This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Recent studies suggest that decreased inhibitory signaling by neurons releasing gamma-aminobutyric acid (GABA) in the prefrontal cortex of the schizophrenic brain may cause abnormal neural circuit activity and impaired cognition. Drugs that normalize GABAergic tone may thus restore or improve cognitive function. The proposed studies will test these hypotheses by manipulating GABA system activity within the prefrontal cortex of male Sprague-Dawley rats. Drugs acting at cannabinoid receptors or neurosteroid binding sites will be administered via intracranial microinjection into the medial prefrontal cortex before behavior testing. Two series of experiments will assess drug treatment effects on prefrontal-dependent cogntive function, and assess whether treatments can reverse cognitive deficits induced by pretreatment with the NMDA receptor antagonist MK-801. Low dose NMDA antagonist adminsistration is a widely used preclinical model of schizophrenia. One series of experiments will examine effects of cannabinoid receptor modulators on performance of behavior tasks that measure working memory, selective attention, and cognitive flexibility (set-shifting). The other series of experiments will study the effects of select neurosteroids on these same cognitive measures. We hypothesisze that select cannabinoid and neurosteroid modulators which reduce prefrontal GABAergic neurotransmission will exacerbate cognitive deficits, whereas compounds which increase GABAergic tone will attenuate or block cognitive impairments.
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