Neuroleptic drugs are highly efficacious antipsychotic agents, but have several undesirable early and late neurological side effects which are poorly understood. Reversible acute extrapyramidal syndromes (EPS) of dystonia or parkinsonism occur in 50% of patients and tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary movements, mostly in the orofacial region, may develop in 20% of patients (possibly in 50% of high risk elderly). Unfortunately, prior to the onset of symptoms cannot identify who is at risk. 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. But little is known about the role of DA receptor subtypes (D-1, D-2) in these disorders or the mechanisms of how symptoms develop. Research in a nonhuman primate model with studies that parallel clinical treatment issues can provide both practical and heuristic data. The proposed studies will evaluated the acute and long-term behavioral effects of the neuroleptic drug haloperidol (HAL) in 44 Cebus albifrons monkeys. The central issues are (1) individual vulnerability of each animal at risk for symptoms; and (2) the time course of developing acute EPS, DA receptor hypersensitivity, and TD during three separate standard treatment regimes; (a) periodic, (b) continuous oral, and (c) continuous depot long-acting treatment. 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 HAL. Once acute EPS and TD develop, the long-term outcome and effects of treatment interventions will be compared with the response of spontaneous orofacial dyskinesias which have developed in a few geriatric monkeys to clarify if the idiopathic and drug-induced dyskinesias share a similar pathophysiology.
