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The Journal of Neuroscience, July 15, 1998, 18(14):5545-5554
Corticolimbic Dopamine Neurotransmission Is Temporally
Dissociated from the Cognitive and Locomotor Effects of
Phencyclidine
Barbara
Adams and
Bita
Moghaddam
Department of Psychiatry, Yale University School of Medicine,
Veterans Administration Medical Center, West Haven, Connecticut
06516
The behavioral syndrome produced by phencyclidine (PCP) and its
analog ketamine represents a pharmacological model for some aspects of
schizophrenia. Despite the multifaceted properties of these drugs, the
main mechanism for their psychotomimetic and cognitive-impairing
effects has been thought heretofore to involve the corticolimbic
dopamine system. The present study examined the temporal relationship
between alterations in corticolimbic dopamine and glutamate
neurotransmission and two dopamine-dependent behavioral effects of PCP
in the rodent that have relevance to the clinical phenomenology,
namely, impairment of working memory, which is used to model the
frontal lobe deficits associated with schizophrenia, and
hyperlocomotion, which is used as a predictor of the propensity of a
drug to elicit or exacerbate psychosis. PCP increased dopamine and
glutamate efflux in the prefrontal cortex and nucleus accumbens, as
measured by microdialysis. The increase in dopamine in both regions
remained elevated well above baseline 2.5 hr after the injection, at
which time the experiment was terminated. However, locomotor activity
returned to baseline in <2 hr after injection. Furthermore, impaired
performance in a discrete trial delayed alternation task, a rodent
working memory task, was only evident up to 60 min after PCP injection;
animals tested 80 min after injection, when cortical dopamine release was elevated at 300% of baseline, did not exhibit impaired
performance. These findings indicate that activation of dopamine
neurotransmission is not sufficient to sustain PCP-induced locomotion
and impairment of working memory. Thus, effects of PCP, including a
glutamatergic hyperstimulation, may be necessary to account for the
psychotomimetic and cognitive-impairing effects of this drug.
Key words:
prefrontal cortex; nucleus accumbens; microdialysis; PCP; schizophrenia; working memory; glutamate; NMDA; ketamine; drug
abuse
Copyright © 1998 Society for Neuroscience 0270-6474/98/18145545-10$05.00/0
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