Influence of Withania somnifera on obsessive compulsive disorder in mice

OBJECTIVE@#To study the influence of methanolic and aqueous extract of Withania somnifera (W. somnifera) root on the marble-burying behavior of mice a well-accepted model of obsessive compulsive behavior.@*METHODS@#Mice were divided in different groups (n = 6). Fluoxetine (5, 10, 15 mg/kg), (10, 25, 50, 100 mg/kg) and methanolic extract W. somnifera (MEWS) (10, 25, 50, 100 mg/kg) were administered i.p. 30 min. prior to the assessment of marble burying behavior and locomotor activity. The control group received vehicle of the extract.@*RESULTS@#Administration of aqueous extracts W. somnifera (AEWS) and MEWS (50 mg/kg) successively decreased the marble burying behavior activity without affecting motor activity. This effect of AEWS and MEWS was comparable to standard fluoxetine, ritanserin and parachlorophenylalanine.@*CONCLUSIONS@#W. somnifera extract is effective in treating obsessive compulsive disorder.

The Role of 5-HT Receptors on the Acetylcholine Release from the Rat Striatum / 대한정신약물학회지

The aim of this study was to investigate the role of the 5-HT receptors in acetylcholine (ACh) release from the striatum. Slices from the rat striatum and synaptosomes were incubated with [3H]-choline and the release of the labelled products was evoked by electrical (3 Hz, 2 ms, 5 V/cm, rectangular pulses, 2 min) and potassium-stimulation (25 mM), respectively, and the influence of various serotonergic drugs on the evoked tritium outflows was investigated. Serotonin decreased the electrically-evoked ACh release in striatum in a concentration-dependent manner without the change of basal release. In hippocampal and entorhinal cortical slices, serotonin did not affect the evoked and basal release of ACh, but, at large dose (30 microM) decreased the evoked ACh release in hippocampus. 2,5-Dimethoxy-4-iodoamphetamine (DOI), a specific 5-HT 2A/2C agonist, decreased evoked ACh release in the striatum. CGS-12066A (5-HT 1B agonist), m-chlorophenyl-biguanide (5-HT 3 agonist) and 5-[(dimethyl -amino)methyl]-3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazole (5-HT 3 antagonist) did not affect the evoked and basal ACh release in all tissues. Ritanserin, a specific 5-HT 2A/2C antagonist, blocked the inhibitory effects of serotonin and DOI, whereas, ketanserin, an another type of specific 5-HT 2A/2C antagonist did not affect the inhibitory effects of serotonin and DOI. In striatal synaptosomal preparation, serotonin and DOI did not affect the K +-evoked ACh release. These findings suggest that ritanserin-sensitive 5-HT 2A/2C receptors located in the soma and/or axons of the striatal cholinergic neurons play a important role in ACh release.

Ritanserin, a 5HT2/1C receptor antagonist, does not block cocaine-induced behavioral alterations and zif268 mRNA expression in the striatum of the rats

Cocaine induces immediate early gene expression and behavioral changes by blocking dopamine transporters in the terminals of nigrostriatal neurons in the striatum. The pharmacological role of serotonin 2/1C (5HT2/1C) receptors in cocaine-induced expression of zif268 (NGFI-A, egr1 and Krox-24) mRNA, a member of the zinc finger, was investigated using quantitative in situ hybridization histochemistry in vivo. Behavioral alterations induced by cocaine were also monitored in relation with blockade of the receptors. Systemic injection of ritanserin (1 mg/kg, s.c.), a 5HT2/1C receptor antagonist, did not reverse behavioral alterations and zif268 mRNA gene expression induced by 15 mg/kg cocaine, i.p., in the dorsal and ventral striatum. These data indicate that ritanserin-sensitive 5HT2/1C receptors are not necessary for cocaine-induced behavioral alterations and zif268 mRNA gene expression in the striatum.

Amperozide decreases cocaine-induced increase in behavior and immediate early gene expression in the dorsal striatum

Cocaine functions as indirect dopamine and serotonin (5-hydroxytryptamine, 5HT) agonists and induces genomic and behavioral alterations in the striatum. Previously we demonstrated that ritanserin, a 5HT2/1C receptor antagonist, is not responsible for cocaine-induced behavioral alterations and zif268 mRNA gene expression in the striatum (see the previous paper in this issue). In this study, it was hypothesized that dopamine and 5HT2/1C receptors are required for cocaine-induced behavioral alterations and c-fos and zif268 mRNA expression. This hypothesis was addressed by infusing amperozide which antagonizes both 5HT2/1C and dopamine receptors and was analyzed using the quantitative in situ hybridization histochemistry in vivo. Systemic injection of amperozide (5 mg/kg, s.c.) significantly blocked increase in behavior, c-fos and zif268 mRNA expression induced by 15 mg/kg cocaine, i.p., in the dorsal striatum. These data suggest that dopamine and 5HT2/1C receptors are necessary for cocaine-induced behavioral alterations and immediate early gene expression in the dorsal striatum.

