patients. Therefore, this review aimed to summarize study results and depict recommended medical treatments for the most common motor and nonmotor symptoms in PD. Additionally, emerging new therapeutic options such as continuous pump therapies, eg, with apomorphine or parenteral levodopa, or the implantation of electrodes for deep brain stimulation were also considered. Keywords: Parkinson's disease, disease management, side effects, nonmotor symptoms, DBS, pump therapies

  12. Synthesis and in vivo distribution in the rat of a dopamine agonist: N-([11C]methyl)norapomorphine

    International Nuclear Information System (INIS)

    A method for the rapid production and purification of 10,11-dihydroxy-N-([11Cmethyl)norapomorphine ([11C]APO), a dopamine agonist (DA), is described. The potency of this ligand for studying the D2-receptors was examined. The label was introduced by N-methylation of norapomorphine hydrobromide with no-carrier-added (n.c.a.) [11C]CH3I, produced from cyclotron-produced [11C]carbon dioxide. In 60 min (EOB) a radiochemical yield of 15% (corrected for decay) was achieved, based on [11C]CH3I. The specific activity ranged from 5 to 11 GBq/μmol. The distribution, after intravenous injection, was studied in rats. The radioactivity level in the striatum was higher than in the cerebellum and frontal cortex and was decreased after D2-blockade. The highest uptake ratio (1.47) was found at 30 min after injection. Dopamine depletion with reserpine did increase the striatum/cerebellum ratio at a low dosage of [11C]APO (10 nmol/kg). High uptakes of [11C]apomorphine were found in the lungs, liver and kidneys. (author)

  13. Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat

    International Nuclear Information System (INIS)

    Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both the antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer

  14. Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease.

    Science.gov (United States)

    Herrera, Andrea; Muñoz, Patricia; Paris, Irmgard; Díaz-Veliz, Gabriela; Mora, Sergio; Inzunza, Jose; Hultenby, Kjell; Cardenas, Cesar; Jaña, Fabián; Raisman-Vozari, Rita; Gysling, Katia; Abarca, Jorge; Steinbusch, Harry W M; Segura-Aguilar, Juan

    2016-09-01

    L-Dopa continues to be the gold drug in Parkinson's disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson's disease. PMID:27001668

  15. Neuroprotective effects of pyrroloquinoline quinone against rotenone injury in primary cultured midbrain neurons and in a rat model of Parkinson's disease.

    Science.gov (United States)

    Zhang, Qi; Chen, Shuhua; Yu, Shu; Qin, Jiaojiao; Zhang, Jingjing; Cheng, Qiong; Ke, Kaifu; Ding, Fei

    2016-09-01

    Mitochondrial dysfunction and oxidative stress have been implicated in the pathogenesis of Parkinson's disease (PD). Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has been reported to protect SH-SY5Y cells from cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor. In this study, we aimed to investigate the neuroprotective effects of PQQ against rotenone injury in primary cultured midbrain neurons and in a rat model of Parkinson's disease. Pre-treatment with PQQ prevented cultured midbrain neurons from rotenone-induced apoptosis, restored mitochondrial membrane potential, inhibited intracellular reactive oxygen species (ROS) production, and affected microtubule depolymerization. On the other hand, intraperitoneal administration of PQQ exerted protective effects on rats that had received rotenone injection into the medial forebrain bundle through decreasing the apomorphine-evoked rotation, inhibiting neuronal loss and TH down-regulation in SNc, increasing the antioxidative ability, and regulating intracellular expressions of Ndufs1 and Ndufs 4. Silencing of Ndufs1 or Ndufs4 in cultured SH-SY5Y cells or midbrain neurons reduced the neuroprotective effects of PQQ. Overall, our results suggest that PQQ neuroprotection may be mediated by the inhibition of mitochondrial dysfunction and oxidative stress as well as by the gene modulation of Ndufs1 and Ndufs4. PMID:27108097

  16. Initial clinical experience with [123I]ioflupane scintigraphy in movement disorders

    International Nuclear Information System (INIS)

    Aim: The objective of this study was to determine whether dopamine transporter (DAT) scintigraphy influences the management of movement disorders in clinically indeterminate cases. Materials and methods: Seventeen patients (ten women, seven men; age range 44-84 years) with a presumptive diagnosis of Parkinson's disease (PD) were referred for single-photon emission computed tomography (SPECT) scintigraphy using [123I]ioflupane between November 2002 and August 2003. The scintigraphic results, clinical diagnosis, and management intentions pre- and post-examination were recorded. Results: Of the 17 patients who underwent scintigraphy, two patients on neuroleptic medication exhibited features of PD; one had an abnormal scintigraphic examination that confirmed PD, the other had a negative examination, confirming drug-induced parkinsonism, and these were managed accordingly. Of the other cases, the results of 10 examinations were compatible with PD. Five were reported as being normal, the final diagnoses in this group included: cerebrovascular disease (CVD); early Alzheimer's; provisional clinical diagnosis of generalized movement disorder; and possible Wilson's disease. One patient was felt to have a parkinsonian syndrome despite the normal result (this patient had a positive apomorphine test). Conclusion: This series illustrates the value of DAT scintigraphy in the management of clinically indeterminate movement disorders at a tertiary referral centre arguing for its use in the initial diagnostic process. However, it is clear that the use of DAT scintigraphy poses significant resource implications. Further evidence should clarify the exact role of DAT scintigraphy in clinically indeterminate cases

  17. MicroRNA-124 loaded nanoparticles enhance brain repair in Parkinson's disease.

    Science.gov (United States)

    Saraiva, C; Paiva, J; Santos, T; Ferreira, L; Bernardino, L

    2016-08-10

    Modulation of the subventricular zone (SVZ) neurogenic niche can enhance brain repair in several disorders including Parkinson's disease (PD). Herein, we used biocompatible and traceable polymeric nanoparticles (NPs) containing perfluoro-1,5-crown ether (PFCE) and coated with protamine sulfate to complex microRNA-124 (miR-124), a neuronal fate determinant. The ability of NPs to efficiently deliver miR-124 and prompt SVZ neurogenesis and brain repair in PD was evaluated. In vitro, miR-124 NPs were efficiently internalized by neural stem/progenitors cells and neuroblasts and promoted their neuronal commitment and maturation. The expression of Sox9 and Jagged1, two miR-124 targets and stemness-related genes, were also decreased upon miR-124 NP treatment. In vivo, the intracerebral administration of miR-124 NPs increased the number of migrating neuroblasts that reached the granule cell layer of the olfactory bulb, both in healthy and in a 6-hydroxydopamine (6-OHDA) mouse model for PD. MiR-124 NPs were also able to induce migration of neurons into the lesioned striatum of 6-OHDA-treated mice. Most importantly, miR-124 NPs proved to ameliorate motor symptoms of 6-OHDA mice, monitored by the apomorphine-induced rotation test. Altogether, we provide clear evidences to support the use of miR-124 NPs as a new therapeutic approach to boost endogenous brain repair mechanisms in a setting of neurodegeneration. PMID:27269730

  18. Action of (D-Pro4)-β-casomorphin/sub 1-5/ on processes of synaptic transmission

    International Nuclear Information System (INIS)

    The peptide (D-Pro4)-β-casomorphin/sub 1-5/ is a potent and long acting analgesic. Furthermore it is able to antagonize apomorphine-induced behavioral patterns, which are preferentially used as screening methods to detect dopaminolytic or neuroleptic properties. Because all of these tests do not exclude interaction of drugs with transmission systems other than the dopaminergic, biochemical studies were undertaken to estimate possible influences of the opioid peptide on processes of dopaminergic, serotonergic, and cholinergic transmission systems. In lower concentrations (D-Pro4)-β-casomorphin/sub 1-5/ enhances the potassium-stimulated release of acetylcholine from hippocampal slices and the basal overflow of dopamine from striatal slices. In high concentrations an augmentation of the potassium evoked release of dopamine and a reduction of the binding of [3h]spiperone on dopaminergic and serotonergic striatal receptors could be observed. These biochemical findings are discussed with regard to the behavioral patterns induced by this opioid peptide. (author)

  19. Peganum Harmala L. Extract Reduces Oxidative Stress and Improves Symptoms in 6-Hydroxydopamine-Induced Parkinson's Disease in Rats.

    Science.gov (United States)

    Rezaei, Maryam; Nasri, Sima; Roughani, Mehrdad; Niknami, Zeinab; Ziai, Seyed Ali

    2016-01-01

    Parkinson's disease is one of the most common neurodegenerative disorders. There are many documents about the effects of oxidative stress in Parkinson's disease etiology. Angiotensin II activates NADPH dependent oxidases and causes superoxides formation. Peganum harmala L. extract, which has angiotensin converting enzyme (ACE) inhibitory effect, is considered to evaluate oxidative stress inhibition and Parkinson's disease improvement. Male rats weighting 200-250 g were divided into 5 groups: Control, Neurotoxin (injection of 6-hydroxydopamine into left hemisphere substantia nigra), Peganum harmala's seeds aqueous extract (10 mg/kg) and captopril (5 mg/kg). Peganum harmala and captopril were injected intraperitonealy -144, -120, -96, -72, -48, -24, -2, 4 and 24 h relative to 6-hydroxydopamine injection time. Muscle stiffness, apomorphine induced unilateral rotation, amount of brain's protein oxidation and lipid peroxidation, ACE activity and histology of substantia nigra were assayed in all groups. Peganum harmala improved Muscle stiffness and one-direction rotation behavior significantly. It also reduced brain's lipid and protein oxidation levels in neurotoxin-injected rats significantly. In Peganum harmala group compared to control group, brain's ACE activity was significantly inhibited. In histological study, Peganum harmala prevented degeneration of dopaminergic neurons, too. In conclusion, aqueous extract of Peganum harmala could prevent symptoms and reduced oxidative stress markers in rats with Parkinson's disease induced by 6-hydroxydopamine. PMID:27610168

  20. Impulse control and related disorders in Parkinson's disease.

    Science.gov (United States)

    Weintraub, Daniel; Nirenberg, Melissa J

    2013-01-01

    Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized complication of dopamine replacement therapy in Parkinson's disease (PD). Other impulsive-compulsive behaviors have been linked to dopaminergic medications; these include punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), particularly at higher dosages; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Risk factors for ICDs may include male sex; younger age; younger age at PD onset; a pre-PD history of ICD(s); personal or family history of substance abuse; bipolar disorder; gambling problems; and impulsive personality traits. The primary treatment of ICDs in PD is discontinuation of DA therapy. Not all patients can tolerate this, however, due to worsening motor symptoms and/or DA withdrawal syndrome (a severe, stereotyped drug withdrawal syndrome similar to that of other psychostimulants). While psychiatric medications are frequently used to treat ICDs in the general population, there is no empirical evidence to suggest that they are effective in PD. Given the paucity of treatment options and potentially serious consequences of ICDs in PD, it is critical for patients to be monitored closely for their development. As empirically validated treatments for ICDs emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD. PMID:23038208

  1. Multicistronic lentiviral vector-mediated striatal gene transfer of aromatic L-amino acid decarboxylase, tyrosine hydroxylase, and GTP cyclohydrolase I induces sustained transgene expression, dopamine production, and functional improvement in a rat model of Parkinson's disease.

    Science.gov (United States)

    Azzouz, Mimoun; Martin-Rendon, Enca; Barber, Robert D; Mitrophanous, Kyriacos A; Carter, Emma E; Rohll, Jonathan B; Kingsman, Susan M; Kingsman, Alan J; Mazarakis, Nicholas D

    2002-12-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra. This loss leads to complete dopamine depletion in the striatum and severe motor impairment. It has been demonstrated previously that a lentiviral vector system based on equine infectious anemia virus (EIAV) gives rise to highly efficient and sustained transduction of neurons in the rat brain. Therefore, a dopamine replacement strategy using EIAV has been investigated as a treatment in the 6-hydroxydopamine (6-OHDA) animal model of PD. A self-inactivating EIAV minimal lentiviral vector that expresses tyrosine hydroxylase (TH), aromatic amino acid dopa decarboxylase (AADC), and GTP cyclohydrolase 1 (CH1) in a single transcription unit has been generated. In cultured striatal neurons transduced with this vector, TH, AADC, and CH1 proteins can all be detected. After stereotactic delivery into the dopamine-denervated striatum of the 6-OHDA-lesioned rat, sustained expression of each enzyme and effective production of catecholamines were detected, resulting in significant reduction of apomorphine-induced motor asymmetry compared with control animals (p < 0.003). Expression of each enzyme in the striatum was observed for up to 5 months after injection. These data indicate that the delivery of three catecholaminergic synthetic enzymes by a single lentiviral vector can achieve functional improvement and thus open the potential for the use of this vector for gene therapy of late-stage PD patients. PMID:12451130

  2. Clinical criteria for the diagnosis of Parkinson's disease.

    Science.gov (United States)

    Reichmann, Heinz

    2010-01-01

    The diagnosis of Parkinson's disease (PD) follows the UK Brain Bank Criteria, which demands bradykinesia and one additional symptom, i.e. rigidity, resting tremor or postural instability. The latter is not a useful sign for the early diagnosis of PD, because it does not appear before Hoehn and Yahr stage 3. Early symptoms of PD which precede the onset of motor symptoms are hyposmia, REM sleep behavioral disorder, constipation, and depression. In addition, an increasing number of patients whose PD is related to a genetic defect are being described. Thus, genetic testing may eventually develop into a tool to identify at-risk patients. The clinical diagnosis of PD can be supported by levodopa or apomorphine tests. Imaging studies such as cranial CT or MRI are helpful to distinguish idiopathic PD from atypical or secondary PD. SPECT and PET methods are valuable to distinguish PD tremor from essential tremor if this is clinically not possible. Using all of these methods, we may soon be able to make a premotor diagnosis of PD, which will raise the question whether early treatment is possible and ethically and clinically advisable. PMID:20616563

  3. Mucoadhesive Amphiphilic Methacrylic Copolymer-Functionalized Poly(ε-caprolactone) Nanocapsules for Nose-to-Brain Delivery of Olanzapine.

    Science.gov (United States)

    Fonseca, Francisco N; Betti, Andresa H; Carvalho, Flávia C; Gremião, Maria P D; Dimer, Frantiescoli A; Guterres, Sílvia S; Tebaldi, Marli L; Rates, Stela M K; Pohlmann, Adriana R

    2015-08-01

    Nose-to-brain drug delivery has been proposed to overcome the low absorption of drugs in central nervous system due to the absence of brain-blood barrier in the olfactory nerve pathway. However, the presence of a mucus layer and quick clearance limit the use of this route. Herein, amphiphilic methacrylic copolymer-functionalized poly(ε-caprolactone) nanocapsules were proposed as a mucoadhesive system to deliver olanzapine after intranasal administration. In vitro evaluations showed that these nanocapsules were able to interact with mucin (up to 17% of increment in particle size and 30% of reduction of particle concentration) and nasal mucosa (2-fold higher force for detaching), as well as to increase the retention of olanzapine (about 40%) on the nasal mucosa after continuous wash. The olanzapine-loaded amphiphilic methacrylic copolymer-functionalized PCL nanocapsules enhanced the amount of drug in the brain of rats (1.5-fold higher compared to the drug solution). In accordance with this finding, this formulation improved the prepulse inhibition impairment induced by apomorphine, which is considered as an operational measure of pre-attentive sensorimotor gating impairment present in schizophrenia. Besides, nanoencapsulated olanzapine did not affect the nasal mucosa integrity after repeated doses. These data evidenced that the designed nanocapsules are a promising mucoadhesive system for nose-to-brain delivery of drugs. PMID:26295147

  4. Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

    International Nuclear Information System (INIS)

    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 [3H]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

  5. Exploration of sex differences in Rhes effects in dopamine mediated behaviors

    Directory of Open Access Journals (Sweden)

    Quintero GC

    2011-11-01

    Full Text Available Gabriel C Quintero1,2, Daniela Spano31INDICASAT AIP, Centro de Neurociencias, Panamá, 2Department of Psychology, University of New Orleans, N Orleans, Louisiana, USA; 3CEINGE Biotechnologie Avanzate, Naples, ItalyAbstract: Studies have shown that Ras homolog enriched in striatum (Rhes proteins are highly expressed in areas of the central nervous system that have high dopaminergic innervation. In this study, we used Rhes mutant mice (Wild type, Rhes KO, Rhes Heterozygous of both sexes to explore differences in the effects of Rhes protein levels in basal levels of activity, anxiety, and stereotypy, in relation to sex. Adult male and female mice were evaluated in an open field test for measuring basal levels of activity and anxiety for 5 consecutive days, and they were tested in the apomorphine-induced stereotypy paradigm. Rhes protein levels affected basal levels of activity but it was not found to be related to sex differences. Moreover, a decrease in Rhes protein levels was linked to a nonsignificant anxiolytic effect, mainly in female mice. Finally, a decrease in Rhes protein levels does not affect dopamine D1 and D2 receptor (D1/D2 synergism in female or male mice. Together, these results suggest that Rhes protein levels affect locomotion activity, and have an influence in anxiety depending on sex; Rhes protein levels do not affect D1/D2 synergism in both sexes.Keywords: behavior, dopamine receptor, Rhes protein, mutant mice, sexes

  6. Panax notoginseng saponins influence on transplantation of neural stem cell-derived dopaminergic neurons in a rat model of Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Chunlong Ke; Baili Chen; Chao Yang; Heng Zhang; Zhengsong Huang

    2008-01-01

    BACKGROUND:Dopaminergic neurons differentiated from neural stem cells have been successfully used in the treatment of rat models of Parkinson's disease;however,the survival rate of transplanted cells has been low.Most cells die by apoptosis as a result of overloaded intracellular calcium and the formation of oxygen free radicals.OBJECTIVE:To observe whether survival of transplanted cells,transplantation efficacy.and dopaminergic differentiation from neural stem cells is altered by Panax notoginseng saponins(PNS) in a rat model of Parkinson's disease.DESIGN,TIME AND SETTING:Cellular and molecular biology experiments with randomized group design.The experiment was performed at the Animal Experimental Center,First Hospital of Sun Yat-sen University from April to October 2007.MATERIALS:Thirty-two adult,healthy,male Sprague Dawley rats,and four healthy Sprague Dawley rat embryos at gestational days 14-15 were selected.The right ventral mesenceDhalon was injected with 6-hydroxydopamine to establish a model of Parkinson's disease.6-hydroxydopamine and apomorphine were purchased from Sigma.USA.METHODS:Neural stem cells derived from the mesencephalon of embryonic rats were cultivated and passaged in serum-free culture medium.Lesioned animals were randomly divided into four groups(n=8):dopaminergic neuron,dopaminergic neuron+PNS,PNS,and control.The dopaminergic neuron group was iniected with 3 μ L cell suspension containing dopaminergic neurons difierentiated from neural stem cells.The dopaminergic neurons+PNS group received 3 μ L dopaminergic cell suspension combined with PNS (250 mg/L).The PNS group received 3 μL PNS(250 mg/L),and the control group received 3 μL DMEM/F12 culture medium.MAIN OUTCOME MEASURES:The rats were transcardially perfused with 4% paraformaldehyde at 60 days post-grafting for immunohistochemistry.The rats were intraperitoneally injected with apomorphine (0.5 mg/kg)to induce rotational behavior.RESULTS:Cell counts of tyrosine hydroxylase

  7. Effects of long term and excessive intake of ethanol on sexual function of rats%长期大量饮酒对大鼠性功能的影响

    Institute of Scientific and Technical Information of China (English)

    甘秀国; 安瑞华; 王涌泉; 单丽芬

    2006-01-01

    [Objective] To investigate the effects of long term and excessive intake of ethanol on sexual function of the rats. [Methods] Thirty adult male Wistar rats were randomly divided into three groups: the control group,20% ethanol group and 40% ethanol group. 0.9% natric chloride、20% and 40% ethanol solution were administered with a dose of 2ml through gastric tubes in the rats every day. Three monthes later, the effects of ethanol on sexual function were studied by sexual behavior, the number of apomorphine-induced penile erection, testosterone in the sera and nitric oxide synthase(NOS) in the penis. [Results] Compared with the control group, sexual behavior,testosterone in the sera and NOS activity in the penis of 20% ethanol group and 40% ethanol group were inhibited significantly (P<0.05). The number of apomorphine-induced penile erection was also decreased notably in 40%ethanol group(P<0.05). [Conclusion] Long term and excessive intake of ethanol can induce sexual dysfunction in rats. The decline of testosterone in the sera and NOS in the penis may be responsible for it.%目的 本实验探讨长期大量饮酒对大鼠性功能的影响.方法 将30只雄性大鼠随机分为对照组,20%酒精剂量组和40%酒精剂量组.分别以生理盐水、20%和40%食用酒精各2 mL给大鼠灌胃,每日1次.3个月后,观察各组大鼠性行为和药物诱发阴茎勃起的变化;用酶放大物理发光仪测定各组大鼠血清睾酮的含量;测定阴茎平滑肌中一氧化氮合成酶的总量.结果 与对照组相比,20%酒精剂量组和40%酒精剂量组大鼠性行为、血清睾酮含量和阴茎组织中一氧化氮合成酶活性有统计学意义(P<0.05),40%酒精剂量组大鼠的药物诱发阴茎勃起实验也受到抑制(P<0.05).结论 大鼠长期大量饮酒后性功能障碍,其机制与血浆睾酮含量降低,阴茎组织中一氧化氮合成酶活性降低有关.

