Acta Pharm. 60 (2010) 129-140
Original research paper
Dose-related
effects of clozapine and risperidone on the pattern of brain regional serotonin
and dopamine metabolism and on extrapyramidal functions in rats
FARHAT BATOOL, AMBREEN HASNAT, MUHAMMAD ABDUL
HALEEM and DARAKHSHAN JABEEN
HALEEM
1 Neurochemistry and Biochemical Neuropharmacology Research Laboratory,
Department of Biochemistry, University of Karachi, Karachi-75270, Pakistan
2
Department
of Biomedical Engineering, Sir Syed University of Engineering and Technology,
Karachi, Pakistan
Accepted February 5, 2010
The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100 %) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, increased significantly (p < 0.01) the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, decreased significantly (p < 0.01) in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptor interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.
Keywords: atypical antipsychotics, dopamine D2 receptors,
extrapyramidal side effects, serotonin1A receptors, schizophrenia