RESUMO
It has been proposed that activation of metabotropic glutamate receptor subtype 2/3 (mGluR2/3) may induce both antipsychotic and anxiolytic effects. The aim of this study was to evaluate further the effect of the mGluR2/3 agonist, LY354740 [(+)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylate monohydrate] in animal models relevant to both psychotic and cognitive impairment in schizophrenia. The elevated plus maze was used to select the doses for further experiments, LY354740 induced anxiolytic-like effects at doses of 3 and 10 mg/kg but not 1 mg/kg. At a dose of 10 mg/kg. LY354740 attenuated phencyclidine (PCP)-induced locomotor activity. Administered alone, it had no effect on horizontal activity, but at doses of 3 and 10 mg/kg, slightly decreased vertical activity (rearings). LY354740 (1-10 mg/kg intraperitoneally) affected neither prepulse inhibition in normal rats nor reversed the disruption of prepulse inhibition produced by PCP (2 mg/kg subcutaneously). Moreover, LY354740 (3-10 mg/kg) did not modify PCP-induced working memory deficits assessed in a spontaneous alternation task and had no effect on PCP-evoked amnesia in the passive avoidance test. LY354740 alone (3 and 10 mg/kg) induced working memory deficits, but had no effect on acquisition of passive avoidance. In conclusion, LY354740 was effective in models for anxiety and positive symptoms of schizophrenia but not in models for sensorimotor gating and cognitive impairment.
Assuntos
Ansiolíticos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Cognição/efeitos dos fármacos , Receptores de Glutamato Metabotrópico/agonistas , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Agonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.
Assuntos
Núcleo Celular/metabolismo , Doença de Machado-Joseph/complicações , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Animais , Ataxina-3 , Dorso/anormalidades , Comportamento Exploratório , Imuno-Histoquímica/métodos , Corpos de Inclusão/metabolismo , Doença de Machado-Joseph/metabolismo , Doença de Machado-Joseph/mortalidade , Doença de Machado-Joseph/psicologia , Transtornos Mentais/etiologia , Camundongos , Camundongos Transgênicos , Atividade Motora , Degeneração Neural/etiologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Peptídeos/genética , Fenótipo , Proteínas Repressoras/genética , Coloração e Rotulagem , Distribuição Tecidual , Tremor/etiologia , Repetições de Trinucleotídeos , Ubiquitina/metabolismoRESUMO
The retinal dopamine (DA) deficiency is an important feature of the pathogenesis in Parkinson's disease (PD) visual dysfunction. Systemic inhibition of complex I (rotenone) in rats has been proposed as a model of PD. In this study, we investigated whether systemic inhibition of complex I can induce impairment of DA-ergic cells in the retina, similar to the destruction of retinal cells found in PD patients. Rotenone (2.5mg/kg i.p., daily) was administered over 60 days. Neurochemically, rotenone treated rats showed a depletion of DA in the striatum and substantia nigra (SN). In addition, the number of retinal DA-ergic amacrine cells was significantly reduced in the rotenone treated animals. This study is the first one giving highlight towards a deeper understanding of systemic complex I inhibition (rotenone as an environmental toxin) and the connection between both, DA-ergic degeneration in the nigrostriatal pathway, and in the DA-ergic amacrine cells of the retina.
Assuntos
Modelos Animais de Doenças , Dopamina/metabolismo , Transtornos Parkinsonianos/metabolismo , Retina/metabolismo , Animais , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Retina/citologiaRESUMO
Many studies indicate a dissociation between two forms of orientation: allocentric orientation, in which an organism orients on the basis of cues external to the organism, and egocentric spatial orientation (ESO) by which an organism orients on the basis of proprioceptive information. While allocentric orientation is mediated primarily by the hippocampus and its afferent and efferent connections, ESO is mediated by the prefronto-striatal system. Striatal lesions as well as classical neuroleptics, which block dopamine receptors, act through the prefronto-striatal system and impair ESO. The purpose of the present study was to determine the effects of the atypical antipsychotics clozapine, olanzapine and risperidone which are believed to exert its antipsychotic effects mainly by dopaminergic, cholinergic and serotonergic mechanisms. A delayed-two-alternative-choice-task, under conditions that required ESO and at the same time excluded allocentric spatial orientation was used. Clozapine and olanzapine treated rats made more errors than risperidone treated rats in the delayed alternation in comparison with the controls. Motor abilities were not impaired by any of the drugs. Thus, with regard to the delayed alternation requiring ESO, clozapine and olanzapine but not risperidone affects the prefronto-striatal system in a similar way as classical neuroleptics does.
Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Clozapina/farmacologia , Antagonistas de Dopamina/farmacologia , Neostriado/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Risperidona/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Percepção Espacial/efeitos dos fármacos , Análise de Variância , Animais , Comportamento de Escolha/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Olanzapina , Orientação/efeitos dos fármacos , Ratos , Ratos Long-EvansRESUMO
A prolonged use of psychostimulants has been suggested to induce long-lasting behavioural sensitisation which plays a role in the acquisition and maintenance of addictive behaviour. A study was conducted to evaluate the effect of repeated oral administration of Catha edulis in rats. Male Sprague-Dawley rats divided into five groups received: saline, S-(-)-cathinone (1.5 mg/kg), D-(+)-amphetamine (1.5 mg/kg) and standardized C. edulis extract (50 or 200 mg/kg) once daily for nine consecutive days and later challenged with the same psychostimulants after five abstinence days. Then, 2 weeks later, rats were decapitated and the level of neurotransmitters were assessed. Behavioural activities were monitored using activity and sniffing boxes. The results demonstrated that the three psychostimulants induced strong behavioural sensitisation in rats. Whereas, neurotransmitters analyses showed no significant changes in the basal level of dopamine in most of the regions except that C. edulis extract (200 mg/kg) significantly reduced the level of DA, DOPAC and HVA in the anterior caudate putamen (P < 0.05). The capacity of C. edulis to elicit a long-lasting behavioural sensitisation support the anecdotal literatures about psychiatric problems associated with C. edulis chewing.
Assuntos
Alcaloides/farmacologia , Catha/química , Estimulantes do Sistema Nervoso Central/farmacologia , Atividade Motora/efeitos dos fármacos , Administração Oral , Anfetamina/farmacologia , Análise de Variância , Animais , Química Encefálica/efeitos dos fármacos , Catecolaminas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletroquímica/métodos , Masculino , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Locomotor sensitisation and deficits in prepulse inhibition (PPI) induced by psychostimulants are two paradigms that have been widely studied as animal behavioural models of psychosis. Clozapine is one of the atypical antipsychotic agents which has been widely employed to reverse the aforementioned behavioural changes in these usual models. In this particular study, locomotor sensitisation and prepulse inhibition deficit were induced under the same context by intermittent oral administration of S-(-)-cathinone or Catha edulis extract in rats. The rats were then challenged by administration of the atypical antipsychotic drug, clozapine and were finally challenged with psychostimulants after 2-week of withdrawal. Locomotor activity and PPI were assessed and later analyses of the neurotransmitter levels were made. The results of this experiment show that repeated oral administration of cathinone or C. edulis extract enhanced locomotor and exploratory activity and lead to a gradual deficit in prepulse inhibition. This locomotor sensitisation and PPI deficit could be reversed by administration of clozapine. A challenge with psychostimulant on day 40 (i.e., after 2-week of withdrawal) resulted in a response similar to the initial exposure (day 1). Neurotransmitter level analyses showed a significant increase in the level of dopamine in the prefrontal cortex (p < 0.05). There was also a significant decrease in the level of 5-hydroxytryptamine (5-HT) in the nucleus accumbens (p < 0.05) and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in the prefrontal cortex (p < 0.01). In the remaining regions (anterior and posterior striatum), there were no significant changes. In conclusion, this is the first study to demonstrate that repeated administration of C. edulis extract, or commercial cathinone, induces prepulse inhibition deficit and clozapine reverses both C. edulis or cathinone-induced sensitised locomotion and prepulse inhibition deficit.
