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

Rationale: The dopamine hypothesis is the most widely investigated theory u nderlying schizophrenia and the mechanisms of action for antipsychotic drug s. However, recent studies call into question this proposal. Thus, the focu s has turned towards other mechanisms, one of which has been glutamatergic systems. Phencyclidine (PCP), a potent NMDA receptor antagonist, causes a s chizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Ketamine, like PCP, is a noncompet itive NMDA receptor antagonist, which is short acting and has been used as a dissociative anesthetic as well as a research tool in psychosis. Objectiv e: 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 i n Cebus monkeys, Methods: Thirty-two (six male, 26 female) Cebus monkeys, w hich were previously sensitized to neuroleptics, were tested with a wide ra nge of doses of ketamine that spanned the clinical effect range from thresh old effects to full anesthesia. Behaviors scored included sedation/arousal, locomotor activity, extrapyramidal symptoms of parkinson-ism and dystonia, as well as reactivity. Results: Ketamine produced dose-related increases i n parkinsonian bradykinesia and dystonia as well as salivation. There were dose-related decreases in locomotor activity and reactivity to environmenta l stimuli. These effects had short time courses and steep dose-response cur ves. Conclusions: These results suggest that ketamine-induced behavioral ef fects in non-human primates offer a model for studying a glutamatergic role in motor and mental function such as attention or perception.