DA-GABA modulation of cortical ACh release

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EXCEED THE SPACE PROVIDED. This is a competitive renewal application. The overall goal of this research is to understand functional transmitter interactions throughout a distributed neural system postulated to mediate attentional processing. This system includes the shell region of the nucleus accumbens (NAC), the basal forebrain (BF, the site of the corticopetal cholinergic neurons) and the medialprefrontal cortex (rnPFC). The functional interactions amongthe various neurotransmitters within this system are not well understood. Attentional processing in rats requires an intact basal forebrain-cortical cholinergic system (BFCS). Moreover, cortical acetylcholine (ACh) is increased during performancein a sustained attention task. The proposed research utilizes a powerful microdialysis procedure in which 3 probes are simultaneouslyplaced into awakerats (into NAC, BF, and mPFC) to directly compare dynamic transmitter interactions under baseline conditionsand under conditions that explicitly tax attentional processing. We hypothesize that glutamatergictransmission within the NAC regulates theexcitability of the BFCS [via the release of GABA and glutamate (Glu) withinthe BF] and that this regulation is modulatedby NAC DA receptor activity. We also propose that the nature of these transmitter interactions isprofoundly influenced by whether or not the animal is engaged in attentionalprocessing at the time of measurement. We will test the following specific hypotheses: 1)that blockade of ionotropic Glu receptors or stimulation of metabotropic Glu receptors in NAC decreases GABA release and stimulates Glu release in BF, and, as a result stimulates ACh release in mPFC, 2) that NAC Dl and D2 receptors bidirectionallymodulate the ability of Glu ligands to affect GABA/Glu release in BF and ACh release in mPFC, 3) that performance in a sustained attention task is accompanied by a different profile of transmitter release in BF and cortex than performance in a control task that does not explicitly tax attentional processing, and 4) that intrabasalis manipulations of GABA or Glu receptor activity will affect performance and cortical ACh release in animals engaged in a task of sustained attention but not in control operant tasks. An understanding of the mechanisms regulating the excitability of the basal forebrain cortical cholinergic system is central to our understanding of the etiology and potential therapeutics of neuropsychiatric disorders characterized by dysfunctionsin attentional processing. PERFORMANCE SITE ========================================Section End===========================================