Assuntos
Alcaloides/farmacologia , Catha/química , Clozapina/farmacologia , Inibição Psicológica , Atividade Motora/efeitos dos fármacos , Psicotrópicos/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , 5-Metoxitriptamina/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Dopamina/metabolismo , Interações Medicamentosas , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo Acústico/efeitos dos fármacos , Serotonina/metabolismoRESUMO
It has recently been shown that 3,4-Methylenedioxymethamphetamine (MDMA) has an anti-parkinsonian effect in rodent models of Parkinson's disease. The mechanism of this anti-parkinsonian action is unknown. Opioids have been suggested to play a role in MDMA-induced behaviour. We therefore investigated MDMA and naloxone in the rat rotational behavioural model. Male Sprague-Dawley rats were lesioned unilaterally with 6-hydroxydopamine at the medial forebrain bundle. Administration of R/S-MDMA (5 mg/kg, s.c.) produced ipsilateral rotations. Naloxone (2, 5, 10 mg/kg, s.c.) did not produce rotations on its own but reduced the number of MDMA-induced ipsilateral rotations. This effect was not dose-dependent. In contrast to reports on mice, in unlesioned animals, naloxone (10 mg/kg, s.c.) did not block MDMA (5 mg/kg, s.c.)-induced hyperactivity in an open field in our experiment. It is concluded that endogenous opioids play a role in MDMA's action in the rat rotational behavioural model.
Assuntos
Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Naloxona/farmacologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Relapse prevention in clean addicts is a great challenge for addiction-therapy. As strong cravings often precede relapse, anti-craving drugs seem to be a promising way for addicts to stay clean. Naloxone and acamprosate are two candidates for anti-craving drugs that are already used for relapse prevention in alcoholic patients. However, it has to be figured out if both drugs are also effective in opiate-addicts. In order to evaluate their effectiveness, a conditioned place preference (CPP) paradigm was used in rats conditioned to 10 mg/kg, i.p., morphine. As acamprosate and naloxone have been suggested to selectively affect different types of craving (withdrawal-craving versus reward-craving), we have tried to modulate craving-behaviour by maintaining two groups of rats under different conditions (isolated versus group-housed). Thereafter, the effectiveness of acamprosate (200 mg/kg, i.p.) and naloxone (2 mg/kg, i.p.) in reducing morphine-CPP expression was evaluated. As a result, isolation produced a weak reduction in morphine-CPP development. Furthermore, acamprosate and naloxone had no effect on morphine-CPP expression. Based on the present results, we assume that the anti-craving drugs acamprosate and naloxone may not be effective for relapse prevention in opiate-addicts.
Assuntos
Dissuasores de Álcool/farmacologia , Condicionamento Operante/efeitos dos fármacos , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Taurina/análogos & derivados , Taurina/farmacologia , Acamprosato , Análise de Variância , Animais , Comportamento Animal , Interações Medicamentosas , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Isolamento Social , Comportamento Espacial/efeitos dos fármacosRESUMO
Exposure to environmental cues is considered a major cause of relapse in detoxified addicts. Recent findings showed an involvement of glutamate in cue-induced relapse and suggest that subtype 5 of metabotropic glutamate receptors (mGluR5) is involved in conditioned drug-reward. The present study applied the conditioned place preference (CPP) paradigm to examine the involvement of mGluR5 in cocaine- and morphine-induced behaviours. Results of previous mice-studies were extended into rats by using the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). As a result, the evaluated behavioural parameters were dose-relatedly affected by MPEP. Low-dosed MPEP (10 mg/kg, i.p.) did not affect spontaneous locomotion, reduced cocaine-induced hyperlocomotion and produced sensitized locomotion, while showing no effect on sensitized locomotion induced by repeated cocaine or morphine. Low-dosed MPEP did not genuinely block development of cocaine- and morphine-CPP, but rendered CPP expression state-dependent. The medium MPEP-dose (30 mg/kg) was most effective in reducing spontaneous locomotion. The high MPEP-dose (50 mg/kg) was most effective in reducing both body-weight and morphine-CPP expression. Cocaine-CPP expression was not affected by any MPEP-dose. In conclusion, mGluR5 are involved in modulation of spontaneous and cocaine-induced locomotion, in state-dependent learning and in expression of morphine-CPP. Thus, MPEP may be beneficial for relapse prevention in morphine-addicts.
Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Entorpecentes/farmacologia , Piridinas/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Cocaína/antagonistas & inibidores , Relação Dose-Resposta a Droga , Aprendizagem/efeitos dos fármacos , Masculino , Morfina/antagonistas & inibidores , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/efeitos dos fármacos , RecompensaRESUMO
Noradrenaline, not only functions as a synaptic transmitter, but also promotes neural differentiation and regenerative processes. In Parkinson's disease, besides the dopaminergic degeneration, noradrenergic neurons of locus coeruleus origin degenerate as well. Drugs enhancing noradrenergic transmission in the locus coeruleus (e.g. alpha2-adrenoceptor antagonists) have been shown to be neuroprotective against Huntington's and ischemic animal models. However, in Parkinsonian animal models, most of the studies evaluated the worsening of experimental nigral neurodegeneration after locus coeruleus lesions. Here, it has been tested, whether treatment with the selective alpha2-adrenoceptor antagonist, 2-methoxy idazoxan (2.5 mg/kg i.p., twice daily for 5 days), before an experimental lesion to nigra, protects dopaminergic neurodegeneration. Dopaminergic degeneration was produced by 6-hydroxydopamine lesion in the median forebrain bundle. The concentrations of dopamine, 5-hydroxytryptamine and its metabolites were analysed in the various regions of the basal ganglia. The concentrations of noradrenaline and dopamine were measured in the regions innervated by locus coeruleus neurons and in the basal ganglia respectively, after 2-methoxy idazoxan treatment. The Parkinsonian behavior was assessed by catalepsy and activity test. 2-Methoxy idazoxan specifically increased the concentration of noradrenaline in the brain regions, innervated by locus coeruleus neurons. 6-OHDA lesion strongly depleted the concentration of dopamine and its metabolites in the striatum and SN, producing catalepsy and hypoactivity. Multiple treatments with 2-methoxy idazoxan reduced some of the observed neurochemical and behavioral indices of 6-hydroxydopamine-induced Parkinsonism, indicating neuroprotection. Although the mechanism underlying the neuroprotective property remains elusive, the therapeutic usage of alpha2-antagonists might be helpful in slowing the neuronal death and progression of Parkinson's disease.
Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Química Encefálica/efeitos dos fármacos , Idazoxano/análogos & derivados , Idazoxano/uso terapêutico , Transtornos Parkinsonianos/prevenção & controle , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/metabolismo , Interações Medicamentosas , Ácido Hidroxi-Indolacético/metabolismo , Idazoxano/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Serotonina/metabolismo , Estatísticas não ParamétricasRESUMO
In Parkinson's disease, besides the dopaminergic neurodegeneration, locus coeruleus noradrenergic neurons degenerate as well. Noradrenergic neurons have potential anti-parkinsonian, neuromodulatory and neuroprotective properties. Presently, an animal model with dopaminergic lesion has been used as a standard model of Parkinson's disease. The behavioral effects of dopaminergic agents in a Parkinson's animal model with additional noradrenergic lesions has not been studied so far. Here, the behavioral effects of dopaminergic agents L-DOPA (15 mg/kg) and D-amphetamine (4 mg/kg) in two different pathophysiological conditions have been explored; One group involving only dopaminergic deficiency with 6-hydroxydopamine (6-OHDA) and the other group with both dopaminergic and noradrenergic deficiency with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). DSP-4 specifically depleted noradrenaline from locus coeruleus terminal fields. 6-OHDA lesion depleted dopamine and its metabolites DOPAC, HVA and 3-MT in the regions of basal ganglia and it was potentiated by additional locus coeruleus denervation. Dopaminergic lesion produced catalepsy and hypoactivity. Hypoactivity in openfield was potentiated by additional noradrenergic denervation of locus coeruleus neurons. L-DOPA produced effective anticataleptic activity in group with both dopaminergic and noradrenergic lesions and D-amphetamine was found to be more effective in group only with dopaminergic lesions, indicating increased dopaminergic neurodegeneration after noradrenergic lesions. L-DOPA produced hyperactivity in dual neurodegenerated group indicating its differential activity in an animal model with noradrenergic and dopaminergic lesions. These findings indicate the neuroprotective and symptomatic role of noradrenergic neurons. It implicates the importance of noradrenergic pathophysiology in Parkinson's disease and its treatment and need for a more relevant animal model.
Assuntos
Adrenérgicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Benzilaminas/toxicidade , Química Encefálica/efeitos dos fármacos , Norepinefrina/deficiência , Doença de Parkinson/metabolismo , Tirosina/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Anfetamina/farmacologia , Análise de Variância , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/metabolismo , Modelos Animais de Doenças , Dopamina/deficiência , Dopaminérgicos/farmacologia , Ácido Homovanílico/metabolismo , Levodopa/farmacologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Doença de Parkinson/etiologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Estatísticas não Paramétricas , Tirosina/metabolismoRESUMO
In this study, it was investigated whether context-dependent sensitization of catalepsy changes the firing pattern in striatum. Rats were treated with either haloperidol (0.5 mg/kg i.p.) or saline, and tested on catalepsy with a concomitant single-unit measurement of the spiny I activity. Administration of haloperidol caused sensitization of catalepsy as measured on bar and grid. Concurrent within this behavioral change, spike-frequency increased over the course of the testing days in haloperidol-treated rats whereas the spike-frequency remained unchanged in saline-treated animals. Burst-frequency remained unchanged within both treatment groups over the days. In conclusion, sensitization of catalepsy is represented by striatal cellular activity as indicated by increases in spike-frequency of spiny I neurons.
Assuntos
Potenciais de Ação/fisiologia , Catalepsia/fisiopatologia , Corpo Estriado/fisiopatologia , Potenciais de Ação/efeitos dos fármacos , Animais , Catalepsia/induzido quimicamente , Antagonistas de Dopamina/farmacologia , Eletrofisiologia , Haloperidol/farmacologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The metabolism of MDA (3,4-methylenedioxyamphetamine), HMMA (3-hydroxy-4-methoxymethylamphetamine) and HME (3-hydroxy-4-methoxyethylamphetamin) of the popular designer drugs MDMA ('ecstasy', 3,4-methylenedioxymethamphetamine) and MDE ('eve', 3,4-methylenedioxyethylamphetamine) was determined in rat serum, whole blood and urine, as well as in whole brain structures (cortex and striatum) after subcutaneous administration of 20 mg/kg MDMA and MDE, respectively. MDMA and MDE were extracted from serum and homogenized brain structures using a solid-phase extraction procedure. The extracts were examined by a validated high-performance liquid chromatography procedure coupled with fluorimetric detection. Our results demonstrate that MDMA is metabolized to a higher degree than MDE, resulting in a higher concentration of neurotoxic dihydroxymetabolites and (S)-MDA. There was no difference between the metabolism of MDMA and MDE and its respective isomers. Different concentrations of the respective isomers of MDMA and MDE let us suggest an enantioselective metabolism for both MDMA and MDE.
Assuntos
Encéfalo/metabolismo , Alucinógenos/sangue , N-Metil-3,4-Metilenodioxianfetamina/sangue , Análise de Variância , Animais , Química Encefálica/efeitos dos fármacos , Córtex Cerebral/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Corpo Estriado/química , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Drogas Desenhadas , Cromatografia Gasosa-Espectrometria de Massas , Alucinógenos/metabolismo , Alucinógenos/farmacocinética , Injeções Subcutâneas , Isomerismo , N-Metil-3,4-Metilenodioxianfetamina/metabolismo , N-Metil-3,4-Metilenodioxianfetamina/farmacocinética , Ratos , Ratos Sprague-Dawley , Serotoninérgicos/sangue , Serotoninérgicos/metabolismo , Serotoninérgicos/farmacocinéticaRESUMO
Parkinson's disease is due to a dopamine deficiency caused by the degeneration of midbrain dopamine neurons. Current therapies are aimed to substitute dopamine or to directly stimulate postsynaptic dopamine receptors. However, not all patients profit from current therapies to the same extent, even serious side effects such as dyskinesias are complicating the therapy. Therefore, there is still a need for better anti-parkinsonian drugs. Here we show that some compounds from the 'Ecstasy'-derivatives exert potent anti-parkinsonian activity. 3,4-Methylenedioxymethamphetamine, 'Ecstasy' dose-dependently and very potently reversed haloperidol-induced parkinsonism in the rat. From the supraadditive effect of the enantiomers it may be concluded that both enantiomers contribute to the antiparkinsonian effects at two different target sites.
