RESUMO
Dysfunctions of the serotonergic system have been suggested to be important in the neurobiology of schizophrenia. Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-hydroxytryptamine(HT)2 receptor agonist disrupted PPI in rats. The inferior colliculus (IC) is a critical nucleus of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The present study investigated the role of serotonergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether 5-HT2A receptor activation or blockade would affect this response. Unilateral microinjection of DOI (10µg/0.3µl) into the IC disrupted PPI, while microinjection of the 5-HT2A receptor antagonist ritanserin (4µg/0.3µl), into this structure did not alter PPI. We also examined the ability of the atypical antipsychotic clozapine (5.0mg/kg; I.P.) to reverse the disruption of PPI produced by unilateral microinjections of DOI into the IC of rats. Pretreatment with clozapine blocked DOI-induced disruption of PPI. Altogether, these results suggest that serotonin-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic clozapine.
Assuntos
Anfetaminas/administração & dosagem , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Colículos Inferiores/efeitos dos fármacos , Colículos Inferiores/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Animais , Masculino , Microinjeções , Ratos Wistar , Receptor 5-HT2A de Serotonina/fisiologia , Ritanserina/administração & dosagem , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagemRESUMO
RATIONALE: Although 5-HT2 receptors seem to play an important role in anxiety, results from numerous studies are still highly variable. Moreover, little is known about the behavioral effects of centrally administered 5-HT2 compounds in animal models of anxiety. OBJECTIVE: The current study was performed to: (1) further investigate the effects of 5-HT2 receptor activation in rats exposed to the elevated plus-maze (EPM) and the open-field arena, two widely used animal models for studying anxiety and locomotor activity; and (2) evaluate the involvement of the 5-HT2 receptors within the basolateral nucleus of the amygdala (BLA) in the modulation of such effects. METHODS: In the first experiment, male Wistar rats were exposed for 5 min to the EPM 27 min following intraperitoneal (i.p.) (1.0 ml/kg) injections of the preferential 5-HT2C receptor agonist 6-chloro-2[1-piperazinyl]pyrazine (MK-212) at doses of 1.0, 2.0, or 4.0 mg/kg. Control animals were injected with saline. The percentage of open-arm entries and the percentage of time spent in these arms were employed as anxiety indexes, whereas the number of closed-arm entries was calculated as indicative of locomotor activity. In the second experiment, rats were exposed for 10 min in an open-field arena to further assess the interference of the same MK-212 doses upon locomotor activity. In Experiment 3, rats were microinjected (0.2 microl) either with the mixed 5-HT 2A/2C receptor antagonist ritanserin (0.5, 1.25, 2.5, and 5.0 microg) or its vehicle into the BLA 12 min following i.p. injections of saline or the intermediate dose of MK-212 (2.0 mg/kg). Fifteen minutes later, each animal was exposed to the EPM as before. RESULTS: Whereas the highest dose of MK-212 (4.0 mg/kg) induced motor-suppressant effects in both EPM and open-field arena, the intermediate dose of the drug (2.0 mg/kg) reduced open-arm exploration without significantly affecting the number of closed-arm entries. This behavioral profile, consistent with selective anxiogenic effect in the EPM, was dose-dependently prevented by ritanserin microinfusion into the BLA. In saline-pretreated animals, however, ritanserin (all doses) was ineffective. CONCLUSIONS: MK-212 increases anxiety and decreases locomotor activity. The anxiogenic-like profile of 5-HT2 receptor activation is prevented by the blockade of 5-HT2 receptors within the BLA, which does not have an effect by itself upon basal anxiety levels triggered by the EPM.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Pirazinas/farmacologia , Ritanserina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Pirazinas/administração & dosagem , Ratos , Ratos Wistar , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/fisiologia , Ritanserina/administração & dosagemRESUMO
Ritanserin is a thymosthenic agent with an extensive hepatic metabolism and long elimination half life in healthy volunteers. It has been used in abstinent chronic alcoholic patients showing an interesting performance in this condition. Ritanserin pharmacokinetics has only been evaluated in single dose healthy volunteer studies and, on the other hand, chronic use of the drug in alcoholic patients during withdrawal period could be anticipated. Therefore, the objective of the present study, is to assess the cumulating kinetics of the serotonin antagonist during chronic administration. Ten abstinent alcoholic patients were included in an open study. The drug was administered at a daily dose of 10 mg for 28 days and the active phase was preceded by a seven-day wash out period with placebo. Blood samples were taken on the 1st, and 28th, day of treatment, 24 hours after taking the drug. Urine samples were taken during the night before the second and 28th dose. Plasma and urine ritanserin concentration was measured by high performance liquid chromatography. Very large variations in initial and steady state concentrations (CV = 65 and 52% respectively) were found, which is reflected in the large variability of the calculated pharmacokinetic parameters. Ritanserin cumulation factor (R) was 6.9 +/- 8.3 (mean+SEM). Two patients showing extensive accumulation had prolonged elimination half lives (433 and 279 hours) that are explained mostly by an expansion of the volume of distribution and, to a lesser extent, by diminished clearance.
