Repeated
phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in
schizophrenia. Alterations in
glutamate transmission and γ-
aminobutyric acid (
GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in
cognitive symptoms of
schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical
antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on
glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect
GABA neuronal markers in the PFC. Finally, we investigated the effects of
clozapine on disruptions in
glutamate levels and
GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC
glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of
parvalbumin and
glutamic acid decarboxylase-67 (two markers of
GABA function) in the PFC, an effect that was maintained after
a 10 day drug-free washout period and unaltered by the resumption of repeated PCP
injections. All of the observed PCP effects were attenuated by chronic treatment with
clozapine, an atypical
antipsychotic that has partial effectiveness on
cognitive impairment in
schizophrenia. These findings suggest that abnormal cortical
glutamate transmission, possibly driven by pathological changes in
GABA function in
parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in
schizophrenia. A better understanding of
glutamate and
GABA dysregulation in
schizophrenia may uncover new treatment targets for
schizophrenia-related
cognitive dysfunction.