Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat

Abstract

• Clozapine is a novel antischizophrenic drug that lacks extrapyramidal side effects in man and is not cataleptogenic in the rat. Its action on the synthesis and disappearance of catecholamines in the rat brain was compared with that of four typical (i.e. cataleptogenic) neuroleptics, haloperidol, chlorpromazine, loxapine, and the 2-chloro isomer of clozapine, HF-2046. Clozapine enhances the dopamine content of the striatum while the typical neuroleptics always decrease the dopamine level, probably as a consequence of turnover stimulation. Upon repeated administration, the dopamine-enhancing effect of clozapine becomes more pronounced while the dopamine turnover stimulation caused by typical neuroleptics diminishes. At high doses, clozapine also stimulates disappearance of dopamine as shown by the accumulation of homovanillic acid. This effect, however, does not decrease upon repeated administration as it does with typical neuroleptics. Single or repeated doses of clozapine do not interfere with dopamine turnover stimulation induced by the administration of haloperidol or loxapine. It is therefore thought that clozapine stimulates the synthesis of striatal dopamine much more strongly than its disappearance, and that it does not primarily block dopamine receptors as typical neuroleptics are thought to do. • Clozapine stimulates the turnover of NA in the brain stem of the rat, but this effect is markedly diminished upon repeated administration. Thus, it appears that clozapine acts on the NA system of brain stem in a way similar to that of the typical neuroleptics.