Neuroleptic drugs are highly efficacious agents in controlling symptoms of schizophrenia and other psychoses, but have undesirable early and late neurological side effects which are poorly understood. Reversible acute extrapyramidal syndromes (EPS) of acute dystonia and parkinsonism occur in up to 95% of patients and are one of the major reasons why schizophrenics discontinue their medication and suffer a psychotic relapse. Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary movements, may develop in 20% of patients (and up to 50% of high risk elderly). Unfortunately, we are not able to predict who is at risk for these side effects. The pathophysiology of acute EPS and TD is believed to involve dopamine (DA) receptor blockade with early EPS due to reduced DA influences and TD due to overactive DA processes. The specific roles of DA receptor subtypes (D1 D2), serotonin and norepinephrine, are minimally understood. Many new compounds which are potentially antipsychotic offer the opportunity to more precisely study the mechanisms of actions of these drugs and to evaluate their potential for improving the antipsychotic efficacy and reducing the neurological side effect risks. Research in a nonhuman primate model with studies that parallel clinical treatment issues in both the short term and long term can provide both practical and heuristic data. The acute EPS studies will evaluate the contribution of specific drugs which affect D1 and D2 receptor subtypes, investigate their interactions, and assess the prevention/aggravation potentials of new antipsychotic drugs with serotonin antagonist properties. Clozapine, a novel antipsychotic drug, will also be evaluated to identify its mechanism of action and potential side effects. The long-term TD studies will examine the effect of continuous and interrupted haloperidol. The central issues are: 1) individual vulnerability, and 2) time course for developing acute EPS, DA receptor hypersensitivity, and TD during these distinct treatment regimes. Behavioral changes will be assessed by perturbations in DA function with DA agonists (apomorphine, amphetamine, bromocriptine, pergolide, and SKF 38393) and antagonists (haloperidol, SCH 23390) before, during, and after haloperidol.