  8. Transplantation of microencapsulated human retinal pigment epithelial cells in Parkinsonian rats%微囊化人视网膜色素上皮细胞移植治疗帕金森病的实验研究

    Institute of Scientific and Technical Information of China (English)

    李锐; 宗伟; 郭民侠; 蒋宏伟

    2009-01-01

    目的 观察微囊化人视网膜色素上皮(RPE)细胞移植治疗帕金森病(PD)大鼠的疗效. 方法 采用机械分离法和酶消化法原代培养人RPE细胞,传代后用高压静电微胶囊成型装置制作海藻酸钠-多聚赖氨酸-海藻酸钠微囊化细胞,将其立体定向移植人6-羟基多巴胺(6-OHDA)所致的PD模型大鼠的右侧纹状体.实验分为模型组、裸细胞(RPE)组、空囊对照(APA)组以及微囊化细胞(APA-RPE)组.检测各组大鼠移植前后阿朴吗啡诱导的旋转行为变化和移植后8周纹状体中多巴胺(DA)的含量. 结果 APA-RPE组大鼠在移植后4周阿朴吗啡诱发的旋转次数[(6.25±1.04)r/min]开始减少,与移植前[(12.88±7.34)r/min]相比减少幅度为51.48%,至第8周[(5.87±2.03)r/min]减少更加明显,减少幅度为54.43%,差异均有统计学意义(P<0.05);与模型组[(108.14±1.89)mol/L]比较,APA-RPE组移植后8周[(342.63±28.32)mol/L]大鼠纹状体DA含量明显增加,差异有统计学意义(P<0.05),而RPE组和APA组未见明显变化. 结论 微囊化人RPE细胞对PD大鼠模型有治疗作用,可作为一种前景良好的治疗PD的方法 进一步研究.%Objective To observe the therapeutic effect of microencapsulated human retinal pigment epithelial (RPE) cell transplantation into the striatum in a rat model of Parkinson' disease (PD). Methods Cultured RPE cells were microencapsulated by alginate-polylysine-alginate (APA) using a high voltage electrostatic system. The Parkinsonian rats were divided into 4 groups, namely the model group, RPE group, APA group and RPE-APA group, and in the latter 3 groups, RPE cells, empty APA microcapsules and APA-capsulated RPE cells, respectively, were transplanted into the right striatum of the rats via stereotactic surgery. After the transplantation, the changes in apomorphine-induced rotation of the rats were investigated and the striatum DA contents were measured with high-performance liquid chromatography with

  9. Treatment of Parkinson's disease: nanostructured sol–gel silica–dopamine reservoirs for controlled drug release in the central nervous system

    Directory of Open Access Journals (Sweden)

    Tessy López

    2010-12-01

    Full Text Available Tessy López1–3, José L Bata-García4, Dulce Esquivel5,2, Emma Ortiz-Islas2, Richard Gonzalez3, Jorge Ascencio6, Patricia Quintana7, Gerko Oskam7, Fernando J Álvarez-Cervera4, Francisco J Heredia-López4, José L Góngora-Alfaro41Departamento de Atención a la Salud, UAM-Xochimilco. Calzada del Hueso, Coyoacán, México; 2Laboratorio de Nanotecnología. Instituto Nacional de Neurología y Neurocirugía MVS, Tlalpan, México; 3Departamento de Química e Ingeniería Biomolecular, Universidad de Tulane, New Orleans, USA; 4Departamento de Neurociencias, Centro de Investigaciones Regionales "Dr Hideyo Noguchi", Universidad Autónoma de Yucatán, Mérida, Yucatán; 5Universidad de Guanajuato, Centro de Investigaciones en Química Inorgánica, Noria Alta Guanajuato; 6Instituto de Ciencias Físicas-UNAM, Cuernavaca; 7Departamento de Física Aplicada, CINVESTAV-IPN, Mérida, Yucatán, MéxicoIntroduction: We have evaluated the use of silica–dopamine reservoirs synthesized by the sol–gel approach with the aim of using them in the treatment of Parkinson's disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface.Methods: Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica–dopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine

  10. 海绵体神经损伤所致ED大鼠模型建立%Rat model of erectile dysfunction caused by cavernous nerve ablation

    Institute of Scientific and Technical Information of China (English)

    张新华; 胡礼泉; 尹静; 莫曾南; 陈坚

    2002-01-01

    目的寻找大鼠海绵体神经并建立神经损伤所致ED大鼠模型.方法对20只大鼠进行解剖,在外科显微镜下找到海绵体神经并经电刺激试验证实.随后将42只实验大鼠随机分为假手术对照组、单侧海绵体神经损伤组及双侧海绵体神经损伤组.术后3周用阿朴吗啡试验来评估所建动物模型.结果盆主要神经节位于背侧前列腺后外侧叶表面,其最大的传出神经就是海绵体神经.诱发阴茎勃起的电刺激参数是:电压5V、刺激频率20Hz及刺激时间5ms.术后3周,阿朴吗啡均能诱发对照组大鼠阴茎勃起,30分钟内平均勃起次数为2.57±1.40,实验组大鼠,无论单侧损伤还是双侧损伤,均丧失勃起功能(0.00±0.00).结论大鼠较大的盆主要神经节及海绵体神经易于辨认,电刺激反应明显,而且大鼠价格便宜,易于饲养及购买,是建立海绵体神经损伤性ED模型的理想动物.此外还发现,无论是单侧海绵体神经损伤还是双侧损伤,损伤后早期,大鼠均丧失勃起功能.%Objective To identify the rat cavernous nerve and establish a rat model of erectile dysfunction (ED) caused by injury of the cavernous nerve. Methods Twenty rats underwent dissections. Cavernous nerves were identified with the aid of an operating microscope and confirmed by electrical stimulation. Then, 42 experimental rats were randomized into 3 groups, including sham-operated controls and unilateral and bilateral cavernous nerve ablation groups. Three weeks after surgery, rat models were evaluated with the Apomorphine test.Results The major pelvic ganglion lies on either side of the dorsolateral lobes of the prostate. It includes 2 inflows, one called hypogastric nerve and the other, the pelvic nerve. The largest outflow is termed the cavernous nerve. Stimulus parameters which could induce obvious penile erection were 5 volts, a frequency of 20 Hertz and a duration of 5 milliseconds. Three weeks after surgery, apomorphine

  11. 化合物XZ07抗精神分裂症活性及作用机制研究%Effects of compound XZ07 on schizophrenia models in mice and its mechanism

    Institute of Scientific and Technical Information of China (English)

    魏雅芹; 徐祥清

    2012-01-01

    Objective To investigate the effects of compound XZ07 on schizophrenia models in mice and its mechanism. Methods Using apomorphine - induced mice climbing model and MK - 801 - induced mice hyperlocomotion model to examine the effects of compound XZ07 on schizophrenia. The affinities of compound XZ07 on rat D2 and 5 - HT1A , 5 - HT2A receptors were evaluated in vitro binding assays using the radioligands [ 3H ] 8 - OH - DPAT , [ 3H ] -Ketanserin,[3 H ]-Spiperone,respectively. Results Compared with model group, compound XZ07 dose - dependently decreased the climbing scores in apomorphine -induced climbing test,meanwhile it also significantly inhibited the spontaneous activity ( P < 0.01 ) in MK - 801 - induced hyperlocomotion test at the dose of 10 and 30 mg/kg, but at low dose ( 3 mg/kg ) it had no affects on the spontaneous activity. At the in vitro binding test compound XZ07 showed high affinity on D2 and 5 - HT1A, 5 - HT2A receptors. Conclusion Compound XZ07 has effects on schizophrenia, its mechanism may be involved in 5 - HT1A , 5 - HT2A and D2 receptors.%目的 了解化合物XZ07抗精神分裂症活性,并对其作用机制进行初步探讨.方法 采用阿扑吗啡诱导小鼠攀爬模型及地卓西平(MK-801 )诱导小鼠高活动性模型,观察化合物XZ07对模型小鼠攀爬行为及活动总路程的影响来了解化合物XZ07抗精神分裂活性;大鼠断头取脑后提取脑内多巴胺(D2)、5-羟色胺1A(5-HT1A)及5-羟色胺2A(5-HT2A)受体蛋白,采用体外配体受体结合试验,通过观察化合物XZ07与D2、5-HT1A及5-HT2A受体的亲和性来初步了解其作用机制.结果 化合物XZ07高、中、低3个剂量都能剂量依赖性地抑制阿朴吗啡小鼠攀爬行为,显著减少小鼠攀爬试验中评分(P<0.01);化合物XZ07高、中剂量能显著减少MK-801诱导的高活动性小鼠90 min内总活动路程(P<0.01);体外受体试验发现,化合物XZ07与D2、5-HT1A及5-HT2A受体均具有较高的亲和力.结论

  12. Research of methods for implantation of deep brain electrode under guidance from microelectrode recordings in monkeys with hemiparkinsonism%微电极引导偏侧帕金森病猴脑深部电极植入方法的研究

    Institute of Scientific and Technical Information of China (English)

    陈磊; 李楠; 王学廉; 高立; 杨晨; 汪鑫; 马久红

    2012-01-01

    目的 微电极记录(MER)联合MRI建立丘脑底核偏侧帕金森病猴脑深部电刺激(DBS)模型.方法 4只恒河猴在DSA下经一侧颈内动脉注射MPTP制作偏侧帕金森病模型,采用Kurlan Scale量表及阿扑吗啡实验评估模型效果.3.0T MRI扫描数据输入Leksell系统预定靶点坐标值,MER记录双侧丘脑底核电信号,确定靶点,植入电极并固定.术后MRI查看电极位置.结果 Kurlan Scale量表评分和阿扑吗啡实验表明:偏侧帕金森病模型建立成功.MER记录到两侧丘脑底核放电,且给药侧放电频率明显高于给药对侧(P<0.01);其修正MRI预定坐标值,术后MRI复查电极末端均位于丘脑底核内.结论 MER是MRI显影不清时丘脑底核定位的必要补充,MER联合MRI可以成功建立定位精确的丘脑底核偏侧帕金森病猴DBS模型.%Objective To establish deep brain stimulation (DBS) model of the subthalamic nucleus (STN) in monkeys with hemiparkinsonism by microelectrode recording (MER) and MRI. Methods MPTP was injected into the unilateral internal carotid in 4 rhesus macaques under DSA to establish hemiparkinsonism model, and the model result was evaluated by Kurlan Scale and apomorphine test The target coordinate was reserved by 3.0T MRI scan data input Leksell system. MER recorded electrical signal of bilateral STN and determined the target, then the electrode was implanted and fixed according to the data of MER. The electrode position was checked by MRI postoperatively. Results Kurlan Scale scores and apomorphine test showed that the hemiparkinsonism model was established successfully. MER recorded the electrical discharge of bilateral STN, and the rate of electrical discharge at the side with MPTP injection was obviously higher than that at the other side (P<0.01). The reserved coordinate by MRI was revised by MER, and all the ends of electrodes were situated in the STN by MRI postoperatively. Conclusions MER is a necessary complement to locating the STN

  13. Characterization of Behavioral and Image of Completely Unilaterally Lesioned Parkinson Rat Model%完全毁损型偏侧帕金森病大鼠模型的行为及影像特征

    Institute of Scientific and Technical Information of China (English)

    王志忠; 姚昊; 欧阳小辉; 何宝明; 张婷

    2011-01-01

    为研究完全毁损型偏侧帕金森病大鼠模型的行为和影像学改变,建立完全毁损型偏侧帕金森病大鼠模型.观察模型大鼠在自然状态下和阿朴吗啡诱导中出现的异常行为学改变,Micro-PET模型大鼠神经系统功能改变.帕金森病大鼠模型在行为学上表现了在自发状态下的患肢运动感觉能力降低.在阿朴吗啡诱导下出现对侧旋转及异常不自主运动.影像学上表现为损毁侧纹状体内多巴胺转运蛋白缺失及毁损侧纹状体、皮层及丘脑的功能活性降低.说明完全毁损型偏侧帕金森病大鼠模型表现为单侧肢体的运动感觉功能障碍和损毁侧纹状体内多巴胺能神经末梢的缺失及相应区域的脑功能降低,类似于人类严重的帕金森末期阶段强直运动功能障碍的表现.%The characterization of behavioral and image of completely unilaterally 6-hydoxydopamine-lesioned Parkinson rat model were investigated. Methods are gaven two 6-hydoxydopamine injection into right medial forebrain bundle ( MFB) to setup completely unilaterally Parkinson rat model and observered their abnormal behavioral under both nature and apomorphine used situation. The 11C-β-CFT and 18FDG Micro-PET are used to image change of the ability of the region of the rat brain.Results are compared with the inactive side, the initiation of stepping movements by the left (contra-lateral) paw are greatly reduced, the initial time is prolonged and the rate of using left paw reduced when the rat in the nature situation; under the apomorphine inducing, the rats show the contraversive rotation and abnormal involuntary movement, such as limb dyskinesia ,axial dystonia and masticatory dyskinesia. The 11C-β-CFT image show the depletion of presynaptic maker DAT in the lesion side of the striatum and the FDG image showes the reduced ability in the lesion side. It is conclused that completely unilaterally Parkinson rat model shows extensive neuropathology and

  14. 疏肝益阳胶囊对动脉性勃起功能障碍大鼠性功能及性腺质量的作用%Effect of Shuganyiyang Capsules on Sexual Function and Sex Gland Weight in Rats with Arteriogenic Erectile Dysfunction

    Institute of Scientific and Technical Information of China (English)

    王济; 白明华; 刘保兴; 杨寅; 杨玲玲; 王琦

    2013-01-01

    目的 观察中药疏肝益阳胶囊对动脉性勃起功能障碍(arteriogenic erectile dysfunction,AED)模型大鼠性功能及睾丸和附属性腺器官质量的改善作用.方法 选取3月龄成年雄性SD大鼠50只,采用双侧髂内动脉结扎法复制AED模型.设假手术组、模型组、西地那非组(每日10.5 mg/kg)、疏肝益阳胶囊大剂量组(每日1 g/kg)、疏肝益阳胶囊小剂量组(每日0.5 g/kg),每组10只,灌胃给药,疗程30 d.行阿朴吗啡(apomorphine,APO)试验检测性功能,取双侧睾丸及附睾、前列腺、精囊腺、球海绵体肌,称湿质量并计算质量系数.结果 APO试验显示疏肝益阳胶囊大、小剂量可显著增加AED大鼠30 min内阴茎勃起次数(P<0.01).疏肝益阳胶囊大、小剂量可显著增加AED大鼠睾丸、附睾、球海绵体肌质量系数(P<0.05).结论 疏肝益阳胶囊可明显改善AED大鼠的性功能,并可使睾丸及其附属性器官质量系数显著增加.%Objective To observe the effect of Shuganyiyang (SGYY) Capsules (for dispersing stagnated liver qi and nourishing yang) on the sexual function and the weights of testes and accessory sex glands in rats with arteriogenic erectile dysfunction (AED). Methods Fifty male Sprague-Dawley rats aged 3 months were selected in the study. Bilateral internal iliac artery ligation was used to induce a rat model of AED. The rats were randomly and equally divided into sham operation group, model group, sidenafil (10. 5 mg/kg daily) group, high-dose SGYY Capsule (1 g/kg daily) group, and low-dose SGYY Capsule (0. 5 g/kg daily) group and received their respective treatments by intragastric administration for 30 d. The sexual function of rats in each group was evaluated by apomorphine (APO) test. The bilateral testes and epididymides, prostate, seminal vesicle, and bulbocavernosus muscle of rats were collected; the wet weight of each organ was measured, and the weight coefficient was calculated. Results The APO test showed that

  15. Avaliação de compostos com atividade antioxidante em células da levedura Saccharomyces cerevisiae Evaluation of compounds with antioxidant activity in Saccharomyces cerevisiae yeast cells

    Directory of Open Access Journals (Sweden)

    Daniele Grazziotin Soares

    2005-03-01

    biological tests, the antioxidant capacity of L- ascorbic acid, vitamin E (alpha-tocoferol and the flavonoids hesperidin, naringin, naringenin, quercetin, rutin and sukuranetin. The study was carried out on eukaryotic cells of the yeast Saccharomyces cerevisiae treated with the above mentioned antioxidants in the presence of the stressing agent apomorphine. The results obtained showed that rutin, hesperidin, sakuranetin, quercetin and naringin were the most effective/potent antioxidant compounds followed by naringenin and a-tocopherol. Vitamin C and a mixture of vitamins C and E did not show antioxidant activity against apomorphine in the performed conditions of this work.

  16. The effect of GSH,GSSG and GSH/GSSG on eNOS expression in the penile corpus cavernosum of DMED rats%糖尿病大鼠阴茎海绵体GSH、GSSG和GSH/GSSG对eNOS表达的影响

    Institute of Scientific and Technical Information of China (English)

    曹会峰; 马龙; 胡存利; 罗振国; 杜从林; 桂士良

    2016-01-01

    Objective To investigate effects of GSH, GSSG and GSH/GSSG on the expression of eNOS in the penile corpus cavernosum of DMED rats.Methods Thirty healthy male Sprague Dawley (SD) rats aged 8 weeks were randomly divided into the control group (C group, 8 rats) and diabetes mellitus (DM) model group(D group, 22 rats). The rats in D group were fed with high calorie and high sugar diet for 4 weeks, then intraperitioneally injected with streptozotocin (STZ, 40mg/kg) to establish diabetes mellitus rat models. The rats in C group were given normal diet. At eighth weeks after STZ injection, the rats were injected with apomorphine, and their penile erections were observed to evaluate their erectile function. All rats were killed after detection of the maximal intracavernous pressure/mean arterial blood pressure(ICPmax/MAP) using electrostmulation, levels of GSH, GSSG and testosterone in plasma and penis were measured, and the expression of eNOS in the penile corpus cavernosum was examined by immunohistochemistry and Western blot.Results Compared with those of the controls (C group), the expression levels of GSH, GSH/GSSG in the plasma and eNOS in the penile tissue of the model rats with diabetes mellitus were all decreased markedly(P<0.05), whereas GSSG level was significantly increased(P<0.05).Conclusion The low level of GSH and GSH/GSSG in the plasma and high concentration of GSSG in the penile corpus cavernosum of the diabetic rats will downregulate the expression of eNOS, which may be an important pathological mechanism for diabetes mellitus erectile dysfunction.%目的:探究在糖尿病大鼠阴茎海绵体中还原型谷胱甘肽(GSH)、氧化型谷胱甘肽(GSSG)和GSH/GSSG对内皮型一氧化氮合酶(eNOS)表达的影响。方法30只SD级8周龄健康雄性大鼠,8只作为正常对照组(C组),剩余22只作为糖尿病实验组(D组);D组大鼠高脂高糖喂养4周后腹腔注射链脲佐菌素(40mg/kg)建DM模型;C组大鼠

  17. 骨髓间充质干细胞改善糖尿病大鼠勃起功能障碍的研究%Effect of bone marrow mesenchymal stem cells on improving erectile dysfunction in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    聂永华; 肖明朝; 苟欣; 汤为学; 陈力学; 蔡贤福

    2012-01-01

    目的:探讨骨髓间充质干细胞(Bone marrow mesenchymal stem cells,BMMSCs)移植到大鼠阴茎海绵体组织后对勃起功能的影响.方法:体外分离培养BMMSCs并利用形态学及流式细胞术进行鉴定证实.用腹腔注射链脲左菌素(Streptozotocin,STZ)建立糖尿病性大鼠模型,并用阿扑吗啡(Apomorphine,APO)筛选出糖尿病勃起功能障碍(Diabetes mellitus induced erectile dysfunction,DMED)大鼠模型,成模后将BMMSCs(2×106个)移植于大鼠阴茎海绵体内.2周后,分别对正常组、糖尿病组及治疗组进行海绵体内压(Intracorporeal pressure,ICP)及平均动脉压(Mean arterial blood pressure,MAP)测定并取大鼠阴茎海绵体组织,荧光显微镜下观察BMMSCs的局部存活情况,苏木素-伊红染色(Hematoxylin and eosin,HE)观察阴茎海绵体组织中血管.结果:荧光显微镜观察提示BMMSCs能在糖尿病大鼠体内存活;勃起功能测定结果表明治疗组大鼠ICP/MAP比值明显高于糖尿病组;HE染色结果显示在治疗组大鼠阴茎海绵体中血管数目[(12.75±1.89)根/HP]多于糖尿病组[(8.05±1.43)根/HP].结论:BMMSCs能够有效改善糖尿病性大鼠勃起功能.%Objective:To study the effect of bone marrow mesenchymal stem cells(BMMSCs) transplanted into corpus cavernosum on improving erectile dysfunction in diabetic rats. Methods: BMMSCs were separated and cultivated in vitro,then were identified by morphological method and flow cytometry. The diabetic rat model was constructed by intrapertoneal injection of streptozotocin(STZ), then model of diabetes mellitus induced erectile dysfunction(DMED) was sieved by apomorphine(APO). BMMSCs(2×l06 pieces) were transplanted into the corpus cavernosum of the rats in DMED model. Two weeks later.the intracorporeal pressure(ICP) and mean arterial blood pressure(MAP) of normal group,diabetic group and treatment group were determined respectively,the surviving and differentiation of BMMSCs in corpus cavernosum was

  18. 硫酸镁对6-羟基多巴胺诱导的帕金森病模型大鼠血中褪黑素的影响%Effect of magnesium on serum melatonin in a rat model of Parkinson' s Disease

    Institute of Scientific and Technical Information of China (English)

    马杰; 周全; 袁苏涛; 孟涛; 林玲

    2012-01-01

    Objective To explore the relationship between magnesium (Mg) and melatonin (MLT) by observation serum MLT levels in advanced Parkinson' s disease (PD) rats,and to clarify the effect of magnesium on serum melatonin in PD model.Methods PD rat model was established by a unilateral injection of 6-OHDA into the right substantia nigra pars compacta (SNc) and the right medial forebrain bundle (MFB).Rats of control group received saline injection.Twenty animals were divided into four groups.PD model (PD/H2O) and control/H2O groups were vehicle-treated rats,and received drinking water (magnesium sulphate vehicle) daily.Magnesium sulphate (MgSO40.36 g/kg/day dissolved in drinking water) was administered in rats of PD/Mg and control/Mg groups for four weeks.Then apomorphine-induced rotational behaviour,serum MLT levels and histological changes were tested.Results The level of MLT in PD groups was ( 153.4 ±29.8) pg/L,which distinctly higher than those in the controls (77.2 ±13.7) pg/L,while the levels of MLT in PD model and control rats receiving Mg were decreased to ( 126.8 ± 15.9) pg/L and (53.4 ± 18.1 ) pg/L respectively.MLT levels appeared to correlate well with the frequency of apomorphine-induced rotations.The frequency of rotations in PD/Mg group decreased compared with those in PD/H2O group.Conclusion The rotational behaviour in advanced PD rat might ameliorated by magnesium,and magnesium may partly inhibit compensatory increased MLT.%目的 观察晚期帕金森病(PD)大鼠血中褪黑素的变化,以及硫酸镁对这种变化的影响.方法 6-羟基多巴胺(6-OHDA)损毁黑质纹状体通路制备PD模型,大鼠分为PD模型组(PD/H2O)、PD加镁组(PD/Mg)、对照组(对照组/H2O)、对照加镁组(对照组/Mg).大鼠通过饮水摄入硫酸镁(每天0.36 g/kg),4周后观察其对阿扑吗啡诱发的旋转行为,并采用酶联免疫吸附试验(ELISA)检测褪黑素水平.结果 PD鼠血清褪黑素水平为(153.4±29.8) pg/L,明显高于对照组(77.2

  19. Discriminative stimulus properties of the dopamine D3 antagonist PNU-99194A.

    Science.gov (United States)

    Franklin, S R; Baker, L E; Svensson, K A

    1998-07-01

    It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct lever choice after a median of 35.5 sessions (range 23-78). In substitution tests, the non-selective D2 receptor antagonist, haloperidol (0.01- 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2-32 mg/kg) and sulpiride (32-200 mg/kg), failed to produce stimulus generalization, while the D3-preferring antagonists, (-)-DS121 (1-10 mg/kg) and (+)-AJ76 (3.2-32 mg/kg), produced complete stimulus generalization. Direct and indirect DA agonists, including apomorphine (0.01-0.32 mg/kg) and d-amphetamine (0.1-1 mg/kg), the D1 agonist SKF38393 (10-100 mg/kg), the D2 selective agonist PNU-95666E (0.32-3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032-1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism. PMID:9694525

  20. Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

    Science.gov (United States)

    Yu, Yong-Peng; Ju, Wei-Ping; Li, Zhen-Guang; Wang, Dao-Zhen; Wang, Yuan-Chen; Xie, An-Mu

    2010-06-01

    Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system. PMID:20399757

  1. Induction of adult human bone marrow mesenchymal stromal cells into functional astrocyte-like cells: potential for restorative treatment in Parkinson's disease.

    Science.gov (United States)

    Bahat-Stroomza, Merav; Barhum, Yael; Levy, Yossef S; Karpov, Olga; Bulvik, Shlomo; Melamed, Eldad; Offen, Daniel

    2009-09-01

    Parkinson's disease (PD) is a neurodegenerative disorder with its motor phenomena due mostly to loss of dopamine-producing neurons in the substantia nigra. Pharmacological treatments aimed to increase the deficient dopaminergic neurotransmission are effective in ameliorating the cardinal symptoms, but none of these therapies is curative. It has been suggested that treatment with neurotrophic factors (NTFs) might protect and prevent death of the surviving dopaminergic neurons and induce proliferation of their axonal nerve terminals with reinnervations of the deafferented striatum. However, long-term delivery of such proteins into the CNS is problematic. We therefore aimed to differentiate ex vivo human bone marrow-derived mesenchymal stromal cells into astrocyte-like cells, capable of generating NTFs for future transplantation into basal ganglia of PD patients. Indeed, mesenchymal stromal cells treated with our novel astrocyte differentiation medium, present astrocyte-like morphology and express the astrocyte markers S100beta, glutamine synthetase and glial fibrillary acidic protein. Moreover, these astrocyte-like cells produce and secrete significant amounts of glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor as indicated by messenger RNA, real-time polymerase chain reaction, ELISA, and Western blot analyses. Such NTF-producing cells transplanted into the striatum of 6-hydroxydopamine-lesioned rats, a model of PD, produced a progressive reduction in the apomorphine-induced contralateral rotations as well as behavioral improvement in rotor-rod and the "sunflower seeds" eating motor tests. Histological assessments revealed that the engrafted cells survived and expressed astrocyte and human markers and acted to regenerate the damaged dopaminergic nerve terminal system. Findings indicate that our novel procedure to induce NTF-producing astrocyte-like cells derived from human bone marrow stromal cells

  2. Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging.

    Science.gov (United States)

    Delfino, Marina; Kalisch, Raffael; Czisch, Michael; Larramendy, Celia; Ricatti, Jimena; Taravini, Irene R E; Trenkwalder, Claudia; Murer, Mario Gustavo; Auer, Dorothee P; Gershanik, Oscar S

    2007-09-01

    The mechanisms underlying dopamine agonist-induced dyskinesia in Parkinson's disease remain poorly understood. Similar to patients, rats with severe nigrostriatal degeneration induced by 6-hydroxydopamine are more likely to show dyskinesia during chronic treatment with unselective dopamine receptor agonists than with D2 agonists, suggesting that D1 receptor stimulation alone or in conjunction with D2 receptor stimulation increases the chances of experiencing dyskinesia. As a first step towards disclosing drug-induced brain activation in dyskinesia, we examined the effects of dopamine agonists on behavior and blood oxygenation level-dependent (BOLD) signal in the striatum and motor cortex of rats with unilateral nigrostriatal lesions. Rats were rendered dyskinetic before pharmacologic functional magnetic resonance imaging by means of a repeated treatment regime with dopamine agonists. The unselective agonist apomorphine and the selective D1/D5 agonist SKF-81297 induced strong forelimb dyskinesia (FD) and axial dystonia and increased BOLD signal in the denervated striatum. Besides, SKF-81297 produced a significant but smaller BOLD increase in the intact striatum and a symmetric bilateral increase in the motor cortex. The D2 family agonist quinpirole, which induced mild dyskinesia on chronic treatment, did not produce BOLD changes in the striatum or motor cortex. Further evidence to support an association between BOLD changes and dyskinesia comes from a direct correlation between scores of FD and magnitude of drug-induced BOLD increases in the denervated striatum and motor cortex. Our results suggest that striatal and cortical activation induced by stimulation of D1/D5 receptors has a primary role in the induction of peak dose dyskinesia in parkinsonism. PMID:17287822

  3. Pharmacological effects of dopaminergic drugs on in vivo binding of [99mTc]TRODAT-1 to the central dopamine transporters in rats

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the influence of drugs competing for the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine levels on the binding of a novel technetium-99m labeled tropane derivative, technetium, [2-[[2-[[[3-(4-chloro-phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo-exo)]-, [99mTc]TRODAT-1, to DAT. This paper describes the further characterization of [99mTc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [99mTc]TRODAT-1 into male Sprague-Dawley rats. The biodistribution studies were performed in the presence of drugs which compete for the binding site. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. It is likely that a low dose of l-DOPA (normally needed in the treatment of Parkinson's disease) will not affect the results on [99mTc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [99mTc]TRODAT-1 binding to DAT in vivo. Competition for [99mTc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [99mTc]TRODAT-1. (orig.)

  4. Effects of prenatal and postnatal maternal ethanol on offspring response to alcohol and psychostimulants in long evans rats.

    Science.gov (United States)

    Barbier, E; Houchi, H; Warnault, V; Pierrefiche, O; Daoust, M; Naassila, M

    2009-06-30

    An important factor that may influence addiction liability is exposure during the early life period. Exposure to ethanol, early in life, can have long-lasting implications on brain function and drugs of abuse response later in life. In the present study we investigated the behavioral responses to ethanol and to psychostimulants in Long Evans rats that have been exposed to pre- and postnatal ethanol. Since a relationship between heightened drug intake and susceptibility to drug-induced locomotor activity/sensitization has been demonstrated, we tested these behavioral responses, in control and early life ethanol-exposed animals. The young adult male and female progeny were tested for locomotor response to alcohol, cocaine and d-amphetamine. Sedative, rewarding effects of alcohol and alcohol consumption were measured. Our results show that early life ethanol exposure behaviorally sensitized animals to subsequent ethanol and psychostimulants exposure. Ethanol-exposed animals were also more sensitive to the hyperlocomotor effects of all drugs of abuse tested and to those of the dopamine receptor agonist apomorphine. Locomotor sensitization to repeated injections of cocaine was facilitated in ethanol-exposed animals. Ethanol-induced conditioned place preference was also facilitated in ethanol-exposed animals. Ethanol consumption and preference were increased after early life ethanol exposure and this was associated with decreased sensitivity to the sedative effects of ethanol. The altered behavioral responses to drugs of abuse were associated with decreased striatal dopamine transporter and hippocampal NMDAR binding. Our results outline an increased vulnerability to rewarding and stimulant effects of ethanol and psychostimulants and support the epidemiological and clinical data that suggested that early chronic exposure to ethanol may increase the propensity for later self-administration of ethanol or other substances. PMID:19348874

  5. Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats.

    Science.gov (United States)

    Lazenka, Matthew F; Legakis, Luke P; Negus, S Stevens

    2016-06-01

    Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56-158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam, and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticlopride, and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1- and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. (PsycINFO Database Record PMID:26987070

  6. Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors.

    Directory of Open Access Journals (Sweden)

    Hélène Hall

    Full Text Available Intraneuronal inclusions containing alpha-synuclein (a-syn constitute one of the pathological hallmarks of Parkinson's disease (PD and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.

  7. Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat.

    Science.gov (United States)

    Tricklebank, M D; Forler, C; Middlemiss, D N; Fozard, J R

    1985-10-29

    The 5-HT receptor subtypes involved in the mediation of reciprocal forepaw treading and the flat body posture induced by the central 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), were examined in intact rats and in rats depleted of monoamines with reserpine. Forepaw treading in non-reserpinised rats was antagonised by the 5-HT2 receptor antagonist, ketanserin, only at doses in excess of those required for occupation of a large proportion of 5-HT2 receptors in brain, and at which there was significant inhibition of stereotyped sniffing induced by the dopamine receptor agonist, apomorphine. Since forepaw treading induced by 5-MeODMT was also blocked in intact rats by haloperidol, blockade of the behaviour by ketanserin may more accurately reflect antagonism at dopamine receptors than at 5-HT2 receptors. In reserpinised rats, i.e. with minimised contributions from other monoamine systems, neither forepaw treading nor the flat body posture were significantly altered by ketanserin, haloperidol or the beta 1- and beta 2-selective adrenoceptor antagonists, betaxolol and ICI 118.551, making a key role for 5-HT2 receptors, dopamine receptors and beta-adrenoceptors unlikely. In contrast, forepaw treading in both reserpinised and non-reserpinised rats was antagonised stereoselectively by pindolol and by spiperone, which interact with 5-HT1 and 5-HT1A recognition sites. The results are consistent with the hypothesis that forepaw treading induced by 5-MeODMT arises by activation of the putative 5-HT1A receptor. Antagonism of the flat body posture by pindolol could be demonstrated only in non-reserpinised rats and the mechanism of induction of this behaviour remains to be established. PMID:2935408

  8. BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation

    Directory of Open Access Journals (Sweden)

    Elizabeth E Manning

    2013-06-01

    Full Text Available Brain-derived neurotrophic factor (BDNF has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the

  9. Evaluation of nigrostriatal damage and its change over weeks in a rat model of Parkinson's disease: small animal positron emission tomography studies with [11C]β-CFT

    International Nuclear Information System (INIS)

    Introduction: The cardinal pathological feature of Parkinson's disease (PD) is progressive loss of dopaminergic neurons. Since dopamine transporter (DAT) is a protein located presynaptically on dopaminergic nerve terminals, radioligands that bind to these sites are promising radiopharmaceuticals for evaluation of the integrity of the dopamine system. This study using positron emission tomography (PET) tracers, [11C]-2β-carbomethoxy-3β-(4-fluorophenyl)-tropane ([11C]β-CFT, radioligand for DAT), was aimed at evaluating the degree of nigrostriatal damage and its change over weeks in a rat model of PD. Methods: The brains of these rats were unilaterally lesioned by mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB). Behavioral studies were carried out by apomorphine (APO) challenge prior to and 1, 2 and 4 weeks after MFB axotomy. Small animal PET scans were performed 2 days after the behavioral test. Immunohistochemistry was conducted 4 days after the last PET scan. Results: Compared with the contralateral intact side, a progressively decreased [11C]β-CFT binding was observed on the lesioned side which correlated inversely with the APO-induced rotations. Postmortem immunohistochemical studies confirmed the loss of both striatal dopamine fibers and nigral neurons on the lesioned side. Conclusion: These findings not only demonstrate that the neuronal degeneration in this model is relatively slow, but also suggest [11C]β-CFT is a sensitive marker to monitor the degree of nigrostriatal damage and its change over weeks. This marker can be used prospectively to study the progression of the disease, thereby making detection of early phases of PD possible.