Effect of Ritanserin on the Circling Movement in the Unilateral Substantia Nigra-Lesioned Rats / 대한정신약물학회지

OBJECTIVE: Recently, the serotonin-dopamine interaction is being regarded as a possible mechanism for both less extrapyramidal symptoms and good therapeutic effect on negative symptoms which are outstanding advantages of atypical antipsychotics. The goal of the study was to further define serotonin dopamine interaction in three different brain area of rats ; prefrontal cortex, striatum and nucleus accumbens. METHOD: The rats used in this study weighed 150-300gm. Under the aesthesia with pentothal sodium(25 mg/kg), stainless steel cannula was inserted in the right substantia nigra according to atlas(Paxinous and Watson) and 6-OHDA was injected at the rate of 1 mul/min to make a unilateral substantia nigra lesion. A week later, apomorphine (s. c. 0.1 mg/kg) was injected through the cannula and the rats with circling behavior counting more than 200 for an hour were selected for the study. Three weeks after that, the rats were further divided into 3 groups according to the brain area that permanent stainless steel cannula was implanted : prefrontal cortex group, striatum group and nucleus accumbens group. Within each group comparison was done between the number of circling behavior obtained by the injection of vehicle plus apomorphine and the one obtained by the injection of ritanserin plus apomorphine. Wilcoxon signed ranks test was used in data-analysis. RESULTS: The effect of ritanserin on the circling behavior in prefrontal cortex was absent but in striatum and nucleus accumbens, increasing effect was noted. CONCLUSIONS: It might be suggested that serotonin has an inhibitory control on dopaminergic function in striatum and nucleus accumbens.

Effect of Trazodone on the Rat Cerebral Hemodynamics / 대한정신약물학회지

OBJECTIVES: The present study assessed the effect of trazodone on the cerebral hemodynamics of male Sprague-Dawley rats. METHOD: The changes of regional cerebral blood flow(rCBF) and pill arterial diameter were measured by laser-Doppler flowmetry and by a videomicroscopy, respectively. The changes in vascular tone and intracellular free Ca2+ concentration ([Ca2+]i) of isolated basilar artery were simultaneously measured using a small vessel myograph and a cation measurement system, respectively. RESULT: Both the rCBF and the pill arterial diameter were dose-dependently decreased by systemic administration of trazodone(0.3-10 mg/kg, i.v.), but not by topical application of trazodone(10-300 micrometer). Pretreatment with 5-HT(2A/2C) receptor antagonist(ketanserin or ritanserin, 1 mg/kg, i.v., respectively) significantly blocked the changes in rCBF induced by trazodone. m-Chlorophenylpiperazine(mCPP ; 0.1-3 mg/kg, i.v. or 5-500 micrometer topical), a major active metabolite of trazodone, also dose-dependently decreased the rCBF as well as the pial arterial diameter. The mCPP-induced decreases in rCBF were significantly blocked by ketanserin. Pretreatment with itraconazole(1 mg/kg, p.o.), a selective inhibitor of CYP3A4, a subfamily of cytochrome P450, markedly attenuated the trazodone-induced changes in rCBF. In an isolated rat basilar arterial strip loaded with fura-2/AM, mCPP(5-500 micrometer caused a vasoconstriction in association with increases in [Ca2+]i, in a concentration-dependent manner. Pretreatment with 1 micrometerketanserin strongly blocked the effects of mCPP on the vascular tone as well as on the [Ca2+]i, of rat basilar artery. CONCLUSION: These results suggest that trazodone decreases rCBF through stimulation of 5-HT(2A/2C) receptors by its active metabolite, mCPP.

