Differences in the effects of haloperidol and clozapine on brain serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats.
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.


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.
Haleem
Darakshan J
DJ
Department of Biochemistry, Neurochemistry and Biochemical Neuropharmacology Research unit, University of Karachi, Pekistan. djh@super.net.pkm
Batool
Farhat
F
Khan
Nadia H
NH
Kamil
Noor
N
Ali
Obaid
O
Saify
Zafar S
ZS
Haleem
Mohammad A
MA
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000009:adverse effects / Q000494:pharmacology; D013997:Time Factors
D018492:Dopamine Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine