RESUMO
Tryptophan depletion techniques are effective in reducing central serotonergic function and have been used to investigate its role in mood and cognition. In the present study a tryptophan-free diet was fed to Lister-hooded male rats chronically for 21 days to investigate the effect of lowering central serotonin concentration on cognition using the novel object-recognition paradigm. Chronically tryptophan-depleted rats had impaired object-recognition memory; this was accompanied by a reduction in central serotonin of 40-50% in the hippocampus, frontal cortex and striatum. In a subsequent experiment, the atypical antipsychotic, risperidone (0.2 mg/kg), but not the typical antipsychotic, haloperidol (0.1 mg/kg), administered i.p. 30 min prior to the retention test, significantly attenuated the chronic tryptophan depletion impairment. These data show that chronic lowering of central serotonin is associated with impaired cognitive performance, and that this can be reversed by the atypical antipsychotic, risperidone.
Assuntos
Transtornos da Memória/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/farmacologia , Antagonistas da Serotonina/farmacologia , Triptofano/deficiência , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia/métodos , Dieta , Modelos Animais de Doenças , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Atividade Motora/efeitos dos fármacos , Ratos , Serotonina/metabolismo , Triptofano/sangueRESUMO
Dietary induced acute tryptophan depletion (ATD) is used to reduce central serotonergic function and to investigate the role of serotonin (5-HT) in psychiatric illness. In healthy volunteers ATD produces working memory deficits and decreases mood in some studies. Brain-derived neurotrophic factor (BDNF) plays a role in both cognition and in the regulation of mood; however, the possible contribution of central BDNF changes to the effects of ATD has not been examined. Therefore, using a rat model we have examined the effect of amino acid mixture-induced ATD on plasma and central BDNF protein levels. ATD significantly reduced free-plasma TRP by 79% and central hippocampal 5-HT by 35% when compared to controls. However, plasma or central BDNF protein levels in the hippocampus and midbrain were not significantly altered by ATD. These results suggest that changes in central BDNF do not contribute to the cognitive or mood effects of ATD.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Triptofano/deficiência , Animais , Ensaio de Imunoadsorção Enzimática/métodos , Ácido Hidroxi-Indolacético/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Triptofano/sangueAssuntos
Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores Enzimáticos/farmacologia , Hipocampo/metabolismo , Fenciclidina/farmacologia , Animais , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Fenciclidina/administração & dosagem , RatosRESUMO
RATIONALE: Tryptophan depletion is used to reduce central serotonergic function and to investigate its role in psychiatric illness. Despite widespread clinical use, its effects on serotonin (5-HT) receptors have not been well characterized. OBJECTIVE: The aim of this study was to examine the effect of acute (ATD) and chronic tryptophan depletion (CTD) on free-plasma tryptophan (TRP), central TRP and 5-HT and brain 5-HT(1A) and 5-HT(2A) receptor binding in the rat. METHODS: TRP and 5-HT were measured by high-performance liquid chromatography and receptor levels determined by homogenate radioligand binding and in-vitro receptor autoradiography. RESULTS: Free-plasma TRP, central TRP and central 5-HT levels were significantly and similarly reduced by ATD and 1- and 3-week CTD compared to controls. ATD significantly reduced 5-HT(1A) binding in the dorsal raphe (14%) but did not significantly alter postsynaptic 5-HT(1A) binding (frontal cortex, remaining cortex and hippocampus) or 5-HT(2A) binding (cortex and striatum). One-week CTD did not significantly alter cortical 5-HT(2A) binding or postsynaptic 5-HT(1A) binding. Furthermore, 3-week CTD did not significantly alter 5-HT(1A) binding but significantly increased cortical 5-HT(2A) binding without affecting striatal or hippocampal levels. In the CTD 1 and 3-week groups, rat body weight was significantly decreased as compared to controls. However, weight loss was not a confounding factor for decreased cortical 5-HT(2A)-receptor binding. CONCLUSION: ATD-induced reduction in somatodendritic 5-HT(1A) autoreceptor binding may represent an intrinsic 'homeostatic response' reducing serotonergic feedback in dorsal raphe projection areas. In contrast, the increase in 5-HT(2A) receptor after CTD may be a compensatory response to a long-term reduction in 5-HT.
Assuntos
Encéfalo/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Triptofano/deficiência , Animais , Autorradiografia , Autorreceptores/metabolismo , Peso Corporal , Cromatografia Líquida de Alta Pressão , Retroalimentação Fisiológica , Masculino , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Triptofano/sangueRESUMO
The 2006 British Association for Psychopharmacology Summer Meeting was held in Oxford, UK. The British Association for Psychopharmacology is now one of the largest national psychopharmacology associations in the world with over 1000 members, and 550 national and international delegates attended the summer meeting. This meeting provides an annual forum for scientists and clinical investigators from academia and the pharmaceutical industry to share information on many aspects of the psychopharmacology of psychiatric illness. In total, 292 abstracts were accepted for presentation at the meeting. These were divided into 57 oral and 235 poster presentations. Research areas covered all aspects of psychopharmacology from basic research to pharmaceutical development and clinical application. This report highlights selected presentations from the meeting, focusing on rapid tryptophan depletion, which is a dietary manipulation that is used to study central serotonin function and putative animal models of depression and schizophrenia.
