Research Project
6503165
DESCRIPTION (provided by applicant): Phencyclidine (PCP) is a dissociate anesthetic that produces psychotomimetic symptoms in humans and has thus been investigated for its ability to produce an animal model for schizophrenia. The delayed effects of PCP, those seen after intoxication has subsided, have been reported to induce a variety of schizophrenia-like behaviors including enhanced behavioral response to amphetamine. In addition, PCP pretreatment produces changes in the regional expression of c-Fos, indicating altered neuronal activity. The goal of these studies is to investigate possible pharmacological and neuroanatomical sites of PCP's action, which underlie its delayed effects on amphetamine-induced behavior and c-Fos expression. Pharmacologically, PCP's action as a sigma receptor agonist has been implicated in other delayed effects of PCP. Anatomically, PCP induces delayed decreases in prefrontal cortex dopamine utilization, an effect which could, based on findings regarding the relationship between prefrontal cortex activity and subcortical dopamine system activity, underlie its delayed effects on amphetamine-induced behavior and c-Fos expression. Thus the proposed experiments will test the hypothesis that sigma receptor activation plays a role in the delayed effects of PCP by examining the ability for a sigma receptor agonist to mimic and a sigma receptor antagonist to block the effects of PCP on amphetamine-induced behavior and c-Fos. These experiments will also test the hypothesis that PCP's action in the prefrontal cortex underlies its delayed effects by examining the ability for intra-prefrontal cortex PCP injections to mimic and prefrontal cortex lesions to block the effects of systemic PCPon amphetamine-induced behavior and c-Fos. Because both sigma receptors and the medial prefrontal cortex have been implicated in the pathophysiology of schizophrenia, PCP's actions at these sites represent plausible mechanisms by which PCP could be inducing schizophrenia-like behaviors. These experiments will begin to identify the mechanisms by which PCP produces schizophrenia-like behaviors in animals, providing insight into potential pathophysiologies underlying schizophrenia in humans.