Effects of Concomitant Treatment with Drugs Affecting Monoaminergic Systems on the Clozapine-induced Myoclonic Jerks in Partially Restrained Rats

This study was performed to investigate the mechanism of the clozapine-induced seizures in partially restrained rats by concomitant treatment with drugs affecting monoaminergic systems. Partially restrained rats treated with acute single doses of 10mg/kg clozapine exhibited myoclonic jerks(MJs). Drugs affecting the monoaminergic systems, including 2mg/kg haloperidol, 5mg/kg propranolol, 2mg/kg ritanserin, 20mg/kg fluoxetine, and 20mg/kg imipramine, were concomitantly treated with clozapine to observe the effects of these drugs on the MJs. The drugs were given intraperitoneally either as acute single doses(haloperidol, propranolol, ritanserin, and fluoxetine) or as chronic doses for 21 days(haloperidol, imipramine, ritanserin, and fluoxetine). The effects of the concomitant treatment of other drugs on the clozapine-induced MJs were evaluated by comparison of the total numbers of the MJs between the clozapine-treated and concomitantly treated groups. The results were as follows. 1) Concomitant treatment with acute single doses of haloperidol, propranolol, and fluoxetine reduced the total numbers of the clozapine-induced MJs, while concomitant treatment with ritanserin did not. 2) Concomitant treatment with chronic doses of imipramine and ritanserin increased the total numbers of the MJs, while concomitant treatment with fluoxetine reduced them. Concomitant chronic treatment with haloperidol did not affect the numbers of the MJs. These results suggest that dopamine and serotonin, not noradrenalin may be involved in the clozapine-induced MJs in partially restrained rats. Future research needs to study the function of each subtype of monoaminergic receptors on the mechanism of the clozapine-induced seizure.

Tratamiento médico de los tumores hipofisiarios productores de corticotrofina y tirotrofina / Medical treatment of adrenocorticotrophin and thyrotrophin-secreting pituitary tumors

Se analiza el estado actual del tratamiento médico de los tumores hipofisiarios productores de corticotrofina (ACTH) y tirotrofina (TSH). Se presentan las investigaciones comunicadas por diversos autores en el tratamiento de la enfermedad de Cushing y el síndrome de Nelson con moduladores de la secreción de ACTH, la bromocriptina, la ciproheptadina, la ritanserina, el ácido valproico y la somatostatina. Los resultados positivos cubren un pequeño número de casos. La primera opción de tratamiento de estos tumores es la cirugía seguida de la radioterapia. Cuando no se logra extirpar completamente los tumores, el uso de drogas que actúan inhibiendo la esteroidogénesis suprarrenal constituye una terapia paliativa. Entre estas drogas se cuentan el ketoconazol, la aminoglutetimida, la metopirona, el mitotano y el trilostan, con diversos grados de efectividad y tolerancia. Los pacientes que presentan tumores hipofisiarios productores de TSH han sido tratados con éxito con análogos de la somatostatina de acción prolongada, octreotide y lanreotide SR. Se ha logrado dramática supresión de la TSH y de la subunidad alfa, así como control del hipertiroidismo y disminución del tamaño de los tumores. Estas drogas ofrecen posibilidades de tratamiento médico para los pacientes que no logran control de su enfermedad con la cirugía

Ritanserin pharmacokinetics in abstnent chronic alcoholics

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

El desarrollo de nuevas drogas antipsicoticas / Development of new antipsychotic drugs

Se da por sentado que en la esquizofrenia, los efectos terapéuticos de los neurolépticos se basan en el bloqueo de los receptores de dopamina situados en el cerebro. Sin embargo, también se admite que los neurolépticos "clásicos" presentan algunos incovenientes importantes: su relativa falta de efectos sobre los síntomas negativos y su capacidad de inducción de síntomas extrapoiramidales (SEP). Experiencias clínicas llevadas a cabo con pipamperona mostraron que un antagonista combinado de serotinina 5-HT2 y dopamina D2 presentaba ventajas en el tratamiento de la esquizofrenia. Esto se hizo patente a través de los efectos antiautísticos observados, de la regulación de los ritmos de sueño y de vigilia perturbados y de la baja tendencia a la inducción de SEP. Los estudios realizados con setoperona, compuesto de perfil farmacológico comparable, confirmaron estas observaciones. No se pudo explorar la exacta implicación del antagnista 5-HT2 en los tratamientos psicofarmacológicos de la esquizofrenia hasta no haberse realizado la síntesis del receptor antagonista selectivo y específico: la ritanserina. En efecto las pruebas de doble ciego efectuadas demostraron una majoría sensible de los síntomas negativos y extrapiramidales. Puesto que las ventajas de la monoterapia en el tratamiento de la esquizofrenia son innegables, lo lógico era pasar a la selección de un compuesto con un antagonismo central comparable al de...