Assuntos
3,4-Metilenodioxianfetamina/análogos & derivados , Inibidores da Captação Adrenérgica/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/fisiopatologia , 3,4-Metilenodioxianfetamina/farmacologia , Animais , Catalepsia/fisiopatologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Haloperidol/farmacologia , Masculino , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Ratos Sprague-DawleyRESUMO
3,4-methylenedioxy-methylamphetamine (MDMA) ('Ecstasy') and its analogue 3,4-methylenedioxy-methylamphetamine (MDE) ('Eve') are well known illicit street drugs mainly abused by young people. In spite of the actual research going on, the classification of their abuse potential remains unclear. Since secondary reinforcers are the main factors responsible for craving and relapse, the aim of our study was to assess the potency of MDMA and MDE in a second order reinforcement paradigm, i.e. conditioned place preference (CPP). For the general assessment of our study conditions, we compared MDMA with amphetamine. Unexpectedly, no significant CPP for MDMA was found in contrast to amphetamine. Detailed analysis of current literature led us to the working hypothesis that social environment is crucial for the development of CPP. In a subsequent experiment we tested the influence of housing conditions on CPP using MDMA and demonstrated that isolated animals show significant CPP compared to group-housed ones. In order to better understand the rewarding mechanisms of Ecstasy-derivatives, we tested both the racemic drugs and the pure isomers in the CPP paradigm. Both MDMA's optical isomers and racemic MDMA showed significant CPP without notable differences, while MDE and its isomers completely failed to show any significant CPP. In conclusion, the mechanism by which MDMA induces addiction is much more complicated than assumed so far and more pronounced in isolated animals. The fact that both optical isomers of MDMA led to CPP implies that at least two pathways by which MDMA induces craving behaviour exist.
Assuntos
3,4-Metilenodioxianfetamina/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Alucinógenos/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Isomerismo , Masculino , Ratos , Ratos Sprague-Dawley , Recompensa , Isolamento SocialRESUMO
To evaluate the putative rewarding properties of the anticraving substance acamprosate, male rats learned to associate injections of vehicle and acamprosate (200 mg/kg ip) with two visually contrasting compartments in a place conditioning paradigm. The degree of preference for the acamprosate-associated compartment was determined, in both a postconditioning test with undrugged animals and a consecutive test with drugged animals, to rule out the possibility that a putatively rewarding effect of acamprosate may have been masked by state-dependent effects. The animals did not show any preference for the substance-paired compartment, neither in the undrugged nor in the drugged state. In conclusion, acamprosate has no rewarding properties as shown in place preference. Therefore, it may prevent a relapse in detoxified alcoholics in a way other than by simply substituting the rewarding effects of ethanol. This adds to the therapeutic value of acamprosate in the treatment of drug craving.
