Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates.
BACKGROUND
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 non-competitive 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.
Shiigi
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Mental Illness Research, Education and Clinical Center (MIRECC) VISN 20 and Mental Health Division, VA Medical Center, Portland, Oregon 97207, USA.
Casey
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002428:Cebus; D004305:Dose-Response Relationship, Drug; D004421:Dystonia / Q000139:chemically induced; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000209:etiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012472:Salivation
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine