Effects of benztropine on ketamine-induced behaviors in Cebus monkeys.

Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, causes a schizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Recent work has shown that ketamine and other NMDA antagonists affect a range of behaviors in nonhuman primates, particularly those associated with motor and mental function such as attention and perception. Several lines of study also suggest that NMDA antagonists interact with cholinergic mechanisms. The effects of benztropine, an anticholinergic agent, on ketamine-induced behaviors were evaluated in a double-blind randomized test design in 20 Cebus monkeys. Benztropine (0.05, 0.1 and 0.25 mg/kg, i.m.) was injected 1 hour before ketamine (2.5 and 5.0 mg/kg, i.m.) administration. Behaviors scored for 90 minutes after ketamine administration included salivation, dystonia and reactivity to external stimuli. Benztropine almost completely blocked ketamine-induced hypersalivation, and partially ameliorated the dystonia syndrome by 50%, but did not affect ketamine-induced decreased reactivity to external stimuli. These results suggest that cholinergic mechanisms only moderately influence ketamine-induced central nervous system effects of motor dysfunction, and may not play a substantive role in the ketamine-induced deficit of reactivity to external stimuli, which involves a complex interaction of mental functions such as attention and perception, as well as motor behavior.

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 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.

Facilitation of memory retrieval by pre-test morphine and its state dependency in the step-through type passive avoidance learning test in mice.

Amnesia produced by scopolamine and cycloheximide were reversed by morphine given 30 min before the test trial (pre-test), and pre-test morphine also facilitated the memory retrieval in the animals administered naloxone during the training trial. Similarly, pre-test scopolamine partially reversed the scopolamine-induced amnesia, but not significantly; and pre-test cycloheximide failed to reverse the cycloheximide-induced amnesia. These results suggest that the facilitation of memory retrieval by pre-test morphine might be the direct action of morphine rather than a state dependent effect.

State dependent and/or direct memory retrieval by morphine in mice.

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.

Facilitation of memory retrieval by pretest morphine mediated by mu but not delta and kappa opioid receptors.

Mice were trained to avoid electric shock (0.6 mA) in a step-through type passive avoidance learning task, retention being measured 24 h after the training trial. Morphine 10 mg/kg administered 30 min before the test trial (pretest) facilitated memory retrieval, and the effect was completely antagonized by 1 mg/kg naloxone, a selective mu-opioid receptor antagonist. On the other hand, pretest administration of 0.01-10 mg/kg DTLET, a selective delta-opioid receptor agonist, did not produce the same effect as morphine. Nor-binaltorphimine, a kappa-opioid receptor antagonist, did not antagonize the effect of pretest morphine, at doses of 1 and 2 mg/kg. These results suggest that the facilitation of memory retrieval by pretest morphine is mediated through mu- but not delta- or kappa-opioid receptors.