Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates

Rationale: The dopamine hypothesis is the most widely investigated theory underlying schizophrenia and the mechanisms of action for antipsychotic drugs. However, recent studies call into question this proposal. Thus, the focus has turned towards other mechanisms, one of which has been glutamatergic systems. Phencyclidine (PCP), a potent NMDA receptor antagonist, causes a schizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Ketamine, like PCP, is a noncompetitive NMDA receptor antagonist, which, is short acting and has been used as a dissociative anesthetic as well as a research tool in psychosis. Objective: To clarify the role of NMDA antagonists further and to develop an animal model of these actions, ketamine was studied across a range of behaviors in Cebus monkeys. Methods: Thirty-two (six male, 26 female) Cebus monkeys, which were previously sensitized to neuroleptics, were tested with a wide range of doses of ketamine that spanned the clinical effect range from threshold effects to full anesthesia. Behaviors scored included sedation/arousal, locomotor activity, extrapyramidal symptoms of parkinsonism and dystonia, as well as reactivity. Results: Ketamine produced dose-related increases in parkinsonian bradykinesia and dystonia as well as salivation. There were dose-related decreases in locomotor activity and reactivity to environmental stimuli. These effects had short time courses and steep dose- response curves. Conclusions: These results suggest that ketamine-induced behavioral effects in non-human primates offer a model for studying a glutamatergic role in motor and mental function such as attention or perception.