  10. Dopamine Dysregulation Syndrome and other psychiatric problems in Parkinson’s Disease: Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    Sibel Ertan

    2011-06-01

    Full Text Available In a small number of patients with Parkinson’s disease (PD, a series of behavioral disorders included within the spectrum of impulsive-compulsive disorders develop under the dopamine replacement therapy (DRT. These behaviors are grouped into three as “impulse control disorders (ICD” characterized by rewards-seeking behaviors, “punding” characterized by aimless, ritualist stereotypical repetative behaviors, and “dopamine dysregulation syndrome (DDS” characterized by drug overuse due to chemical addiction. The prevalance of DDS in PD was reported to be around 3-4%. Patients with DDS have an urge to increase their dopaminergic doses beyond their needs for parkinsonien symptoms. DDS is reported to be more common especially in patients with an early onset of disease, high doses of DRT, previous history of or current depression, history of alcohol or substance abuse, and in those having impulsive personality constantly seeking for a change or novelty. DDS is commonly observed in association with “punding” and ICD. The pathophysiology underlying these disorders is explained by specific mechanisms in addition to DRT. Dopamine is not only responsible in the control of the movement, but also plays an important role in the modulation of brain reward systems. The potential maladaptive dysfunction of the mesolimbic dopaminergic system underlies the pathogenesis of DDS. Although the most potent trigger of DDS in PD is known as L-dopa, subcutaneous apomorphine and oral dopamine agonists could also be responsible from the development of DDS. The patients and caregivers should be informed for these behavioral disorders that might emerge under DRT, the possible risk factors should be questioned before dopaminergic therapy, and the choice of drug should be made under these concerns. In patients with DDS, fast-acting DRT formulations should be avoided. In DDS cases associated with hypomaniac or psychotic episodes, treatment should made with

  11. Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study

    International Nuclear Information System (INIS)

    Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D2 type in mammals. The present study assessed, in the frog, both the anatomical localization of D2-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [125I]iodosulpride-labelled D2 binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D2 antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity.In the frog olfactory bulb, both anatomical localization of D2-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  12. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse Nucleus Accumbens

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    Giuseppe eGangarossa

    2013-02-01

    Full Text Available The nucleus accumbens (NAc is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP or the Cre-recombinase (Cre under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific ERK phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist, quinpirole (a D2R-like agonist, apomorphine (a non-selective DA receptor agonist, raclopride (a D2R-like antagonist, and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study.

  13. Visualisation of serotonin-1A (5-HT{sub 1A}) receptors in the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Passchier, J.; Waarde, A. van [PET Center, University Hospital Groningen (Netherlands)

    2001-01-01

    The 5-HT{sub 1A} subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT{sub 1A} receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-{sup 11}C] WAY-100635 (WAY), [carbonyl-{sup 11}C]desmethyl-WAY-100635 (DWAY), p-[{sup 18}F]MPPF and [{sup 11}C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT{sub 1A} receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  14. Cognitive Judgment Bias Interacts with Risk Based Decision Making and Sensitivity to Dopaminergic Challenge in Male Rats.

    Science.gov (United States)

    Drozd, Robert; Cieslak, Przemyslaw E; Rychlik, Michal; Rodriguez Parkitna, Jan; Rygula, Rafal

    2016-01-01

    Although the cognitive theory has implicated judgment bias in various psychopathologies, its role in decision making under risk remains relatively unexplored. In the present study, we assessed the effects of cognitive judgment bias on risky choices in rats. First, we trained and tested the animals on the rat version of the probability-discounting (PD) task. During discrete trials, the rats chose between two levers; a press on the "small/certain" lever always resulted in the delivery of one reward pellet, whereas a press on the "large/risky" lever resulted in the delivery of four pellets. However, the probability of receiving a reward from the "large/risky" lever gradually decreased over the four trial blocks. Subsequently, the rats were re-trained and evaluated on a series of ambiguous-cue interpretation (ACI) tests, which permitted their classification according to the display of "optimistic" or "pessimistic" traits. Because dopamine (DA) has been implicated in both: risky choices and optimism, in the last experiment, we compared the reactivity of the dopaminergic system in the "optimistic" and "pessimistic" animals using the apomorphine (APO; 2 mg/kg s.c.) sensitivity test. We demonstrated that as risk increased, the proportion of risky lever choices decreased significantly slower in "optimists" compared with "pessimists" and that these differences between the two groups of rats were associated with different levels of dopaminergic system reactivity. Our findings suggest that cognitive judgment bias, risky decision-making and DA are linked, and they provide a foundation for further investigation of the behavioral traits and cognitive processes that influence risky choices in animal models. PMID:27601984

  15. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction.

    Science.gov (United States)

    Wu, Chi-Rei; Tsai, Chia-Wen; Chang, Shu-Wei; Lin, Chia-Yuan; Huang, Li-Chun; Tsai, Chia-Wen

    2015-01-01

    The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of γ-glutamate-cysteine ligase catalytic subunit, γ-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD. PMID:25446857

  16. Correction of diabetic erectile dysfunction with adipose derived stem cells modified with the vascular endothelial growth factor gene in a rodent diabetic model.

    Directory of Open Access Journals (Sweden)

    Guihua Liu

    Full Text Available The aim of this study was to determine whether adipose derived stem cells (ADSCs expressing vascular endothelial growth factor (VEGF gene can improve endothelial function, recover the impaired VEGF signaling pathway and enhance smooth muscle contents in a rat diabetic erectile dysfunction (DED model. DED rats were induced via intraperitoneal injection of streptozotocin (40 mg/kg, and then screened by apomorphine (100 µg/kg. Five groups were used (n = 12/group-Group 1 (G1: intracavernous injection of lentivirus-VEGF; G2: ADSCs injection; G3: VEGF-expressing ADSCs injection; G4: Phosphate buffered saline injection; G1-G4 were DED rats; G5: normal rats. The mean arterial pressure (MAP and intracavernosal pressure (ICP were measured at days 7 and 28 after the injections. The components of the VEGF system, endothelial, smooth muscle, pericytes markers in cavernoursal tissue were assessed. On day 28 after injection, the group with intracavernosum injection of ADSCs expressing VEGF displayed more efficiently and significantly raised ICP and ICP/MAP (p<0.01 than those with ADSCs or lentivirus-VEGF injection. Western blot and immunofluorescent analysis demonstrated that improved erectile function by ADSCs-VEGF was associated with increased expression of endothelial markers (VEGF, VEGF R1, VEGF R2, eNOS, CD31 and vWF, smooth muscle markers (a-actin and smoothelin, and pericyte markers (CD146 and NG2. ADSCs expressing VEGF produced a therapeutic effect and restored erectile function in diabetic rats by enhancing VEGF-stimulated endothelial function and increasing the contents of smooth muscle and pericytes.

  17. 脑内移植NGF诱导的PC-12细胞治疗大鼠帕金森病的研究%Treatment with the Transplantation of Induced PC-12 by NGF in Parkinsonian Rats

    Institute of Scientific and Technical Information of China (English)

    刘晓志; 段相林; 钱忠明; 常彦忠

    2007-01-01

    实验利用SD大鼠复制6-羟多巴胺(6-hydroxydopamine,6-OHDA)完全损伤型帕金森动物模型,将神经生长因子(nerve growth factor,NGF)处理后的肾上腺嗜铬细胞瘤细胞(plleoclxromocytoma cells,PC-12)移植人模型大鼠纹状体内,观察模型动物行为改善和移植PC-12细胞的存活情况.经行为学检测,6-OHDA动物模型复制成功率达55.1%.免疫组织化学、蛋白印迹检测结果显示模型动物黑质多巴胺能神经元数目减少,黑质酪氨酸羟化酶含量降低证明模型动物稳定、可靠.PC-12细胞经NGF(50 μg/L)连续诱导7 d,细胞逐渐平展、细胞膜变皱褶等神经元形态学特征出现后,于纹状体内行细胞移植术,经阿普吗啡(apomorphine,APO)诱导旋转行为有明显改善,蛋白印迹检测也发现移植侧具有显著的酪氨酸羟化酶免疫阳性信号.因此,NGF诱导后的PC-12细胞可以作为治疗帕金森的一种细胞供体.

  18. Effect of dopamine on food-hoarding in Mongolian gerbils (Meriones unguiculatus)%多巴胺对长爪沙鼠贮食行为的影响

    Institute of Scientific and Technical Information of China (English)

    杨慧娣; 王倩; 王德华

    2015-01-01

    长爪沙鼠的贮食行为具有高低二型性.禁食诱导的贮食行为可能与中脑多巴胺(Dopamine,DA)系统有关,但尚乏证据.本文通过Fos标记相关脑区的活性,酪氨酸羟化酶(TH)标记DA神经元,以免疫组化方法观察对高贮食组长爪沙鼠腹腔注射DA拮抗剂haloperidol(1 mg/kg)和对低贮食组长爪沙鼠腹腔注射DA激动剂apomorphine(0.3 mg/kg)的行为和神经变化,验证中枢DA对贮食行为的调节.结果显示,haloperidol抑制了禁食诱导的沙鼠的贮食行为,这种抑制刺激了伏隔核和尾壳核Fos-ir阳性细胞表达,但却降低了黑质区Fos-ir和Fos-ir/TH-ir的细胞表达.Apomorphine增加了禁食诱导的沙鼠的贮食行为,降低伏隔核和尾壳核Fos-ir阳性细胞表达.这些结果表明,中脑DA系统参与调节了禁食条件下长爪沙鼠的贮食行为.

  19. 远志3,6'-二芥子酰基蔗糖在药物诱发抑郁模型上的药效评价%Antidepressant Effect of 3',6-Disinapoyl Sucrose from Polygala tenuifolia Willd in Pharmacological Depression Model

    Institute of Scientific and Technical Information of China (English)

    刘屏; 王东晓; 郭代红; 涂海华; 马亮; 谢婷婷; 孔令义

    2008-01-01

    目的 在药物诱发抑郁模型上观察3,6'-二芥子酰基蔗糖(3',6-disinapoyl sucrose,DISS)的抗抑郁作用及可能的作用机制.方法 采用小鼠5-羟色胺酸(5-hydroxytryptophan,5-HTP)增强实验,小鼠育亨宾(yohimbine,YOH)毒性增强实验,小鼠阿朴吗啡(apomorphine,APO)诱导体温下降实验探讨DISS的抗抑郁作用及可能的作用环节,用小鼠自主活动监测仪记录小鼠自发活动行为.结果 在小鼠5-HTP增强实验模型上,给予DISS,对5-HTP诱导的小鼠甩头行为具有显著增强作用.在小鼠YOH毒性增强实验模型上,DISS可增强YOH毒性作用.在小鼠APO诱导体温下降实验模型上,ig给予DISS有显著性的拮抗体温降低的作用.结论 DISS在药理学抑郁模型有显著的抗抑郁活性.并且其抗抑郁活性与增强5-羟色胺(5-HT)和去甲肾上腺素能(NE)神经功能均有关.DISS在抗抑郁有效剂量范围内无中枢兴奋或抑制性作用.

  20. Intrastriatal injection of botulinum neurotoxin-A is not cytotoxic in rat brain - A histological and stereological analysis.

    Science.gov (United States)

    Mehlan, Juliane; Brosig, Hans; Schmitt, Oliver; Mix, Eilhard; Wree, Andreas; Hawlitschka, Alexander

    2016-01-01

    Parkinson's disease (PD) is caused by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in a deficiency of dopamine in the striatum and an increased release of acetylcholine by tonically active interneurons. Botulinum neurotoxin-A (BoNT-A) is well known for blocking transmitter release by cholinergic presynaptic terminals. Treating striatal hypercholinism by local application of BoNT-A could be a possible new local therapy option of PD. In previous studies of our group, we analyzed the effect of BoNT-A injection into the CPu of 6-OHDA lesioned hemiparkinsonian rats. Our studies showed that BoNT-A application in hemiparkinson rat model is capable of abolishing apomorphine induced rotations for approximately 3 months. Regularly occurring axonal swellings in the BoNT-A infiltrated striata were also discovered, which we named BoNT-A induced varicosities (BiVs). Résumé: Here we investigated the long-term effect of the injection of 1ng BoNT-A into the right CPu of naive Wistar rats on the number of ChAT-ir interneurons as well as on the numeric density and the volumetric size of the BiVs in the CPu. Significant differences in the number of ChAT-ir neurons between the right BoNT-A treated CPu and the left untreated CPu were not detected up to 12 month post BoNT-A injection. The numeric density of BiVs in the treated CPu reached a maximum 3 months after BoNT-A treatment and decreased afterwards, whereas the volume of single BiVs increased steadily throughout the whole time course of the experiment. PMID:26562665

  1. Phenotypic modulation of corpus cavernosum smooth muscle cells in a rat model of cavernous neurectomy.

    Directory of Open Access Journals (Sweden)

    Fan Yang

    Full Text Available Patients undergoing radical prostatectomy (RP are at high risk for erectile dysfunction (ED due to potential cavernous nerve (CN damage during surgery. Penile hypoxia after RP is thought to significantly contribute to ED pathogenesis.We previously showed that corpora cavernosum smooth muscle cells (CCSMCs undergo phenotypic modulation under hypoxic conditions in vitro. Here, we studied such changes in an in vivo post-RP ED model by investigating CCSMCs in bilateral cavernous neurectomy (BCN rats.Sprague-Dawley rats underwent sham (n = 12 or BCN (n = 12 surgery. After 12 weeks, they were injected with apomorphine to determine erectile function. The penile tissues were harvested and assessed for fibrosis using Masson trichrome staining and for molecular markers of phenotypic modulation using immunohistochemistry and western blotting. CCSMC morphological structure was evaluated by hematoxylin-eosin (H&E staining and transmission electron microscopy (TEM.Erectile function was significantly lower in BCN rats than in sham rats. BCN increased hypoxia-inducible factor-1α and collagen protein expression in corpora cavernous tissue. H&E staining and TEM showed that CCSMCs in BCN rats underwent hypertrophy and showed rough endoplasmic reticulum formation. The expression of CCSMC phenotypic markers, such as smooth muscle α-actin, smooth muscle myosin heavy chain, and desmin, was markedly lower, whereas vimentin protein expression was significantly higher in BCN rats than in control rats.CCSMCs undergo phenotype modulation in rats with cavernous neurectomy. The results have unveiled physiological transformations that occur at the cellular and molecular levels and have helped characterize CN injury-induced ED.

  2. Pharmacological effects of dopaminergic drugs on in vivo binding of [{sup 99m}Tc]TRODAT-1 to the central dopamine transporters in rats

    Energy Technology Data Exchange (ETDEWEB)

    Dresel, S.H.J.; Kung, M.P.; Ploessl, K.; Meegalla, S.K. [Department of Radiology, University of Pennsylvania, Philadelphia (United States); Kung, H.F. [Department of Radiology, University of Pennsylvania, Philadelphia (United States)]|[Department of Pharmacology, University of Pennsylvania, Philadelphia (United States)

    1998-01-01

    The purpose of this study was to investigate the influence of drugs competing for the dopamine transporter (DAT) or changing intra- and/or extracellular dopamine levels on the binding of a novel technetium-99m labeled tropane derivative, technetium, [2-[[2-[[[3-(4-chloro- phenyl)-8-methyl-8-azabicyclo[3, 2, 1]oct-2-yl]methyl] (2-mercaptoethyl)amino]ethyl]amino]ethanethiolato(3)]-oxo-[1R-(exo-exo)]-, [{sup 99m}Tc]TRODAT-1, to DAT. This paper describes the further characterization of [{sup 99m}Tc]TRODAT-1 binding sites in rats under conditions which may exist in patients receiving various drug treatments. All experiments were carried out using an i.v. injection of [{sup 99m}Tc]TRODAT-1 into male Sprague-Dawley rats. The biodistribution studies were performed in the presence of drugs which compete for the binding site. Additionally, the influence of dopamine receptor agonists, such as apomorphine and (+)bromocriptine, on biodistribution was tested. It is likely that a low dose of l-DOPA (normally needed in the treatment of Parkinson`s disease) will not affect the results on [{sup 99m}Tc]TRODAT-1 single-photon emission tomographic (SPET) imaging studies. In conclusion, the results clearly demonstrate the specificity of [{sup 99m}Tc]TRODAT-1 binding to DAT in vivo. Competition for [{sup 99m}Tc]TRODAT-1 binding was observed only with drug treatment that significantly increases dopamine levels or actively competes for binding at DAT. The results suggest that prior knowledge of whether patients are receiving various drug treatments may assist in the interpretation of DAT status as assessed by SPET imaging studies using [{sup 99m}Tc]TRODAT-1. (orig.) With 4 figs., 1 tab., 73 refs.

  3. Antinociceptive Activity of Trichilia catigua Hydroalcoholic Extract: New Evidence on Its Dopaminergic Effects

    Directory of Open Access Journals (Sweden)

    Alice F. Viana

    2011-01-01

    Full Text Available Trichilia catigua is a native plant of Brazil; its barks are used by some local pharmaceutical companies to prepare tonic drinks, such as Catuama. The present study was addressed to evaluate the effects of T. catigua hydroalcoholic extract in mouse nociception behavioral models, and to evaluate the possible mechanisms involved in its actions. Male Swiss mice were submitted to hot-plate, writhing and von Frey tests, after oral treatment with T. catigua extract (200 mg kg−1, p.o.. The extract displayed antinociceptive effect in all three models. For characterization of the mechanisms involved in the antinociceptive action of the extract, the following pharmacological treatments were done: naloxone (2.5 mg kg−1, s.c., SR141716A (10 mg kg−1, i.p., SCH23390 (15 μg kg−1, i.p., sulpiride (50 mg kg−1, i.p., prazosin (1 mg kg−1, i.p., bicuculline (1 mg kg−1, i.p. or dl-p-chlorophenylalanine methyl ester (PCPA, 100 mg kg−1, i.p.. In these experiments, the action of T. catigua extract was evaluated in the hot-plate test. The treatment with SCH23390 completely prevented the antinociceptive effect, while naloxone partially prevented it. The possible involvement of the dopaminergic system in the actions of T. catigua extract was substantiated by data showing the potentiation of apomorphine-induced hypothermia and by the prevention of haloperidol-induced catalepsy. In conclusion, the antinociceptive effects of T. catigua extract seem to be mainly associated with the activation of dopaminergic system and, to a lesser extent, through interaction with opioid pathway.

  4. Why can't rodents vomit? A comparative behavioral, anatomical, and physiological study.

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    Charles C Horn

    Full Text Available The vomiting (emetic reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver, Ctenohystrica (guinea pig, nutria, and squirrel-related (mountain beaver species. Prototypical emetic agents, apomorphine (sc, veratrine (sc, and copper sulfate (ig, failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted. These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew. Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.

