Differences in the effects of haloperidol and clozapine on brain serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats
Darakhshan J. Haleem, Farhat Batool, Nadia H. Khan, Noor Kamil, Obaid Ali, Zafar S. Saify, Mohammad A. Haleem
Med Sci Monit 2002; 8(9): BR354-361
Background: An important goal of current neuroleptic research is to develop antipsychotic compounds with a low incidence of extrapyramidal side effects (EPS). Clozapine, the first of the atypical
antipsychotics to be proven effective in treatment-resistant schizophrenia, is reported to produce less EPS than typical neuroleptics, such as haloperidol.
Material/Methods: The present study compares the neurochemical profiles of clozapine and haloperidol in rats. Animals injected (i. p.) with haloperidol or clozapine were sacrificed 1h later to collect brain
samples. Neurochemical estimations were carried out by HPLC-EC.
Results: Administration of haloperidol at doses of 1.0, 2.5 and 5.0 mg/kg increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum and rest of the
brain. Clozapine-injected rats (2.5, 5.0 and 10.0 mg/kg) showed smaller increases in the striatum, but not in the rest of the brain. Dihydroxyphenylacetic acid (DOPAC), another DA metabolite not affected by haloperidol, increased in the striatum and decreased in the rest of the brain of clozapine-injected rats. 5-Hydroxyindoleacetic acid, the predominant metabolite of serotonin, increased with haloperidol and decreased with clozapine. A high dose of haloperidol (5.0 mg/kg) increased DA and 5-HT, while an equivalent does of clozapine (10.0 mg/kg) decreased levels in the rest of the brain. The effects of both drugs on the HVA/5-HIAA and DOPAC/5-HIAA ratios were also different.
Conclusions: The differing activities of the two drugs at DA and serotonin receptors implies an important role for serotonin in treatment-resistant schizophrenia and a lower incidence of EPS.
Keywords: Animals, Brain - drug effects, Brain - metabolism, Chromatography, High Pressure Liquid, Clozapine - adverse effects, Clozapine - pharmacology, Dopamine - metabolism, Dopamine Antagonists - adverse effects, Dopamine Antagonists - pharmacology, Dose-Response Relationship, Drug, Haloperidol - adverse effects, Haloperidol - pharmacology, Male, Rats, Rats, Wistar, Serotonin - metabolism, Serotonin Antagonists - adverse effects, Serotonin Antagonists - pharmacology, Time Factors