Assuntos
Alcoolismo/metabolismo , Ritanserina/farmacocinética , Adulto , Peso Corporal , Cromatografia Líquida , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ritanserina/administração & dosagem , Ritanserina/metabolismoRESUMO
La ritanserina es un agente timosténico que, en voluntarios sanos, se metaboliza principalmente en el hígado y presenta una prolongada vida media de eliminación. Ha sido usada en alcohólicos crónicos en abstinencia mostrando interesantes resultados. La farmacocinética de la ritanserina ha sido evaluada únicamente en estudios a dosis única en voluntarios sanos, si bien se considera que la medicación debe ser usada en forma crónica por pacientes alcoholistas para la deshabituación. Por lo tanto, el objetivo del presente estudio fue evaluar la cinética de acumulación del antagonista serotoninérgico durante la administración crónica. Se incluyeron 10 pacientes alcohólicos en abstinencia en un estudio abierto. El fármaco se adminsitró a una dosis diaria de 10 mg durante 28 días y la fase activa fue precedida por un período de 7 días de "lavado" con placebo. Las muestras de sangre se tomaron el día 1 y 28 del tratamiento, 24 horas luego de haber tomado la medicación. Se recogieron muestras de orina durante la noche en forma previa a la segunda y vigesimoctava dosis. Las concentraciones de ritanserina en plasma y orina se midieron por cromatografía líquida de alta performance. Se encontró una gran variación en las concentraciones plasmáticas tanto iniciales como correspondientes al estado de equilibrio (CV = 65 y 52 por ciento respectivamente), lo que se refleja en la variabilidad de los parámetros farmacocinéticos calculados. El factor de acumulación (R) fue 6,9 + or - 8,3 X + or - SEM. Dos pacientes que mostraron acumulación extensa presentaron una prolognada vida media de eliminación (433 y 289 horas), lo que en su mayor parte se explicaría por una expansión del volumen de distribución y, en menor grado, por una disminución del clearance
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Alcoolismo/metabolismo , Ritanserina/farmacocinética , Peso Corporal , Cromatografia Líquida , Doença Crônica , Taxa de Depuração Metabólica , Ritanserina/administração & dosagem , Ritanserina/sangue , Ritanserina/urinaRESUMO
La ritanserina es un agente timosténico que, en voluntarios sanos, se metaboliza principalmente en el hígado y presenta una prolongada vida media de eliminación. Ha sido usada en alcohólicos crónicos en abstinencia mostrando interesantes resultados. La farmacocinética de la ritanserina ha sido evaluada únicamente en estudios a dosis única en voluntarios sanos, si bien se considera que la medicación debe ser usada en forma crónica por pacientes alcoholistas para la deshabituación. Por lo tanto, el objetivo del presente estudio fue evaluar la cinética de acumulación del antagonista serotoninérgico durante la administración crónica. Se incluyeron 10 pacientes alcohólicos en abstinencia en un estudio abierto. El fármaco se adminsitró a una dosis diaria de 10 mg durante 28 días y la fase activa fue precedida por un período de 7 días de "lavado" con placebo. Las muestras de sangre se tomaron el día 1 y 28 del tratamiento, 24 horas luego de haber tomado la medicación. Se recogieron muestras de orina durante la noche en forma previa a la segunda y vigesimoctava dosis. Las concentraciones de ritanserina en plasma y orina se midieron por cromatografía líquida de alta performance. Se encontró una gran variación en las concentraciones plasmáticas tanto iniciales como correspondientes al estado de equilibrio (CV = 65 y 52 por ciento respectivamente), lo que se refleja en la variabilidad de los parámetros farmacocinéticos calculados. El factor de acumulación (R) fue 6,9 + or - 8,3 X + or - SEM. Dos pacientes que mostraron acumulación extensa presentaron una prolognada vida media de eliminación (433 y 289 horas), lo que en su mayor parte se explicaría por una expansión del volumen de distribución y, en menor grado, por una disminución del clearance (AU)