Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats.
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, significantly (p < 0.01) increased 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, significantly (p < 0.01) decreased 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 receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.
Neurochemistry and Biochemical Neuropharmacology Research Laboratory, Department of Biochemistry, University of Karachi, Karachi-75270, Pakistan. batool@uok.edu.pk
Farhat
F
Batool
Ambreen
A
Hasnat
Muhammad Abdul
MA
Haleem
Darakhshan Jabeen
DJ
Haleem
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001519:Behavior / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000493:pharmacokinetics / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005116:Extrapyramidal Tracts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018967:Risperidone / Q000493:pharmacokinetics / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014364:Tryptophan; D003024:Clozapine; D018967:Risperidone; D004298:Dopamine; D006719:Homovanillic Acid