  5. Ag and Au nanoparticles for SERS substrates produced by pulsed laser ablation

    Energy Technology Data Exchange (ETDEWEB)

    Agarwal, N.R.; Castiglioni, C.; Lucotti, A. [DCMIC, Politecnico di Milano, Milano (Italy); Fazio, E.; Neri, F. [Dip. Fisica della Materia e Ingegneria Elettronica, Universita di Messina, Messina (Italy); Trusso, S. [CNR- Istituto per i Processi Chimico-Fisici, Messina (Italy); Santo, N. [Centro Interdipartimentale Microscopia Avanzata, Universita degli Studi di Milano, Milano (Italy); Ossi, P.M. [Dip. Energia, Politecnico di Milano, Milano (Italy)

    2011-08-15

    A method for the growth of films consisting of Nanoparticles (NP) of Ag and Au is presented. Nanostructured films were obtained by means of nanosecond pulsed laser ablation of a metallic target in presence of a controlled Ar atmosphere. The morphology of these films from island structures to isolated nanoparticles, measured by SEM, depends on the varying gas pressure (10-100 Pa) and on the number of laser pulses (500-30000), keeping other deposition parameters such as the target to substrate distance, incidence angle, laser wavelength, laser fluence constant. Fast imaging of the plasma, performed using a intensified and gateable CCD camera at different time delays with respect to the arrival of the laser pulse, allows revelation of the propagation regime of the ablation plume and inference of plasma initial velocity. This data along with the measured average ablated mass per pulse were taken as inputs to a model to estimate the average size of NPs grown in the expanding plume. The theoretical NP sizes were compared with sizes measured from TEM images. These images indicate narrow gradients of NP sizes. Hence strict control of growth parameters aids fine tuning of NP size that is essential for many applications, including Surface Enhanced Raman Spectroscopy (SERS) active substrates. UV-Visible Spectroscopy helped in determination of appropriate laser wavelength for resonant excitation of the localized surface plasmon. SERS Spectra obtained with increasingly lower concentrations of reference dye Rhodamin 6G (Rh6G) and medical drug Apomorphine, are discussed as a perspective of application to biomedical sensors. (copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  6. Dopaminergic Neurotransmission in the Nucleus Accumbens Modulates Social Play Behavior in Rats.

    Science.gov (United States)

    Manduca, Antonia; Servadio, Michela; Damsteegt, Ruth; Campolongo, Patrizia; Vanderschuren, Louk Jmj; Trezza, Viviana

    2016-08-01

    Social play behavior is a highly rewarding form of social interaction displayed by young mammals. Social play is important for neurobehavioral development and it has been found to be impaired in several developmental psychiatric disorders. In line with the rewarding properties of social play, we have previously identified the nucleus accumbens (NAc) as an important site of action for endocannabinoid and opioid modulation of this behavior. NAc dopamine has a well-known role in certain components of reward processes, such as incentive motivation. However, its contribution to the positive emotional aspects of social interactions is less clear. Therefore, we investigated the role of dopaminergic neurotransmission in the NAc in social play behavior in rats. We found that intra-NAc infusion of the dopamine releaser/reuptake inhibitor amphetamine increased social play behavior that was dependent on activation of both D1 and D2 dopamine receptors. This increase in social play behavior was mimicked by intra-NAc infusion of the dopamine receptor agonist apomorphine, but not of the dopamine reuptake inhibitor GBR-12909. Blockade of either D1 or D2 NAc dopamine receptors reduced social play in animals highly motivated to play as a result of longer social isolation before testing. Last, blockade of NAc dopamine receptors prevented the play-enhancing effects of endocannabinoid and opioid receptor stimulation. These findings demonstrate an important modulatory role of NAc dopaminergic neurotransmission in social play. Thus, functional activity in the mesolimbic dopamine pathway plays an important role in adaptive social development, whereas abnormal NAc dopamine function may underlie the social impairments observed in developmental psychiatric disorders such as autism, attention deficit hyperactivity disorder or early-onset schizophrenia. PMID:26860202

  7. The effect of cilostazol on erectile function in diabetic rat model%西洛他唑对糖尿病模型大鼠勃起功能的影响

    Institute of Scientific and Technical Information of China (English)

    窦红珍; 肖明朝; 苟欣; 李国秧; 李静

    2009-01-01

    目的:探讨西洛他唑对精尿病模型大鼠勃起功能的影响.方法:50只SD雄性大鼠腹腔注射链脲佐菌素建立糖尿病动物模型,成模8周后随机分为糖尿病对照组(DM组)和西洛他唑治疗组(CI组),同时喂养10只大鼠为正常对照组(C组).各组动物灌服西洛他唑[20mg/kg·d)]或者NS.灌胃处理8周后用阿朴吗啡(Apomorphine,APO)诱导法观察勃起功能,用电生理方法测定坐骨神经的运动神经传导速度(Motor merve conduction velocity,MNCV);并取阴茎海绵体组织用比色法检测一氧化氮合酶(Nitric oxide synthaes,NOS)水平,用TUNEL法观察阴茎海绵体平滑肌细胞凋亡情况.结果:与DM组相比,CI组的勃起功能、MNCV、NOS水平明显改善,凋亡指数显著降低(P<0.05).结论:西洛他唑对DM大鼠勃起功能的下降具有明显治疗作用.

  8. Behavioural effects of basal ganglia rho-kinase inhibition in the unilateral 6-hydroxydopamine rat model of Parkinson's disease.

    Science.gov (United States)

    Inan, Salim Yalcin; Soner, Burak Cem; Sahin, Ayse Saide

    2016-08-01

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders, which affects more than six million people in the world. While current available pharmacological therapies for PD in the early stages of the disease usually improve motor symptoms, they cause side effects, such as fluctuations and dyskinesias in the later stages. In this later stage, high frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment option which is most successful to treat drug resistant advanced PD. It has previously been demonstrated that activation of Rho/Rho-kinase pathway is involved in the dopaminergic cell degeneration which is one of the main characteristics of PD pathology. In addition, the involvement of this pathway has been suggested in diverse cellular events in the central nervous system; such as epilepsy, anxiety-related behaviors, regulation of dendritic and axonal morphology, antinociception, subarachnoid haemorrhage, spinal cord injury and amyotrophic lateral sclerosis. However, up to date, to our knowledge there are no previous reports showing the beneficial effects of the potent Rho-kinase inhibitor Y-27632 in the 6-hydroxydopamine (6-OHDA) rat model of PD. Therefore, in the present study, we investigated the behavioural effects of basal ganglia Y-27632 microinjections in this PD model. Our results indicated that basal ganglia Y-27632 microinjections significantly decreased the number of contralateral rotations-induced by apomorphine, significantly increased line crossings in the open-field test, contralateral forelimb use in the limb-use asymmetry test and contralateral tape playing time in the somatosensory asymmetry test, which may suggest that Y-27632 could be a potentially active antiparkinsonian agent. PMID:26996632

  9. Effects of chronic renal failure on the expression of connexin 43 in the rat's corpus cavernosum

    Institute of Scientific and Technical Information of China (English)

    Qiang Fu; Jia-Jv Lv; Hui Zhang

    2008-01-01

    Aim: To explore the mechanism of chronic renal failure (CRF)-related erectile dysfunction (ED). Methods: CRF experimental models were established by 5/6 nephrectomy from male Sprague-Dawley rats. Both the rats from the control group (NCRF group, n = 6) and the experimental group (CRF group, n = 30) were injected with a low dose (80 μg/kg) of apomorphine in the 12th week after resection surgery to measure corresponding penile erections.Western blot method was thereafter conducted to measure the expression of connexin 43 (CX43) in the rat corpus cavernosum in the 12th week after the resection surgery. Results: There was one death in the NCRF group and five in the CRF group. The penile erection ratio of the CRF group was 28% (7/25), whereas that of the NCRF group was 100% (5/5), which presents a significant difference between the two groups (P < 0.05). In terms of penile erection frequency, the average of the CRF group was 1.0±0.0, which was significantly different from that of the NCRF group (2.2±0.8) (P < 0.05). As for the expression of CX43 in the rat corpus cavernosum, a notable difference existed between the CRF group (0.21±0.07) and the NCRF group (0.53±0.27) (P < 0.01). Conclusion: CRF signifi-cantly reduces the erectile function of rats. A close correlation exists between the expression of CX43 in rats' corpus cavemosum and CRF-related ED.

  10. Environment-contact administration of rotenone: A new rodent model of Parkinson's disease.

    Science.gov (United States)

    Liu, Yan; Sun, Jian-Dong; Song, Lian-Kun; Li, Jing; Chu, Shi-Feng; Yuan, Yu-He; Chen, Nai-Hong

    2015-11-01

    Epidemiological studies suggest an association between pesticides and the incidence of Parkinson's disease (PD). Individuals are likely to be exposed to numerous natural or synthetic environmental agents by ingestion, inhalation, or skin contact. Here, we describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. Our results showed that rotenone exposure had no detrimental effect on body weights of mice during 6 weeks, nor did it cause systemic toxicity (HPLC analysis of rotenone in blood and brain, as well as complex I activity measurements in brain and muscle), but it caused significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of α-synuclein in the substantia nigra and striatum (α-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. Furthermore, we observed that α-synuclein accumulated in the anterior olfactory nucleus and the enteric nervous system at 2 weeks. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Therefore, it provides new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies. PMID:26239001

  11. Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Gu Qing

    2009-06-01

    Full Text Available Abstract Background New strategies for the treatment of Parkinson's disease (PD are shifted from dopamine (DA replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE cells as substitution for degenerated dopaminergic (DAergic neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA. Methods We evaluated the protective effects of conditioned medium (CM from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF and brain derived neurotrophic factor (BDNF released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR. Results We report here: (1 CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2 cultured RPE cells express L-dopa decarboxylase (DDC and synthesize DA; (3 RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4 GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues. Conclusion These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.

  12. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Xingli Deng

    Full Text Available Striatal transplantation of dopaminergic (DA neurons or neural stem cells (NSCs has been reported to improve the symptoms of Parkinson's disease (PD, but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.

  13. AB211. Effect of early chronic low-dose tadalafil administration on erectile dysfunction after cavernous nerve injury in the rat model

    Science.gov (United States)

    Bian, Jun; Liu, Cundong; Yang, Jiankun; Zhou, Qizhao; Sun, Xiangzhou; Deng, Chunhua

    2016-01-01

    Objective To investigate the effect of early chronic tadalafil administration on erectile dysfunction after cavernous nerve (CN) injury in the rat model. Methods Using the CN crush injury model, animals were divided into four groups: no CN injury (sham), bilateral CN injury exposed to either no tadalafil (control) or tadalafil at a dose (2 mg/kg) daily postoperation for 4 weeks, and normal group. At the time point, we assessed erectile function by apomorphine test, measurement of maximum intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio with major pelvic ganglion (MPG) electrical stimulation. For the histological analyses, the mid-shaft of penis were harvested. Immunohistochemical antibody staining was performed for nNOS and the numbers of nNOS-positive nerve fibers were recorded. Results Penile erection was observed in 50% (6/12) of the rats for (1.13±0.92) times within 30 min in control group, as compared with 0% (0/11) of the rats for (0.00±0.00) times in CN crush group (P0.05), while ICP/MAP ratio after MPG electrical stimulation of control group was significantly higher than that of CN crush group (P<0.05), but significantly lower than that of sham group (P<0.05) and normal group (P<0.05). The numbers of nNOS-positive nerve fibers was significantly larger in control group than in CN crush group (54.11±5.02 vs. 21.34±3.17, P<0.05), but was significantly smaller than that of sham group (76.48±8.24, P<0.05) and normal group (81.09±7.25, P<0.05). Conclusions Early chronic low-dose tadalafil administration on erectile dysfunction after CN injury contributes to restoration of erectile function.

  14. Initial clinical experience with [{sup 123}I]ioflupane scintigraphy in movement disorders

    Energy Technology Data Exchange (ETDEWEB)

    Manoharan, P. [Department of Radiology, Leeds General Infirmary, Leeds (United Kingdom)]. E-mail: prakashmanoharan@yahoo.co.uk; Jamieson, S. [Department of Neurology, Leeds General Infirmary, Leeds (United Kingdom); Bury, R.F. [Department of Radiology, Leeds General Infirmary, Leeds (United Kingdom)

    2007-05-15

    Aim: The objective of this study was to determine whether dopamine transporter (DAT) scintigraphy influences the management of movement disorders in clinically indeterminate cases. Materials and methods: Seventeen patients (ten women, seven men; age range 44-84 years) with a presumptive diagnosis of Parkinson's disease (PD) were referred for single-photon emission computed tomography (SPECT) scintigraphy using [{sup 123}I]ioflupane between November 2002 and August 2003. The scintigraphic results, clinical diagnosis, and management intentions pre- and post-examination were recorded. Results: Of the 17 patients who underwent scintigraphy, two patients on neuroleptic medication exhibited features of PD; one had an abnormal scintigraphic examination that confirmed PD, the other had a negative examination, confirming drug-induced parkinsonism, and these were managed accordingly. Of the other cases, the results of 10 examinations were compatible with PD. Five were reported as being normal, the final diagnoses in this group included: cerebrovascular disease (CVD); early Alzheimer's; provisional clinical diagnosis of generalized movement disorder; and possible Wilson's disease. One patient was felt to have a parkinsonian syndrome despite the normal result (this patient had a positive apomorphine test). Conclusion: This series illustrates the value of DAT scintigraphy in the management of clinically indeterminate movement disorders at a tertiary referral centre arguing for its use in the initial diagnostic process. However, it is clear that the use of DAT scintigraphy poses significant resource implications. Further evidence should clarify the exact role of DAT scintigraphy in clinically indeterminate cases.

  15. Interactions of dopaminergic agonists and antagonists with dopaminergic D3 binding sites in rat striatum. Evidence that (/sup 3/H)dopamine can label a high affinity agonist-binding state of the D1 dopamine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.E.; Creese, I.

    1985-02-01

    The interactions of dopaminergic agonists and antagonists with /sup 3/H-agonist labeled D3 dopaminergic binding sites of rat striatum have been characterized by radioligand-binding techniques. When the binding of (/sup 3/H)dopamine and (/sup 3/H)apomorphine to D2 dopamine receptors is blocked by the inclusion of D2 selective concentrations of unlabeled spiroperidol or domperidone, these ligands appear to label selectively the previously termed D3 binding site. Antagonist/(/sup 3/H)dopamine competition curves are of uniformly steep slope (nH . 1.0), suggesting the presence of a single D3 binding site. The relative potencies of antagonists to inhibit D3 specific (/sup 3/H)dopamine binding are significantly correlated with their potencies to block D1 dopamine receptors as measured by the inhibition of both dopamine-stimulated adenylate cyclase and (/sup 3/H)flupentixol-binding activities. The affinities of agonists to inhibit D3 specific (/sup 3/H)dopamine binding are also correlated with estimates of these agonists affinities for the high affinity binding component of agonist/(/sup 3/H)flupentixol competition curves. Both D3 specific (/sup 3/H) dopamine binding and the high affinity agonist-binding component of dopamine/(/sup 3/H)flupentixol competition curves show a similar sensitivity to guanine nucleotides. Taken together, these data strongly suggest that the D3 binding site is related to a high affinity agonist-binding state of the D1 dopamine receptor.

  16. Identification of the binding subunit of the D/sub 1/-dopamine receptor by photoaffinity crosslinking

    Energy Technology Data Exchange (ETDEWEB)

    Amlaiky, N.; Berger, J.G.; Chang, W.; McQuade, R.D.; Caron, M.G.

    1986-03-01

    A derivative of the potent D/sub 1/ antagonist SCH-23390 has been synthesized. This compound, (R,S)-1-(m-aminophenyl)-7-chloro-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-38548), has been radioiodinated by a chloramine T procedure yielding 3 radioiodinated products. One of these separated isomers (R/sub f/ = 0.35; CH/sub 2/Cl/sub 2/:MEOH:TEA; 82.5:17.5:0.1 on TLC) binds reversibly to rat striatal membranes with high affinity (K/sub D/ approx. 80 pM) appropriate stereoselectivity and D/sub 1/-dopaminergic specificity. (/sup 125/I)SCH-38548 can be covalently incorporated into a peptide of M/sub r/ approx. 72,000 using the heterobifunctional crosslinking reagent N-succinimidyl-6-(4'-azido-2'-nitro-phenylamino) hexanoate. Covalent incorporation of (/sup 125/I) SCH-38548 into the M/sub r/ approx. 72,000 peptide can be blocked by dopaminergic agents with D/sub 1/-dopaminergic specificity (for agonists: SKF 38393 > apomorphine > dopamine; for antagonists: SCH-23390 > cis-flupentixol >>> trans-flupentixol). The D/sub 1/-dopaminergic selectivity and specificity of the labeling was further demonstrated by the fact that other antagonists such as domperidone, ketanserin, phentolamine and alprenolol did not compete for the covalent labeling of the M/sub r/ approx. 72,000 peptide. This new radioligand should be useful in the molecular characterization of the D/sub 1/-dopaminergic receptor from various sources.

  17. Evaluation of brain targeting efficiency of intranasal microemulsion containing olanzapine: pharmacodynamic and pharmacokinetic consideration.

    Science.gov (United States)

    Patel, Rashmin B; Patel, Mrunali R; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    The objective of this study was to develop and evaluate olanzapine (OZP) -loaded microemulsions (OZPME) for intranasal delivery in the treatment of schizophrenia. The OZPME was formulated by the spontaneous microemulsification method and characterized for physicochemical parameters. Pharmacodynamic assessments (apomorphine - induced compulsive behavior and spontaneous locomotor activity) were performed using mice. All formulations were radiolabeled with technetium-99 ((99m)Tc), and biodistribution of drug in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rabbits was performed to determine the uptake of the OZP into the brain. OZPME were found clear and stable with average globule size of 23.87 ± 1.07 nm. In pharmacodynamic assessments, significant (p < 0.05) difference in parameters estimated were found between the treated and control groups. (99m)Tc-labeled OZP solution (OZPS)/OZPME/OZP mucoadhesive microemulsion (OZPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of OZPMME compared to intravenous OZPME was found to be five to six times higher signifying larger extent of distribution of the OZP in brain. Drug targeting efficiency and direct drug transport were found to be highest for intranasal OZPMME, compared to intravenous OZPME. Furthermore, rabbit brain scintigraphy also demonstrated higher intranasal uptake of the OZP into the brain. This investigation demonstrates a prompt and larger extent of transport of OZP into the brain through intranasal OZPMME, which may prove beneficial for treatment of schizophrenia. PMID:24845478

  18. Are human dental papilla-derived stem cell and human brain-derived neural stem cell transplantations suitable for treatment of Parkinson's disease?

    Institute of Scientific and Technical Information of China (English)

    Hyung Ho Yoon; Joongkee Min; Nari Shin; Yong Hwan Kim; Jin-Mo Kim; Yu-Shik Hwang; Jun-Kyo Francis Suh; Onyou Hwang; Sang Ryong Jeon

    2013-01-01

    Transplantation of neural stem cells has been reported as a possible approach for replacing impaired dopaminergic neurons. In this study, we tested the efficacy of early-stage human dental papilla-derived stem cells and human brain-derived neural stem cells in rat models of 6-hydroxydopamine-induced Parkinson's disease. Rats received a unilateral injection of 6-hydroxydopamine into right medial forebrain bundle, followed 3 weeks later by injections of PBS, early-stage human dental papilla-derived stem cells, or human brain-derived neural stem cells into the ipsilateral striatum. All of the rats in the human dental papilla-derived stem cell group died from tumor formation at around 2 weeks following cell transplantation. Postmortem examinations revealed homogeneous malignant tumors in the striatum of the human dental papilla-derived stem cell group. Stepping tests revealed that human brain-derived neural stem cell transplantation did not improve motor dysfunction. In apomorphine-induced rotation tests, neither the human brain-derived neural stem cell group nor the control groups (PBS injection) demonstrated significant changes. Glucose metabolism in the lesioned side of striatum was reduced by human brain-derived neural stem cell transplantation. [18 F]-FP-CIT PET scans in the striatum did not demonstrate a significant increase in the human brain-derived neural stem cell group. Tyrosine hydroxylase (dopaminergic neuronal marker) staining and G protein-activated inward rectifier potassium channel 2 (A9 dopaminergic neuronal marker) were positive in the lesioned side of striatum in the human brain-derived neural stem cell group. The use of early-stage human dental papilla-derived stem cells confirmed its tendency to form tumors. Human brain-derived neural stem cells could be partially differentiated into dopaminergic neurons, but they did not secrete dopamine.

  19. Pharmacological modulation of HDAC1 and HDAC6 in vivo in a zebrafish model: Therapeutic implications for Parkinson's disease.

    Science.gov (United States)

    Pinho, Brígida R; Reis, Sara D; Guedes-Dias, Pedro; Leitão-Rocha, Ana; Quintas, Clara; Valentão, Patrícia; Andrade, Paula B; Santos, Miguel M; Oliveira, Jorge M A

    2016-01-01

    Histone deacetylases (HDACs) are key epigenetic enzymes and emerging drug targets in cancer and neurodegeneration. Pan-HDAC inhibitors provided neuroprotection in Parkinson's Disease (PD) models, however, the HDAC isoforms with highest neuroprotective potential remain unknown. Zebrafish larvae (powerful pharmacological testing tools bridging cellular and in vivo studies) have thus far been used in PD modelling with limited phenotypic characterization. Here we characterize the behavioural and metabolic phenotypes of a zebrafish PD model induced with MPP(+), assess the feasibility of targeting zebrafish HDAC1 and HDAC6 isoforms, and test the in vivo effects of their selective inhibitors MS-275 and tubastatin A, respectively. MPP(+) induced a concentration-dependent decrease in metabolic activity and sensorimotor reflexes, and induced locomotor impairments rescuable by the dopaminergic agonist apomorphine. Zebrafish HDAC1 and HDAC6 isoforms show high sequence identity with mammalian homologues at the deacetylase active sites, and pharmacological inhibition increased acetylation of their respective histone and tubulin targets. MS-275 and tubastatin rescued the MPP(+)-induced decrease in diencephalic tyrosine hydroxylase immunofluorescence and in whole-larvae metabolic activity, without modifying mitochondrial complex activity or biogenesis. MS-275 or tubastatin alone modulated spontaneous locomotion. When combined with MPP(+), however, neither MS-275 nor tubastatin rescued locomotor impairments, although tubastatin did ameliorate the head-reflex impairment. This study demonstrates the feasibility of pharmacologically targeting the zebrafish HDAC1 and HDAC6 isoforms, and indicates that their inhibition can rescue cellular metabolism in a PD model. Absence of improvement in locomotion, however, suggests that monotherapy with either HDAC1 or HDAC6 inhibitors is unlikely to provide strong benefits in PD. This study highlights parameters dependent on the integrity of

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1982-01-07

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

  1. Functional antidopaminergic and anticholinergic effects of thioridazine and its metabolites

    Energy Technology Data Exchange (ETDEWEB)

    Niedzwiecki, D.

    1986-01-01

    The relative potency of thioridazine and two of its clinically active metabolites, mesoridazine and sulforidazine was studied. In each of three separate methods, mesoridazine and sulforidazine exhibited greater potency than did thioridazine. Both metabolites showed greater affinities for striatal DA receptors as estimated by their competition for (/sup 3/H)spiperone binding sites in crude striatal membrane preparations. On a more functional level, both metabolites more potently antagonized the inhibitory effects of either the direct acting DA agonist apomorphine, or of endogenous DA, on the electrically evoked release of radiolabeled DA and ACh from perfused striatal slices. While thioridazine effectively blocked the agonist-induced inhibition at those striatal DA receptors which control DA release, it showed significantly lower potency at the striatal DA receptors which modulate ACh release. Thioridazine exhibited moderate affinity for striatal muscarinic cholinergic receptors. It was only five times less potent than atropine in competing for (/sup 3/H) quinuclidinylbenzilate binding sites in striatal membrane preparations. Unlike dopamine receptors, thioridazine showed greater antimuscarinic potency than did its metabolites. Despite this significant affinity for muscarinic binding sites in striatal homogenates, neither thioridezine nor its metabolites could block the inhibitory effects of the full muscarinic agonist carbachol, on the evoked release of ACh from striatal slices. This lack of effect contrasted with the antagonism of the carbachol-induced inhibition by such classical muscarinic blockers as quinuclindinylbenzilate or atropine. In combination with available pharmacokinetic data, these studies have demonstrated that the metabolites of thioridazine probably contribute to the antidopaminergic effects of this drug within the CNS.

  2. 姜辣素在2种呕吐动物模型中止呕作用机制的探讨%Mechanisms of antiemetic effect of gingerols in two vomiting animal models

    Institute of Scientific and Technical Information of China (English)

    王耀霞; 杨志宏; 岳旺; 刘占涛; 韩庆方

    2009-01-01

    目的 开发姜的止呕制剂,弥补临床上5-羟色胺Ⅲ亚型受体(5-hydroxytryptamine-3 receptor,5-HT3)及神经激肽Ⅰ亚型受体(neurokinin-1 receptor,NK1)拮抗剂靶点单一、价格昂贵、毒性及不良反应大等缺点.方法 用特异性5-HT3受体激动剂1-phenylbiguanide hydrochloride(PBG)和多巴胺受体激动剂阿朴吗啡(apomorphine)建立新型水貂呕吐模型和经典大鼠异嗜模型,观察姜辣素对水貂呕吐行为和大鼠异嗜高岭土行为的抑制作用.结果 姜辣素对水貂呕吐行为和大鼠异嗜高岭土行为均表现出显著的抑制作用(P<0.05),并呈现一定的量效关系.结论 姜辣素有止呕作用,其止呕机制可能涉及到5-羟色胺和多巴胺受体系统;姜辣素在研究天然多靶点新型止呕药方面具有潜在的应用价值.

  3. Time-Dependent Inhibition of CYP2C19 by Isoquinoline Alkaloids: In Vitro and In Silico Analysis.

    Science.gov (United States)

    Salminen, Kaisa A; Rahnasto-Rilla, Minna; Väänänen, Raija; Imming, Peter; Meyer, Achim; Horling, Aline; Poso, Antti; Laitinen, Tuomo; Raunio, Hannu; Lahtela-Kakkonen, Maija

    2015-12-01

    The cytochrome P450 2C19 (CYP2C19) enzyme plays an important role in the metabolism of many commonly used drugs. Relatively little is known about CYP2C19 inhibitors, including compounds of natural origin, which could inhibit CYP2C19, potentially causing clinically relevant metabolism-based drug interactions. We evaluated a series (N = 49) of structurally related plant isoquinoline alkaloids for their abilities to interact with CYP2C19 enzyme using in vitro and in silico methods. We examined several common active alkaloids found in herbal products such as apomorphine, berberine, noscapine, and papaverine, as well as the previously identified mechanism-based inactivators bulbocapnine, canadine, and protopine. The IC50 values of the alkaloids ranged from 0.11 to 210 µM, and 42 of the alkaloids were confirmed to be time-dependent inhibitors of CYP2C19. Molecular docking and three-dimensional quantitative structure-activity relationship analysis revealed key interactions of the potent inhibitors with the enzyme active site. We constructed a comparative molecular field analysis model that was able to predict the inhibitory potency of a series of independent test molecules. This study revealed that many of these isoquinoline alkaloids do have the potential to cause clinically relevant drug interactions. These results highlight the need for studying more profoundly the potential interactions between drugs and herbal products. When further refined, in silico methods can be useful in the high-throughput prediction of P450 inhibitory potential of pharmaceutical compounds. PMID:26400396

  4. Evaluation of nigrostriatal damage and its change over weeks in a rat model of Parkinson's disease: small animal positron emission tomography studies with [{sup 11}C]{beta}-CFT

    Energy Technology Data Exchange (ETDEWEB)

    Liu Limin; Wang Yong; Li Bo; Jia Jun; Sun Zuoli [Department of Physiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069 (China); Zhang Jinming; Tian Jiahe [Department of Nuclear Medicine, Chinese PLA General Hospital, Beijing 100853 (China); Wang Xiaomin [Department of Physiology, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069 (China)], E-mail: xmwang@ccmu.edu.cn

    2009-11-15

    Introduction: The cardinal pathological feature of Parkinson's disease (PD) is progressive loss of dopaminergic neurons. Since dopamine transporter (DAT) is a protein located presynaptically on dopaminergic nerve terminals, radioligands that bind to these sites are promising radiopharmaceuticals for evaluation of the integrity of the dopamine system. This study using positron emission tomography (PET) tracers, [{sup 11}C]-2{beta}-carbomethoxy-3{beta}-(4-fluorophenyl)-tropane ([{sup 11}C]{beta}-CFT, radioligand for DAT), was aimed at evaluating the degree of nigrostriatal damage and its change over weeks in a rat model of PD. Methods: The brains of these rats were unilaterally lesioned by mechanical transection of the nigrostriatal dopamine pathway at the medial forebrain bundle (MFB). Behavioral studies were carried out by apomorphine (APO) challenge prior to and 1, 2 and 4 weeks after MFB axotomy. Small animal PET scans were performed 2 days after the behavioral test. Immunohistochemistry was conducted 4 days after the last PET scan. Results: Compared with the contralateral intact side, a progressively decreased [{sup 11}C]{beta}-CFT binding was observed on the lesioned side which correlated inversely with the APO-induced rotations. Postmortem immunohistochemical studies confirmed the loss of both striatal dopamine fibers and nigral neurons on the lesioned side. Conclusion: These findings not only demonstrate that the neuronal degeneration in this model is relatively slow, but also suggest [{sup 11}C]{beta}-CFT is a sensitive marker to monitor the degree of nigrostriatal damage and its change over weeks. This marker can be used prospectively to study the progression of the disease, thereby making detection of early phases of PD possible.

  5. Are Dopamine Agonists Neuroprotective in Parkinson′s Disease?

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Dopamine (DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson′s disease (PD) and in PD patient with levodopa (L-DOPA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoplasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer′s disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinical trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as 18 F-L-DOPA PET and 123 I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.``

  6. Fenpropathrin, a Widely Used Pesticide, Causes Dopaminergic Degeneration.

    Science.gov (United States)

    Xiong, Jing; Zhang, Xiaowei; Huang, Jinsha; Chen, Chunnuan; Chen, Zhenzhen; Liu, Ling; Zhang, Guoxin; Yang, Jiaolong; Zhang, Zhentao; Zhang, Zhaohui; Lin, Zhicheng; Xiong, Nian; Wang, Tao

    2016-03-01

    Fenpropathrin is one of the widely used pyrethroids in agriculture and household and also reported to have neurotoxic effects in rodent models. In our Parkinson's disease (PD) clinic, there was a unique patient with a history of daily exposure to fenpropathrin for 6 months prior to developing Parkinsonian symptoms progressively. Since whether fenpropathrin is related to any dopaminergic degeneration was unknown, we aimed in this study to evaluate the neurotoxic effects of fenpropathrin on the dopaminergic system and associated mechanisms in vitro and in vivo. In cultured SH-SY5Y cells, fenpropathrin caused cell death, reactive oxygen species generation, Lewy body-associated proteins aggregation, and Lewy body-like intracytoplasmic inclusions formation. In rodent animals, two different injections of fenpropathrin were used for administrations, intraperitoneal (i.p), or stereotaxical (ST). The rats exhibited lower number of pokes 60 days after first i.p injection, while the rats in ST group showed a significant upregulation of apomorphine-evoked rotations 60 days after first injection. Decreased tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) immunoreactivity, while increased dopamine transporter (DAT) immunoreactivity were observed in rats of either i.p or ST group 60 days after the last exposure to fenpropathrin. However, the number of TH-positive cells in the substantia nigra was more reduced 120 days after the first i.p injection than those of 60 days. Our data demonstrated that exposure to fenpropathrin could mimic the pathologic and pathogenetic features of PD especially in late onset cases. These results imply fenpropathrin as a DA neurotoxin and a possible environmental risk factor for PD. PMID:25575680

  7. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Nicolas Maurice

    Full Text Available Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD. Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure in pharmacological (neuroleptic treatment and lesional (unilateral intranigral 6-hydroxydopamine injection PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease.

  8. Chronic low-dose melatonin treatment maintains nigrostriatal integrity in an intrastriatal rotenone model of Parkinson's disease.

    Science.gov (United States)

    Carriere, Candace H; Kang, Na Hyea; Niles, Lennard P

    2016-02-15

    Parkinson's disease is a major neurodegenerative disorder which primarily involves the loss of dopaminergic neurons in the substantia nigra and related projections in the striatum. The pesticide/neurotoxin, rotenone, has been shown to cause systemic inhibition of mitochondrial complex I activity in nigral dopaminergic neurons, with consequent degeneration of the nigrostriatal pathway, as observed in Parkinson's disease. A novel intrastriatal rotenone model of Parkinson's disease was used to examine the neuroprotective effects of chronic low-dose treatment with the antioxidant indoleamine, melatonin, which can upregulate neurotrophic factors and other protective proteins in the brain. Sham or lesioned rats were treated with either vehicle (0.04% ethanol in drinking water) or melatonin at a dose of 4 µg/mL in drinking water. The right striatum was lesioned by stereotactic injection of rotenone at three sites (4 μg/site) along its rostrocaudal axis. Apomorphine administration to lesioned animals resulted in a significant (p<0.001) increase in ipsilateral rotations, which was suppressed by melatonin. Nine weeks post-surgery, animals were sacrificed by transcardial perfusion. Subsequent immunohistochemical examination revealed a decrease in tyrosine hydroxylase immunoreactivity within the striatum and substantia nigra of rotenone-lesioned animals. Melatonin treatment attenuated the decrease in tyrosine hydroxylase in the striatum and abolished it in the substantia nigra. Stereological cell counts indicated a significant (p<0.05) decrease in dopamine neurons in the substantia nigra of rotenone-lesioned animals, which was confirmed by Nissl staining. Importantly, chronic melatonin treatment blocked the loss of dopamine neurons in rotenone-lesioned animals. These findings strongly support the therapeutic potential of long-term and low-dose melatonin treatment in Parkinson's disease. PMID:26740407

  9. Dopaminergic modulation of mitral cell activity in the frog olfactory bulb: a combined radioligand binding-electrophysiological study

    Energy Technology Data Exchange (ETDEWEB)

    Duchamp, A.; Moyse, E.; Delaleu, J.-C.; Coronas, V.; Duchamp-Viret, P. [Laboratoire de Physiologie Neurosensorielle, Universite Claude Bernard and CNRS, F69622 Villeurbanne (France)

    1997-04-28

    Dopamine content in the amphibian olfactory bulb is supplied by interneurons scattered among mitral cells in the external plexiform/mitral cell layer. In mammals, dopamine has been found to be involved in various aspects of bulbar information processing by influencing mitral cell odour responsiveness. Dopamine action in the bulb depends directly on the localization of its receptor targets, found to be mainly of the D{sub 2} type in mammals. The present study assessed, in the frog, both the anatomical localization of D{sub 2}-like, radioligand-labelled receptors of dopamine and the in vivo action of dopamine on unitary mitral cell activity in response to odours delivered over a wide range of concentrations. The [{sup 125}I]iodosulpride-labelled D{sub 2} binding sites were visualized on frozen sagittal sections of frog brains by film radioautography. The sites were found to be restricted to the external plexiform/mitral cell layer; other layers of the olfactory bulb were devoid of specific labelling. Electrophysiological recordings of mitral unit activity revealed that dopamine or its agonist apomorphine induced a drastic reduction of spontaneous firing rate of mitral cells in most cases without altering odour intensity coding properties of these cells. Moreover, pre-treatment with the D{sub 2} antagonist eticlopride blocked the dopamine-induced reduction of mitral cell spontaneous activity.In the frog olfactory bulb, both anatomical localization of D{sub 2}-like receptors and functional data on dopamine involvement in information processing differ from those reported in mammals. This suggests a phylogenetic evolution of dopamine action in the olfactory bulb. In the frog, anatomical data perfectly corroborate electrophysiological results, together strongly suggesting a direct action of dopamine on mitral cells. In a physiologically operating system, such an action would result in a global improvement of signal-to-noise ratio. (Copyright (c) 1997 Elsevier Science B

  10. Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

    Science.gov (United States)

    Sun, Xian-Chang; Ren, Xiao-Fan; Chen, Lei; Gao, Xian-Qi; Xie, Jun-Xia; Chen, Wen-Fang

    2016-01-01

    Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1. PMID:26455404

  11. AB230. Calpain inhibition improves diabetic erectile dysfunction in rats

    Science.gov (United States)

    Li, Hao; Wang, Tao; Liu, Jihong

    2016-01-01

    Objective Diabetic erectile dysfunction is an intractable disease which results from both vascular and nervous dysfunction in penis. Calpain mediates the vascular dysfunction during hyperglycemia and is involved in some neurodegenerative diseases. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction in rats. Methods Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at the dose of 60 mg/kg in rats. After 2 months, diabetic erectile dysfunction was confirmed by apomorphine test. Then the animals were divided into three groups: (I) nondiabetic control groups, (II) diabetic rats + vehicle and (III) diabetic rats + MDL28170. Two weeks later the erectile function was measured by electrical stimulation of the cavernous nerve and the ratio between intracavernosal pressure (ICP) and mean systemic arterial blood pressure (MAP) at the peak of erectile response was calculated. After that penis tissue was harvested. Calpain activity in corpus cavernosum was measured by western blot. Neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) were observed by immunohistochemistry and western blot. The endothelial content in the cavernosum was measured by immunohistochemistry. Results The calpain activity was increased in diabetic rats and inhibited by MDL28170. The erectile function was improved by MDL28170 treatment. The expression of nNOS and eNOS, as well as the content of endothelium in corpus cavernosum were also increased by inhibition of calpain. Conclusions Calpain activation may play a role in the erectile dysfunction of diabetic rats. Inhibition of calpain could improve diabetic erectile dysfunction by increasing expression of nNOS and eNOS in the corpus cavernosum. This could be a novel therapeutic target to protect the erectile function in diabetic patient.

  12. Ascorbic acid enables reversible dopamine receptor /sup 3/H-agonist binding

    Energy Technology Data Exchange (ETDEWEB)

    Leff, S.; Sibley, D.R.; Hamblin, M.; Creese, I.

