DA-GABA modulation of cortical ACh release

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DESCRIPTION (provided by applicant): 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 medial prefrontal cortex (mPFC). The functional interactions among the various neurotransmitters within this system are not well understood. Attentional processing in rats requires and intact basal forebrain-cortical cholinergic system (BFCS). Moreover, cortical acetylcholine (Ach) is increased during performance in a sustained attention task. The proposed research utilizes a powerful microdialysis procedure in which 3 probes are simultaneously placed into awake rats (into NAC, BF, and mPFC) to directly compare dynamic transmitter interactions under baseline conditions and under conditions that explicitly tax attentional processing. We hypothesize that glutamatergic transmission within the NAC regulates the excitability of the BFCS [via the release of GABA and glutamate (Glu) within the BF] and that this regulation is modulated by NAC DA receptor activity. We also propose that the nature of these transmitter interactions is profoundly influenced by whether or not the animal is engaged in attentional processing at the time of the measurement. We will test the following specific hypothesis: 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 D1 and D2 receptors bidirectionally modulate 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 dysfunction in attentional processing.