Assuntos
Psicofarmacologia , Animais , Congressos como Assunto , Humanos , Reino UnidoRESUMO
Many atypical antipsychotic drugs, such as clozapine, can induce significant weight gain which can have serious implications for drug compliance and morbidity. Food intake and weight gain are regulated primarily by the hypothalamus; the arcuate nucleus (ARC) of the hypothalamus is the region initially mediating the effects of circulating hormones on food intake. Neuropeptide Y (NPY) is an important hypothalamic peptide involved in body weight regulation. Immunohistochemical staining of NPY in the ARC was carried out in male Sprague-Dawley rats treated with haloperidol (1.5 mg/kg, i.p.) or clozapine (25 mg/kg, i.p.) for 3 weeks. Clozapine, but not haloperidol, produced an increase in NPY immunoreactivity in the ARC, suggesting that effects on NPY may be involved in increases in body weight following clozapine treatment.
Assuntos
Antipsicóticos/farmacologia , Clozapina/farmacologia , Haloperidol/farmacologia , Hipocampo/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most selective for alpha(1d)-adrenergic receptors (alpha(1d)-AR) reported to date. In cloned receptor assay systems, 12 displays at least 95-fold selectivity for the alpha(1d)-AR over all other G-protein-coupled receptors tested, and the subtype selectivity of 11 was confirmed in pharmacologically defined isolated tissue preparations.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Piperazinas/síntese química , Compostos de Espiro/síntese química , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Humanos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 1/fisiologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Baço/efeitos dos fármacos , Baço/fisiologia , Estereoisomerismo , Relação Estrutura-Atividade , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
The alpha1A- and alpha1B-adrenoceptor affinity of the typical (chlorpromazine, haloperidol, pimozide, thioridazine and trifluoperazine) and atypical (clozapine, olanzapine, quetiapine, risperidone and sertindole) antipsychotics was determined by competition binding at alpha1A- and alpha1B-adrenoceptors in rat submaxillary gland and liver. Although all antipsychotics bound to both subtypes with relatively high affinity (K(i)s<74 nM), none were selective (>10-fold). Comparison with published dopamine D2 receptor affinities suggests that antipsychotic blockade of alpha1A- and/or alpha1B-adrenoceptors may contribute to the antipsychotic activity of all the atypical and several of the typical antipsychotics examined.
Assuntos
Antagonistas Adrenérgicos alfa/metabolismo , Antipsicóticos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Antipsicóticos/farmacologia , Masculino , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
GABAergic neuronal subpopulations, defined by the presence of the calcium binding proteins, parvalbumin (PV) and calretinin (CR) are differentially affected in schizophrenia, with selective PV deficits reported in the prefrontal cortex and hippocampus. To assess the possible contribution of antipsychotic treatment to these effects we examined the size and density of PV-and CR-IR neurons in the rat frontal cortex and hippocampus following three weeks of chronic haloperidol or clozapine administration. Neither antipsychotic significantly altered PV- or CR-IR neuronal cell parameters in these areas or in any of their subregions, relative to controls. These results suggest antipsychotic exposure does not contribute to PV-IR neuronal deficits in schizophrenic patients, providing further evidence in support of a developmental abnormality in specific subpopulations of GABAergic neurons in schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Parvalbuminas/metabolismo , Animais , Tamanho Celular/efeitos dos fármacos , Clozapina/farmacologia , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Haloperidol/farmacologia , Hipocampo/metabolismo , Hipocampo/patologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Many antipsychotics exhibit potent anti-alpha(1)-adrenergic receptor activity, which has been suggested to contribute to typical and atypical antipsychotic effects and to the production of centrally mediated side effects. OBJECTIVES: To assess the relative contribution of alpha(1)-adrenoceptors to the mechanism of action of haloperidol and clozapine and to identify possible sites of action. METHODS: We examined the effect of chronic haloperidol and clozapine treatment on alpha(1)-adrenoceptor characteristics in several rat brain regions. For comparison, D(2)-like dopamine receptor density in the striatum was also determined. RESULTS: Clozapine administration (25 mg/kg/day i.p., 21 days) significantly increased alpha(1)-adrenoceptor density in the frontal cortex (44%), remaining cortex (49%) and thalamus (93%) but binding levels in the hippocampus and spinal cord were unchanged relative to vehicle. Haloperidol treatment (1.5 mg/kg/day i.p., 21 days) also significantly increased the density of alpha(1)-adrenoceptor binding in the thalamus (73%), but had no effect on alpha(1)-adrenoceptor levels in any other region examined. alpha(1)-Adrenoceptor affinity in the cortex was not significantly altered by either antipsychotic treatment. Haloperidol, in contrast to clozapine, significantly upregulated dopamine D(2)-like binding in the striatum. CONCLUSIONS: Central alpha(1)-adrenoceptors are differentially regulated after chronic haloperidol and clozapine treatment. It is suggested that thalamic alpha(1)-adrenoceptors may represent a common anatomical locus contributing to the antipsychotic activity and/or alpha(1)-adrenoceptor centrally mediated side effects of both drugs, whereas the selective upregulation of cortical alpha(1)-adrenoceptor density by clozapine may contribute, in part, to its superior atypical properties.