    1981-11-16

    The effects of ascorbic acid on dopaminergic /sup 3/H-agonist receptor binding were studied in membrane homogenates of bovine anterior pituitary and caudate, and rat striatum. In all tissues virtually no stereospecific binding (defined using 1uM (+)butaclamol) of the /sup 3/H-agonists N-propylnorapomorphine (NPA), apomorphine, or dopamine could be demonstrated in the absence of ascorbic acid. Although levels of total /sup 3/H-agonist binding were three to five times greater in the absence than in the presence of 0.1% ascorbic acid, the increased binding was entirely non-stereospecific. Greater amounts of dopamine-inhibitable /sup 3/H-NPA binding could be demonstrated in the absence of 0.1% ascorbic acid, but this measure of ''specific binding'' was demonstrated not to represent dopamine receptor binding since several other catecholamines and catechol were equipotent with dopamine and more potent than the dopamine agonist (+/-)amino-6,7-dihydroxy-1,2,3,4-tetrahydronapthalene (ADTN) in inhibiting this binding. High levels of dopamine-displaceable /sup 3/H-agonist binding were detected in fresh and boiled homogenates of cerebellum, an area of brain which receives no dopaminergic innervation, further demonstrating the non-specific nature of /sup 3/H-agonist binding in the absence of ascorbic acid. These studies emphasize that under typical assay conditions ascorbic acid is required in order to demonstrate reversible and specific /sup 3/H-agonist binding to dopamine receptors.

  13. Levetiracetam attenuates rotenone-induced toxicity: A rat model of Parkinson's disease.

    Science.gov (United States)

    Erbaş, Oytun; Yılmaz, Mustafa; Taşkıran, Dilek

    2016-03-01

    Levetiracetam (LEV), a second-generation anti-epileptic drug, is used for treatment of both focal and generalized epilepsy. Growing body of evidence suggests that LEV may have neuroprotective effects. The present study was undertaken to investigate the neuroprotective effects of LEV on rotenone-induced Parkinson's disease (PD) in rats. Twenty-four adult Sprague-Dawley rats were infused with rotenone (3 μg/μl in DMSO) or vehicle (1 μl DMSO) into the left substantia nigra pars compacta (SNc) under stereotaxic surgery. PD model was assessed by rotational test ten days after drug infusion. The valid PD rats were randomly distributed into two groups; Group 1 (n=8) and Group 2 (n=8) were administered saline (1 ml/kg/day, i.p.) and LEV (600 mg/kg/day, i.p.) through 21 days, respectively. The effects of LEV treatment were evaluated by behavioral (rotation score), biochemical (brain homovalinic acid level and oxidant/antioxidant status) and immunohistochemical (tyrosine hydroxylase) parameters. Apomorphine-induced rotations in PD rats were significantly suppressed by LEV treatment. While unilateral rotenone lesion induced a dramatic loss of dopaminergic neurons both in the striatum and SNc, LEV treatment significantly attenuated the degenerative changes in dopaminergic neurons. Furthermore, LEV significantly decreased lipid peroxide levels, a marker of lipid peroxidation, and induced glutathione levels, catalase and superoxide dismutase activity in PD rats compared with saline group. We conclude that LEV may have beneficial effects on dopaminergic neurons against rotenone-induced injury. The underlying mechanism may be associated with the attenuation of oxidative stress. PMID:26896611

  14. Atypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.

    Science.gov (United States)

    Tatara, Ayaka; Shimizu, Saki; Masui, Atsushi; Tamura, Miyuki; Minamimoto, Shoko; Mizuguchi, Yuto; Ochiai, Midori; Mizobe, Yusuke; Ohno, Yukihiro

    2015-11-01

    Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin. PMID:26363311

  15. Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Modo Michel M

    2010-01-01

    Full Text Available Abstract Background Predominantly, magnetic resonance imaging (MRI studies in animal models of Parkinson's disease (PD have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS, whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin. Results Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN, but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model. Conclusions A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.

  16. Agonist binding to high-affinity dopamine sites

    Energy Technology Data Exchange (ETDEWEB)

    Tedesco, J.L.

    1985-01-01

    The authors have characterized the dopamine D/sub 3/ site and its binding requirements. The dopamine D/sub 3/ site in calf caudate crude homogenate has a site density of 214-230 fmoles/mg. protein by both /sup 3/H-apomorphine (/sup 3/H-AOP) and /sup 3/H-dopamine (/sup 3/H-DA) Scatchard analysis of specific binding (SB). Stereospecific subsets of /sup 3/H-APO and /sup 3/H-DA sites were defined by the use of agonist and antagonist enantiomer-pairs as a rigorous test for D/sub 3/ site heterogeneity. IC/sub 50/ values for both /sup 3/H-APO and /sup 3/H-DA SB sites were assessed for 55 agonist ligands and an excellent correlation was obtained. The authors conclude that both /sup 3/H-ligands label the same D/sub 3/ site. The D/sub 3/ site affinities of 105 dopamine-agonist ligands, in particular 2-aminotetralins,, aporphines and flexible dopamine analogues were measured. Low D/sub 3/-site affinities of N-quaternary analogues confirm the need for a lone pair. Subadditivity of substituents' effects in semi-flexible DA analogues confirms their postulate that sidechain conformation is the critical determinant of affinity. They conclude that there are at least two high-affinity ligand conformations of the DA sidechain pharmacophore. These binding requirements are presented as two interface-Geometry tetrahedral models of the double H-bond interface between the D/sub 3/ site and the ideal ligand.

  17. Chronic high-frequency stimulation therapy in hemiparkinsonian rhesus monkeys using an implanted human DBS system.

    Science.gov (United States)

    Cao, Yiqun; Yin, Peihao; Hu, Xiaowu; Ge, Yiqin; Zhou, Xiaoping

    2013-05-01

    Deep brain stimulation (DBS) is routinely used in the treatment of Parkinson's disease, tremor disease, dystonia, and epilepsy. This study aims to establish a hemiparkinsonian monkey model and to investigate the effect of implanted human DBS system for the chronic alleviation of parkinsonian symptoms. Hemiparkinsonism was induced in four rhesus monkeys by unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. DBS leads were implanted stereotaxically in the right subthalamic (STN) of the monkeys. Subcutaneous extension wires were used to connect the leads to the internal pulse generators (IPG) for stimulation in two of the monkeys (human DBS test group). Post-operative imaging studies confirmed optimal locations of lead contacts. One week later, the IPG was turned on to determine the optimal stimulating parameters, using apomorphine (APO)-induced rotation as a behavioral readout. Animal behavior was scored on a scale of 0-10 over a 12-month period using the modified disability rating scale of hemiparkinsonian monkeys (DRSH). Parkinsonian symptoms in the group of monkeys with DBS improved dramatically (DRSH 3-4) compared to controls (DRSH 7-8). DBS leads were within the STN without intracranial hemorrhage, infection, or other serious complications. Histological examination showed cell necrosis and lymphocytic infiltration of the tissues around the lead and STN gliosis surrounding the lead contact. This study demonstrates that therapeutically effective human DBS systems can be established in relevant disease models in monkeys. Such combination of human DBS systems in hemiparkinsonian monkeys should be valuable in studying the mechanism of action and chronic consequences of DBS therapy in humans. PMID:22622869

  18. Transplantation of human umbilical cord blood-derived mononuclear cells induces recovery of motor dysfunction in a rat model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Chen C

    2016-04-01

    Full Text Available Chao Chen,1,* Jing Duan,1,* Aifang Shen,2,* Wei Wang,1 Hao Song,1 Yanming Liu,1 Xianjie Lu,1 Xiaobing Wang,2 Zhiqing You,1 Zhongchao Han,3,4 Fabin Han1 1Center for Stem Cells and Regenerative Medicine, The Liaocheng People's Hospital, Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People's Republic of China; 2Department of Gynecology and Obstetrics, The Liaocheng People's Hospital, Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People's Republic of China; 3The State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences, Peking Union of Medical College, Tianjin, People's Republic of China; 4National Engineering Research Center of Cell Products, AmCellGene Co. Ltd., TEDA, Tianjin, People's Republic of China*These authors contributed equally to this workAbstract: Human umbilical cord blood-derived mononuclear cells (hUCB-MNCs were reported to have neurorestorative capacity for neurological disorders such as stroke and traumatic brain injury. This study was performed to explore if hUCB-MNC transplantation plays any therapeutic effects for Parkinson's disease (PD in a 6-OHDA-lesioned rat model of PD. hUCB-MNCs were isolated from umbilical cord blood and administered to the striatum of the 6-OHDA-lesioned rats. The apomorphine-induced locomotive turning-overs were measured to evaluate the improvement of motor dysfunctions of the rats after administration of hUCB-MNCs. We observed that transplanted hUCB-MNCs significantly improve the motor deficits of the PD rats and that grafted hUCB-MNCs integrated to the host brains and differentiated to neurons and dopamine neurons in vivo after 16 weeks of transplantation. Our study provided evidence that transplanted hUCB-MNCs play therapeutic effects in a rat PD model by differentiating to neurons and dopamine neurons. Keywords: hUCB-MNCs, Parkinson's disease, transplantation

  19. Chronic estrogen and progesterone treatment inhibits ketamine-induced disruption of prepulse inhibition in rats.

    Science.gov (United States)

    van den Buuse, Maarten; Mingon, Rebecca L; Gogos, Andrea

    2015-10-21

    Ketamine is a dissociative anesthetic and antagonist of N-methyl-d-aspartate receptors (NMDAr). Hypofunction of NMDAr may underlie some schizophrenia symptoms and the psychotomimetic effects of ketamine have been used to model this hypofunction. Gender differences exist in the age of onset and symptom profile of schizophrenia and sex steroid hormones have been successfully trialed as adjunctive treatment in this illness; however, the mechanism of action of these hormone treatment strategies remains unclear. The aim of this study was therefore to investigate the effect of sex steroid hormones on ketamine-induced disruption of prepulse inhibition (PPI), an endophenotype of schizophrenia. Female ovariectomized (OVX) rats did not show altered effects of ketamine compared to intact rats. There were also no significant changes in the effect of ketamine on PPI in OVX rats implanted with a high dose of estrogen. In contrast, in OVX rats implanted with a low dose of estrogen plus progesterone, the effect of 10mg/kg ketamine was significantly reduced. There were no parallel changes in startle amplitude. These results differ from previous studies on the effect of sex steroid hormones on the disruption of PPI by treatment with the NMDAr antagonist, MK-801, or dopaminergic drugs, such as apomorphine. We speculate that this differential effect of sex steroids on the action of ketamine is mediated by mechanisms other than dopaminergic stimulation or NMDA receptor blockade, for example GABAA receptors. These results extend our understanding of the effects of sex steroid hormones on PPI and their use as potential treatments in schizophrenia. PMID:26391745

  20. Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Mikkelsen, Jens D; Jelsing, Jacob; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-09-01

    Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, have been demonstrated to promote neuroprotection in the rat 6-hydroxydopamine (6-OHDA) neurotoxin model of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive nigrostriatal dopaminergic neuron loss. In this report, we characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500µg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3µg, partial lesion) or high (13.5µg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting. In conclusion, liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD. PMID:27233809

  1. 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

  2. Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat.

    Science.gov (United States)

    Mumford, G K; Holtzman, S G

    1991-09-01

    Caffeine engenders qualitatively different subjective effects in humans at low and high doses. Low doses of caffeine are mildly reinforcing and produce psychomotor stimulation. High doses of caffeine can produce subjective feelings of anxiety, dysphoria and depression. The present study was designed to model these different subjective states in rats using a discrete trial shock avoidance/escape drug discrimination paradigm. Rats were trained to discriminate between i.p. injections of saline and either 10 or 56 mg/kg of caffeine. Rats trained at 10 mg/kg of caffeine acquired the discrimination in an average of 93 sessions and generalized completely to a variety of xanthine and nonxanthine behavioral stimulants including: d-amphetamine, apomorphine, 7-(beta-chloroethyl)theophylline, 9-chloro-2-(2-furanyl)-5,6-dihydro-1, 2,4-triazolo[1,5-c]quinazolin-5-imine (CGS 15943), cocaine, 1,7-dimethylxanthine, diethylpropion, beta-hydroxyethyltheophylline, methylphenidate, phenidimetrazine and theophylline. Rats trained at 56 mg/kg of caffeine acquired the discrimination in an average of 43 sessions and generalized completely only to theophylline. A variety of drugs representing diverse pharmacologic classifications including: benzodiazepine inverse agonists, pentylenetetrazol, yohimbine, ethylketocyclazocine and phencyclidine, were not generalized from either training dose, demonstrating the pharmacologic specificity of the discrimination. The discriminative effects of 10 mg/kg of caffeine appear to derive from a state of behavioral arousal, possibly mediated by catecholamines, and parallel the subjective effects produced by low doses of caffeine in humans. The discriminative effects of 56 mg/kg of caffeine are qualitatively different from those of 10 mg/kg but cannot be defined further at this time. PMID:1890622

  3. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

    International Nuclear Information System (INIS)

    The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  4. Critical review of the clinical relevance of growth hormone and its measurement in the nuclear medicine laboratory

    International Nuclear Information System (INIS)

    A wide variety of metabolic and stressful stimuli, both physical and psychologic, produce rapid elevation of plasma growth hormone (GH). In addition, spontaneous elevation of GH occurs during the day, and a rise in GH occurs in association with the initial slow-wave sleep episode at night. Although the identity of the GH releasing factor has not yet been established, a hypothalamic factor inhibiting GH release named somatostatin identified and synthesized. Most, if not all, of the GH rises are mediated by neural mechanisms, and therefore they may be disrupted by many disease processes affecting the pituitary or the hypothalamus. In acromegaly, hypersecretion of GH occurs, and remnants of hypothalamic control can frequently be demonstrated, suggesting a hypothalamic origin for at least some cases. Provocative stimuli commonly used to assess adequacy of GH responses include hypoglycemia, arginine infusion, and exercise. Administration of L-dopa or apomorphine also produces GH elevation, and since these agents may activate specific dopamine mechanisms, they are of particular interest. Two comprehensive commercial kits have been evaluated, and three major defects have been identified. The literature provided in both kits was inadequate. Both kits required an initial dilution without any replication, so that dilution error would be undetected. One of the kits did not provide a full complement of materials. Quantities of HGH antigen and antisera sufficient for large numbers of assays are also available commercially. However, no commercial source was found for control sera containing known quantities of HGH. Individual laboratories to provide their own supply of sera to use for quality control. It is now known that GH exists in multiple forms in plasma and that antisera may differ in ability to bind these forms. It will, therefore, be necessary for laboratories to revalidate the assay if a different antiserum is used. (U.S.)

  5. Aripiprazole (Otsuka Pharmaceutical Co).

    Science.gov (United States)

    Ozdemir, Vural; Fourie, Jeanne; Ozdener, Fatih

    2002-01-01

    Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484]. PMID:12054061

  6. Are Dopamine Agonists Neuroprotective in Parkinson‘s disease?

    Institute of Scientific and Technical Information of China (English)

    乐卫东; Jank.J

    2002-01-01

    Dopamine(DA) agonists are playing increasingly important role in the treatment of not only advanced Parkinson's disease(PD) and in PD patient with levodopa(L-DO-PA)-induced motor fluctuations,but also in early treatment of the disease.This shift has been largely due to the demonstrated L-DOPA-sparing effect of DA agonists and their putative neuroprotective effect,based largely on experimental in vitro and in vivo studies.In this article we review the evidence of neuroprotection by DA agonists pramipexole,ropinirole,pergolide,bromocriptine and apomorphine in cell cultures and animal models of nigral injury.Most of the studies suggest that DA agonists exert their neuroprotection via directly scavenging free radicals or increasing the activities of radical-scavenging enzymes,and enhancing neurotrophic activity.The finding that pramipexole can normalize mitochondrial membrane potential and inhibit activity of caspase-3 in cytoylasmic hybrid cells made from mitochondrial DNA of nonfamilial Alzheimer's disease patients,however,suggests even a broader implication for the neuroprotective role of DA agonists.Although the clinical evidence for neuroprotection by DA agonists is still limited,the preliminary results from several on-going clinal trials are promising.Several longitudinal studies are currently in progress designed to demonstrate a delay or slowing of progresion of PD using various surrogate markers of neuronal degeneration such as18F-L-DOPA PET and123I β-CIT SPECT.The results of these experimental and clinical studies will improve our understanding of the action of DA agonists and provide critical information needed for planning future therapeutic strategies in PD and related neurodegenerative disorders.

  7. Distribution and compartmental organization of GABAergic medium-sized spiny neurons in the mouse nucleus accumbens.

    Science.gov (United States)

    Gangarossa, Giuseppe; Espallergues, Julie; de Kerchove d'Exaerde, Alban; El Mestikawy, Salah; Gerfen, Charles R; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

    2013-01-01

    The nucleus accumbens (NAc) is a critical brain region involved in many reward-related behaviors. The NAc comprises major compartments the core and the shell, which encompass several subterritories. GABAergic medium-sized spiny neurons (MSNs) constitute the output neurons of the NAc core and shell. While the functional organization of the NAc core outputs resembles the one described for the dorsal striatum, a simple classification of the NAc shell neurons has been difficult to define due to the complexity of the compartmental segregation of cells. We used a variety of BAC transgenic mice expressing enhanced green fluorescence (EGFP) or the Cre-recombinase (Cre) under the control of the promoter of dopamine D1, D2, and D3 receptors and of adenosine A2a receptor to dissect the microanatomy of the NAc. Moreover, using various immunological markers we characterized in detail the distribution of MSNs in the mouse NAc. In addition, cell-type specific extracellular signal-regulated kinase (ERK) phosphorylation in the NAc subterritories was analyzed following acute administration of SKF81297 (a D1R-like agonist), quinpirole (a D2 receptors (D2R)-like agonist), apomorphine (a non-selective DA receptor agonist), raclopride (a D2R-like antagonist), and psychostimulant drugs, including cocaine and d-amphetamine. Each drug generated a unique topography and cell-type specific activation of ERK in the NAc. Our results show the existence of marked differences in the receptor expression pattern and functional activation of MSNs within the shell subterritories. This study emphasizes the anatomical and functional heterogeneity of the NAc, which will have to be considered in its further study. PMID:23423476

  8. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

    Science.gov (United States)

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane; Amalric, Marianne; Kerkerian-Le Goff, Lydia

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  9. Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson’s Disease

    Science.gov (United States)

    Maurice, Nicolas; Deltheil, Thierry; Melon, Christophe; Degos, Bertrand; Mourre, Christiane

    2015-01-01

    Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson’s disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models. In the hemi-parkinsonian 6-hydroxydopamine lesion model, subchronic bee venom treatment significantly alleviates contralateral forelimb akinesia and apomorphine-induced rotations. Moreover, a single injection of bee venom reverses haloperidol-induced catalepsy, a pharmacological model reminiscent of parkinsonian akinetic deficit. This effect is mimicked by apamin, a blocker of small conductance Ca2+-activated K+ (SK) channels, and blocked by CyPPA, a positive modulator of these channels, suggesting the involvement of SK channels in the bee venom antiparkinsonian action. In vivo electrophysiological recordings in the substantia nigra pars reticulata (basal ganglia output structure) showed no significant effect of BV on the mean neuronal discharge frequency or pathological bursting activity. In contrast, analyses of the neuronal responses evoked by motor cortex stimulation show that bee venom reverses the 6-OHDA- and neuroleptic-induced biases in the influence exerted by the direct inhibitory and indirect excitatory striatonigral circuits. These data provide the first evidence for a beneficial action of bee venom on the pathological functioning of the cortico-basal ganglia circuits underlying motor PD symptoms with potential relevance to the symptomatic treatment of this disease. PMID:26571268

  10. 纹状体内注射6-羟基多巴胺制备兔帕金森病模型%Making Parkinsonian model of rabbit by injecting 6-OHDA into corpus striatum

    Institute of Scientific and Technical Information of China (English)

    刘晓静; 尹逊河; 王宪龙; 郭丽红

    2012-01-01

    The aim of this research was to study the method of modeling Parkinson disease(PD) by injecting 6-hydroxydopamine(6-OHDA) into right side of rabbit corpus striatum.After the surgery,the change of behavior induced by apomorphine was observed every week.The rabbits were sacrificed after six weeks and the change of morphology,structure,amount of TH positive neurons were observed in substantia nigra part using SABC immunohistochemical technique.The results showed that the abnormal behaviors,including moving stiffly,seeking for food,appeared in a part of the rabbits after operation.The rate of the apomorphin-induced rotation was over 7 r/min among 16 rabbits(80%) after 6 weeks of the injection.The rabbit with more than 7 rotation per minute was regarded as a successful PD model.TH immunohistochemical staining showed that the TH positive neurons were seen within the nigral in normal control group,sham surgery group,and the unlesioned side of model group.They had the hyperchromic cytoplasm,the clear tubers,numerous positive cells and the long axons,which had no noble diversity among above three groups(P〉0.05).While in the opposite area of the model group TH positive neuron staining became lighter,cell body and tuber got blurrier,especially,the number and the axons length of the TH-positive neurons decreased and got shorter dramatically than that in the unlesioned side of the model group and the other two groups(P〈0.05).The results suggest that injecting 6-OHDA into the unilateral striatum was a feasible method for establishing rabbit model of PD,which is simple manipulation with satisfying achievement ratio and lower mortality.%应用脑立体定位技术微量注射6-OHDA于兔右侧纹状体内。术后每周观察以阿扑吗啡(Apomorphin,APO)诱导的旋转行为,并于术后6周处死兔,以黑质酪氨酸羟化酶(Tyrosine hydroxylase,TH)免疫组化染色,观察黑质多巴胺能神经元的形态、结构及数量变化。结果

  11. Experimental Study on Early Parkinson's Disease Rat Model Induced by 6-OHDA%6-羟基多巴胺损伤早期帕金森病大鼠模型的实验研究

    Institute of Scientific and Technical Information of China (English)

    沈福玉; 施建生

    2014-01-01

    目的:观察6-羟基多巴胺(6-hydroxydopamine,6-OHDA)损伤早期帕金森病(Parkinson's disease, PD)大鼠行为学及黑质部位组织学的变化特点。方法偏侧前脑内侧束注射6-OHDA,通过阿扑吗啡诱发旋转试验、跨步调节试验和姿势部对称试验评估注射后24 h、7 d及28 d大鼠行为学的变化;通过免疫组织化学染色观察黑质部位酪氨酸羟化酶(tyrosine hydroxylase, TH)阳性细胞计数的变化。结果6-OHDA组大鼠跨步调节试验评分减少,姿势不对称试验评分增加,阿扑吗啡诱发大鼠向损伤对侧旋转,与对照组和假手术组比较统计学差异显著(P<0.05);6-OHDA 7 d组、28 d组与24 h组比较,跨步调节试验评分进一步减少、姿势不对称试验评分进一步增加,阿扑吗啡诱发旋转次数增加,有统计学差异(P<0.05);6-OHDA 24 h组黑质TH阳性细胞减少,与对照组和假手术组比较有统计学差异(P<0.05),7 d组及28 d组TH阳性细胞进一步减少,与24 h组比较统计学差异显著(P<0.05)。结论通过阿扑吗啡诱发旋转结合非药物诱发试验进行行为学评估,可确定偏侧前脑内侧束注射6-OHDA损伤早期帕金森病动物模型。%ObjectiveTo observe the characteristic changes of behaviors and substantia nigra (SN) histology of Parkinson's disease (PD) rat model induced by 6-OHDA. Methods 6-hydroxydopamine (6-OHDA) was injected into the rats' unilateral medial forebrain bundle. The behaviors of the rats on the 24th hour ,7th day and 28th day were assessed by tests of the apomorphine induced rotations, the adjusting steps and the postural asymmetry.The forms and counts of tyrosine hydroxylase positive (TH) cells were surveyed by the immunohistochemistry staining. Results Rats of PD models appeared significant decrease in score of the adjusting steps test, while increase in score of the postural asymmetry test, and rotated to the uninjured side

  12. Establishing motor disorder mouse models of Parkinson disease Comparison of 6-hydroxydompamine and 1-methyl-4-phenyl-1,2,3,6-tetarhydropyridine

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    BACKGROUND: At present, pathogenesis and mechanism of Parkinson disease (PD) are still unclear.Animal models of PD are essential tools in studies on etiology and therapy and should mimic the chronic pathological process, histological characteristics and motor behavior dysfunction. In recent years, transgenic mice have been widely utilized to study the mechanism of PD, and it has become imperative that a PD mouse model of motor behavioral dysfunction be established.OBJECTIVE: To compare the behavioral and histochemical characters of two neurotoxic mice model induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1, 2, 3, 6 -tetrahydropyridine (MPTP),and a better method to mimic Parkinson disease will be found out.DESIGN: Parallel experiment.SETTING: Laboratory of Molecular Genetics, Department of Medical Genetics, Shanghai Jiao Tong University.MATERIALS: Sixty 129Sv/C57BL6J male wild mice, SPF grade, 8 - 12 weeks old, weighing 20 - 25 g,were provided by Experimental Animal Center, Shanghai Jiao Tong University. All the surgery operation was performed according to the rules of Shanghai Jiaotong University Animal Committee.METHODS: The experiment was carried out in the Laboratory of Molecular Genetics (National Key Laboratory), Department of Medical Genetics, Shanghai Jiao Ttong University from March to August 2006.① Thirty-two male mice were randomly divided into control group and drug treatment group with 16 mice in each group. Surgery was carried out and 6-OHDA was administrated to substantia nigra pars compacta (SNpc) and nigra-striatum pathway according to the different parameters with intoxication apparatus. Saline was injected to the other 16 mice according to the same paradigm. 1 mg/kg apomorphine was injected intraperitoneally 2 weeks later after surgery to induce the imbalanced rotation behavior for 40 minutes. ②Twenty-eight mice were randomly divided into 4 groups with 7 in each group, including low-dose,moderate-dose, high-dose groups and

  13. Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Yang X

    2013-08-01

    Full Text Available Xinxin Yang, Na Wu, Lu Song, Zhenguo Liu Department of Neurology, Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Background: Levodopa remains the most effective drug for the treatment of Parkinson’s disease (PD. However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID, which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood. Methods: In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 µg, 2 µg, or 5 µg prior to levodopa treatment. Abnormal involuntary movements (AIMs scores and apomorphine-induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845 levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR. Results: We found that both 2 µg and 5 µg KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 µg reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 µg reduced the expression of Gad1 and Nur77 in PD rats. Conclusion: These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats. Keywords: Parkinson’s disease, levodopa

  14. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson's Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties.

    Science.gov (United States)

    Ximenes, José Christian Machado; Neves, Kelly Rose Tavares; Leal, Luzia Kalyne A M; do Carmo, Marta Regina Santos; Brito, Gerly Anne de Castro; Naffah-Mazzacoratti, Maria da Graça; Cavalheiro, Ésper Abrão; Viana, Glauce Socorro de Barros

    2015-01-01

    Parkinson's disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA) is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson's disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g) were divided into the groups: sham-operated (SO), untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg). Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests). Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations), histological (Fluoro-Jade staining), and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC). The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These results were

  15. Valproic Acid Neuroprotection in the 6-OHDA Model of Parkinson’s Disease Is Possibly Related to Its Anti-Inflammatory and HDAC Inhibitory Properties

    Directory of Open Access Journals (Sweden)

    José Christian Machado Ximenes

    2015-01-01

    Full Text Available Parkinson’s disease is a neurodegenerative disorder where the main hallmark is the dopaminergic neuronal loss. Besides motor symptoms, PD also causes cognitive decline. Although current therapies focus on the restoration of dopamine levels in the striatum, prevention or disease-modifying therapies are urgently needed. Valproic acid (VA is a wide spectrum antiepileptic drug, exerting many biochemical and physiological effects. It has been shown to inhibit histone deacetylase which seems to be associated with the drug neuroprotective action. The objectives were to study the neuroprotective properties of VA in a model of Parkinson’s disease, consisting in the unilateral striatal injection of the neurotoxin 6-OHDA. For that, male Wistar rats (250 g were divided into the groups: sham-operated (SO, untreated 6-OHDA-lesioned, and 6-OHDA-lesioned treated with VA (25 or 50 mg/kg. Oral treatments started 24 h after the stereotaxic surgery and continued daily for 2 weeks, when the animals were subjected to behavioral evaluations (apomorphine-induced rotations and open-field tests. Then, they were sacrificed and had their mesencephalon, striatum, and hippocampus dissected for neurochemical (DA and DOPAC determinations, histological (Fluoro-Jade staining, and immunohistochemistry evaluations (TH, OX-42, GFAP, TNF-alpha, and HDAC. The results showed that VA partly reversed behavioral and neurochemical alterations observed in the untreated 6-OHDA-lesioned rats. Besides, VA also decreased neuron degeneration in the striatum and reversed the TH depletion observed in the mesencephalon of the untreated 6-OHDA groups. This neurotoxin increased the OX-42 and GFAP immunoreactivities in the mesencephalon, indicating increased microglia and astrocyte reactivities, respectively, which were reversed by VA. In addition, the immunostainings for TNF-alpha and HDAC demonstrated in the untreated 6-OHDA-lesioned rats were also decreased after VA treatments. These

  16. Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons.

    Directory of Open Access Journals (Sweden)

    Patrick Aldrin-Kirk

    Full Text Available Synucleinopathies, characterized by intracellular aggregation of α-synuclein protein, share a number of features in pathology and disease progression. However, the vulnerable cell population differs significantly between the disorders, despite being caused by the same protein. While the vulnerability of dopamine cells in the substantia nigra to α-synuclein over-expression, and its link to Parkinson's disease, is well studied, animal models recapitulating the cortical degeneration in dementia with Lewy-bodies (DLB are much less mature. The aim of this study was to develop a first rat model of widespread progressive synucleinopathy throughout the forebrain using adeno-associated viral (AAV vector mediated gene delivery. Through bilateral injection of an AAV6 vector expressing human wild-type α-synuclein into the forebrain of neonatal rats, we were able to achieve widespread, robust α-synuclein expression with preferential expression in the frontal cortex. These animals displayed a progressive emergence of hyper-locomotion and dysregulated response to the dopaminergic agonist apomorphine. The animals receiving the α-synuclein vector displayed significant α-synuclein pathology including intra-cellular inclusion bodies, axonal pathology and elevated levels of phosphorylated α-synuclein, accompanied by significant loss of cortical neurons and a progressive reduction in both cortical and striatal ChAT positive interneurons. Furthermore, we found evidence of α-synuclein sequestered by IBA-1 positive microglia, which was coupled with a distinct change in morphology. In areas of most prominent pathology, the total α-synuclein levels were increased to, on average, two-fold, which is similar to the levels observed in patients with SNCA gene triplication, associated with cortical Lewy body pathology. This study provides a novel rat model of progressive cortical synucleinopathy, showing for the first time that cholinergic interneurons are vulnerable

  17. Experimental study on establishment of the animal model of Parkinson's disease by one-spot injection of 6-hydroxydopamine%单点注射6-羟基多巴胺成功建立帕金森病大鼠模型的实验研究

    Institute of Scientific and Technical Information of China (English)

    盘晓荣; 胡玉英; 俸道荣; 许立民

    2010-01-01

    目的 探讨成功建立帕金森病(Parkinson's disease,PD)大鼠模型的快速有效方法.方法 将Wistar大鼠92只,随机分为实验组(80只)及对照组(12只),采用脑立体定向术,实验组在大鼠右侧中脑腹侧被盖区(ventral tegmental area,VTA)注入6-OHDA,经阿朴吗啡(Apomorphine,APO)诱导表现为恒定左侧旋转且旋转圈数﹥210 r/30 min的视为成功PD大鼠模型,对照组则在脑部相应位置注入生理盐水.免疫组化法观察成功模型毁损侧黑质酪氨酸羟化酶(TH)阳性神经元的形态及数量变化.结果 (1)行为学检测:模型组与对照组手术后分别死亡2只及1只,实验组78只大鼠中36只左侧恒定旋转圈数﹥210 r/30 min,造模成功率为46.2%,并且维持时间长.(2)免疫组化:成功大鼠模型毁损侧黑质区TH阳性的神经元较对侧及对照组明显减少(P<0.01).结论 大鼠中脑VTA单点注射6-OHDA制作PD大鼠模型,易于定位,操作简单,动物死亡率低,模型成功率较高,成本较低,是较快建立稳定PD大鼠模型的可行方法.

  18. 模拟高原缺氧对雄性大鼠性功能的影响%Effect of hypoxia simulating high altitude on sexual function in male rats

    Institute of Scientific and Technical Information of China (English)

    熊智勇; 葛亮; 季惠翔; 支轶; 吴晓军; 卢根生

    2010-01-01

    目的 探讨模拟高原缺氧对雄性大鼠性功能的影响.方法 将60只SD健康雄性大鼠随机分为平原对照组、缺氧2周组、缺氧4周组、缺氧6周组,每组15只.缺氧组大鼠置于模拟海拔4 500 m低压舱中,23 h/d,连续减压2、4、6周.观察各组大鼠性行为参数(乘骑、插入、射精的次数及潜伏期)和阿朴吗啡(apomorphine,APO)诱发阴茎勃起次数的变化;用ACCESS全自动免疫分析系统测定大鼠血清睾酮的含量;用化学比色法测定阴茎海绵体组织一氧化氮合酶(nitric oxide synthase,NOS)的活性;Masson染色观察阴茎海绵体组织结构变化.结果 与平原对照组相比,各缺氧组大鼠的性行为参数(射精次数除外)受到抑制(P<0.05);APO诱发阴茎勃起的次数明显降低 (P<0.05);血清睾酮含量和阴茎组织中NOS活性均减低(P<0.05);Masson染色显示:大鼠阴茎海绵体平滑肌纤维减少,胶原纤维增多,窦状隙变小、变窄.且随着缺氧时间的延长,缺氧组大鼠的性行为逐渐受到抑制(P<0.05),血清睾酮含量及阴茎组织中NOS活性逐渐降低(P<0.05),阴茎海绵体组织结构纤维化程度加重.结论 高原缺氧环境下成年雄性大鼠性功能受到抑制,且性功能受抑制程度与缺氧时间有一定的关系.

  19. 不同强度经颅直流电刺激对帕金森大鼠旋转行为学的影响

    Institute of Scientific and Technical Information of China (English)

    李一言; 田学隆; 蒋巍巍; 钱龙; 俞雪鸿

    2012-01-01

    目的 研究不同强度阳极经颅直流电刺激(transcranial direct current stimulation,tDCS)对帕金森病(Parkinson's disease,PD)大鼠旋转行为学的影响.方法 根据完全随机原则,将成功造模的32例PD大鼠分成3个刺激组和1个假刺激组,每组8只.给予3个刺激组的左侧初级运动皮层(M1)区直流电刺激分别为20、80、200 μA的阳极刺激,刺激时间为30 min;给予假刺激组30 s的假刺激.tDCS后,对PD大鼠腹腔注射阿朴吗啡(apomorphine,APO),记录PD大鼠旋转的潜伏期、持续时间和平均转速(30 min内).结果 刺激后,80 μA刺激组、200 μA刺激组均与假刺激组的平均转速组间存在显著差异(P<0.05);80 μA刺激组和200 μA刺激组的平均转速间差异无显著性(P>0.05);各组潜伏期和持续时间组间差异无显著性(P>0.05).结论 适当强度的tDCS对PD大鼠的旋转运动功能具有显著的改善作用.考虑到安全性,最佳的刺激强度为80μA.

  20. α4 nicotinic acetylcholine receptor modulated by galantamine on nigrostriatal terminals regulates dopamine receptor-mediated rotational behavior.

    Science.gov (United States)

    Inden, Masatoshi; Takata, Kazuyuki; Yanagisawa, Daijiro; Ashihara, Eishi; Tooyama, Ikuo; Shimohama, Shun; Kitamura, Yoshihisa

    2016-03-01

    Galantamine, an acetylcholine esterase (AChE) inhibitor used to treat dementia symptoms, also acts as an allosteric potentiating ligand (APL) at nicotinic acetylcholine receptors (nAChRs). This study was designed to evaluate the allosteric effect of galantamine on nAChR regulation of nigrostrial dopaminergic neuronal function in the hemiparkinsonian rat model established by unilateral nigral 6-hydroxydopamine (6-OHDA) injection. Methamphetamine, a dopamine releaser, induced ipsilateral rotation, whereas dopamine agonists apomorphine (a non-selective dopamine receptor agonist), SKF38393 (a selective dopamine D1 receptor agonist), and quinpirole (a selective dopamine D2 receptor agonist) induced contralateral rotation. When 6-OHDA-injected rats were co-treated with nomifensine, a dopamine transporter inhibitor, a more pronounced and a remarkable effect of nicotine and galantamine was observed. Under these conditions, the combination of nomifensine with nicotine or galantamine induced the ipsilateral rotation similar to the methamphetamine-induced rotational behavior, indicating that nicotine and galantamine also induce dopamine release from striatal terminals. Both nicotine- and galantamine-induced rotations were significantly blocked by flupenthixol (an antagonist of both D1 and D2 dopamine receptors) and mecamylamine (an antagonist of nAChRs), suggesting that galantamine modulation of nAChRs on striatal dopaminergic terminals regulates dopamine receptor-mediated movement. Immunohistochemical staining showed that α4 nAChRs were highly expressed on striatal dopaminergic terminals, while no α7 nAChRs were detected. Pretreatment with the α4 nAChR antagonist dihydroxy-β-erythroidine significantly inhibited nicotine- and galantamine-induced rotational behaviors, whereas pretreatment with the α7 nAChR antagonist methyllycaconitine was ineffective. Moreover, the α4 nAChR agonist ABT-418 induced ipsilateral rotation, while the α7 nAChR agonist PNU282987 had no