Assuntos
Dissuasores de Álcool/efeitos adversos , Dissuasores de Álcool/farmacologia , Alcoolismo/tratamento farmacológico , Condicionamento Clássico , Taurina/efeitos adversos , Taurina/farmacologia , Acamprosato , Animais , Masculino , Movimento , Ratos , Ratos Sprague-Dawley , Taurina/análogos & derivadosRESUMO
The alpha2-adrenoreceptor antagonist idazoxan counteracts catalepsy induced by neuroleptic agents and improves Parkinsonian signs in 1-methyl-4-phenyl 1,2,3,6,tetrahydropyridine-treated monkeys and in patients. The present study addressed the question of whether systemic administration of idazoxan (1.5 mg/kg i.p.) improves Parkinsonian symptoms in a rat model of permanent dopaminergic neurodegeneration. Dopaminergic degeneration was induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB). Parkinsonian behaviour was assessed by catalepsy and open-field exploratory behaviour tests. Since dopaminergic and serotonergic mechanisms are thought to account for the anti-cataleptic/anti-Parkinsonian property of idazoxan, dopamine, 5-hydroxytryptamine (5-HT) and its metabolites in the regions of the basal ganglia and prefrontal cortex were analysed by HPLC. 6-OHDA lesions in the MFB produced catalepsy and hypoactivity in the open field and depleted dopamine and its metabolites in the basal ganglia and prefrontal cortex, but did not affect 5-HT. Treatment with idazoxan counteracted the observed Parkinsonian behaviour in 6-OHDA-lesioned rats and increased the spontaneous open-field activity in control rats. In both 6-OHDA and control animals, idazoxan increased DA level in the prefrontal cortex, but not in any other structures including the striatum. Idazoxan also increased the levels of 5-HT in the anterior striatum, prefrontal cortex and the ventral tegmental area of both 6-OHDA and control animals. These findings indicate that systemic administration of idazoxan counteracts 6-OHDA-induced Parkinsonian symptoms in rats and that both dopaminergic and serotonergic mechanisms could contribute to its anti-Parkinsonian effect.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antiparkinsonianos/farmacologia , Encéfalo/efeitos dos fármacos , Idazoxano/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Antagonistas Adrenérgicos alfa/uso terapêutico , Animais , Encéfalo/metabolismo , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/análise , Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Ácido Hidroxi-Indolacético/metabolismo , Idazoxano/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/análise , Serotonina/metabolismo , Fatores de TempoRESUMO
RATIONALE: Repeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training. OBJECTIVES: The aim of this study was to provide a neurobiological mechanistic explanation for these findings. MATERIALS AND METHODS: We use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague-Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context. RESULTS: Simulation results show that catalepsy sensitization, and its context dependency, can be explained by "NoGo" learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model's account of context dependency. CONCLUSIONS: Simulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal.
Assuntos
Catalepsia/psicologia , Antagonistas de Dopamina , Antagonistas dos Receptores de Dopamina D2 , Extinção Psicológica/efeitos dos fármacos , Haloperidol , Animais , Gânglios da Base/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Simulação por Computador , Masculino , Modelos Neurológicos , Ratos , Ratos Sprague-Dawley , RecompensaRESUMO
Sustained drug delivery providing continuous dopaminergic stimulation is thought to prevent or delay the induction of motor complications (dyskinesia) in Parkinson's disease, whereas pulsatile administration is supposed to promote them. This study investigated the inducibility of sensitization and abnormal involuntary movements (AIMs), comparing continuous and pulsatile administration of rotigotine with pulsatile administration of 3,4-dihydroxy-L-phenylalanine (L-DOPA) for reference. Rats were unilaterally lesioned with 6 hydroxydopamine (6-OHDA). For pulsatile administration, L-DOPA-methylester (10 mg/kg L-DOPA i.p.) or rotigotine (1 mg/kg i.p.) were administered once or twice daily. For continuous administration, a slow release formulation of rotigotine was injected s.c. at a dose of 1 mg/kg every 48 h (experiment I) or every 24 h (experiment II). Pulsatile administration of rotigotine and L-DOPA caused contraversive rotations increasing progressively upon each successive treatment. AIMs started to occur after the second administration of L-DOPA but hardly after pulsatile rotigotine. Continuous rotigotine increased rotations, which reached a plateau after the second administration. No AIMs were observed under continuous administration. The continuous administration of rotigotine did not induce sensitization or AIMs, suggesting that continuous stimulation of dopaminergic receptors by rotigotine has no propensity to induce dyskinesia in this experimental model.
Assuntos
Agonistas de Dopamina/administração & dosagem , Discinesia Induzida por Medicamentos , Discinesias/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem , Adrenérgicos/toxicidade , Animais , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/complicações , Ratos , Ratos Sprague-Dawley , RotaçãoRESUMO
The effect of transient inactivation of the amygdala on expression of cocaine conditioned place preference (CPP) and locomotion was studied. We found that rats with bilateral but not unilateral amygdala cannula placement exhibited increased CPP expression during a vehicle and a cocaine test as well as increased cocaine-induced hyper-locomotion. We discuss the observed effects as being caused by the cannulation per se and we conclude that the applied cannulation produced an increased responsiveness of the amygdala by a yet undetermined mechanism.