Extrapyramidal and Monoaminergic Effects of Neuroleptics: Modulation by L-Tryptophan and L-Valine

Abstract

A goal of current neuroleptic research is to develop antipsychotic compounds with low incidence of extrapyramidal side effects (EPS). These include acute parkinsonian like effects and late appearing tardive dyskinesia. Clozapine, the first of the atypical antipsychotic effective in treatment resistant schizophrenia is reported to produce smaller EPS than typical neuroleptic such as haloperidol. In general, fewer incidences of EPS have been reported in patients treated with the atypical than typical neuroleptics. In the present project, research strategies have been developed to investigate the role of serotonin in the precipitation of EPS. Trial has been made to see whether the increases serotonin by the administration of tryptophan and also possible decreases of serotonin by the administration valine could have a potential beneficial effect on the elicitation of EPS. In the first part of the present study, cataleptogenic effects of typical (haloperidol and chlorpromazine) and atypical (clozapine and risperidone) neuroleptics are monitored. The results show that atypical neuroleptic clozapine is cataleptogenic only at high doses. Haloperidol was more cataleptogenic than chlorpromazine. Risperidone was also cataleptogenic at the doses used. Smaller cataleptogenic potential of clozapine, risperidone as well as the typical neuroleptic chlorpromazine was associated with a decrease in serotonin (5-hydroxytryptamine; 5-HT) metabolism particularly in the striatum. The results suggested that an increase in dopamine/serotonin metabolite ratio particularly in the striatum of clozapine than haloperidol injected animals may be involved in the ability of clozapine to exhibit extra beneficial therapeutic profile and ability to produce smaller catalepsy. In the next part of the study, haloperidol administered for five weeks followed by a withdrawal period of one week was found to produce dyskinetic movement and this was associated with mildly greater decrease of dopamine metabolism in haloperidol withdrawal than repeated haloperidol treated rats. In view of a role of 5-HT-IA receptors, in the elicitation of hyperactivity syndrome pre and postsynaptic responses to 5-HT-1 A agonist were monitored after single and repeated administration of haloperidol. The results showed that a supersensitive postsynaptic as well as presynaptic 5-HT-lA receptor dependent response modulating dopaminergic control of motor activity may be involved in the dyskinetic movements observed after haloperidol withdrawal. In the last part of the study, it was found that administration of valine or tryptophan along with haloperidol did not alter akinetic or cataleptogenic effects of haloperidol. Following haloperidol withdrawal home cage activity increased in tryptophan injected animals. Cataleptogenic effects were also much smaller in these rats. This was associated with an increase in serotonin and a decrease in dopamine turnover in the striatum of tryptophan than saline or valine injected animals. In conclusion the results suggested that atypical neuroleptics produce smaller acute cataleptogenic effects because activity of these drugs towards somatodendritic serotonin receptors decreases the inhibitor control of serotonin over activity. Long term administration of a typical neuroleptic such as haloperidol increases. the efficacy of presynaptic feedback control over 5-HT metabolism. A greater decrease of inhibitor control of serotonin over activity may be involved in the elicitation of tardive dyskinesia, Administration of tryptophan as it increases the formation of serotonin is not effective in the modulation of acute parkinsonian like effects. On the other hand, long term administration of tryptophan was found to oppose the effects of haloperidol particularly on activity. The results suggest that tryptophan supplementation may also help prevent late appearing tardive dyskinesias. On the other hand, l 5-HT-lA agonists acting selectively at somatodendritic receptors may help to prevent both acute and late appearing EPS.