PCP and its analog ketamine produce a behavioral syndrome that models some aspects of schizophrenia. Previously, the psychotomimetic and cognitive-impairing effects were attributed mainly to the corticolimbic dopamine system. This study measured dopamine and glutamate efflux in the prefrontal cortex and nucleus accumbens of rodents after PCP injection, using microdialysis. PCP increased both dopamine and glutamate levels. Dopamine remained elevated above baseline 2.5 hours after injection, yet locomotor activity returned to baseline in less than 2 hours, and working memory impairment (measured by a delayed alternation task) was only evident up to 60 minutes after injection.
Drug models help researchers understand schizophrenia's neurobiology but have limitations that affect how results are interpreted. The N-methyl D-aspartate antagonist model, using drugs like phencyclidine and ketamine, has gained attention because these drugs produce symptoms beyond psychosis, including thought disorder, negative symptoms, cognitive deficits, and abnormal electrophysiologic test results similar to those in schizophrenia. Subanesthetic doses of ketamine in healthy individuals induce paranoia, perceptual alterations, and these other schizophrenia-like symptoms. This paper discusses the shortcomings of drug models generally and focuses on the NMDA antagonist model, emphasizing what ketamine's effects reveal about schizophrenia's pathophysiology and potential treatments.