The overall goal of this project is to provide a bridge between the animal studies proposed in the Center on D 1 receptor modification of cortical function with the clinical studies proposed in project 9. Our working hypothesis is that D1 receptor modulation causes state-dependent secondary alterations in the function of other key neurotransmitters such as glutamate, GABA, DA, and serotonin in the prefrontal cortex. Hence, we propose to examine the effect of focal or systemic D1 receptor manipulation, administered in a parallel manner to both the electrophysiological and clinical studies proposed in other projects of this Center, on the release of cortical DA, serotonin, GABA, and glutamate while the animal is under various states that include (1) rest, (2) cognitive activation caused by engagement in working memory task, and (3) cognitive impairment caused by chronic neuroleptic treatment.
The specific aims are: 1) Determine the effect of intracortical application of a D1 agonist and antagonist on extracellular efflux of glutamate, GABA, DA, and serotonin in awake, chaired animals at rest or engaged in a working memory task, or a control visually guided task. Based on in vitro and in-vivo analysis of D1 actions, we hypothesize that the D1 agonists will reduce glutamate, GABA, DA and serotonin release. 2) Determine the effect of acute and subchronic systemic treatment with DAS-431 (the D1 agonist to be employed clinically in project 7) on extracellular efflux of glutamate, GABA, DA, and serotonin in chaired animals at rest, engaged in a working memory task, or a control visually guided task. 3) Determine the acute and subchronic effect of DAS-431 on extracellular efflux of glutamate, GABA, DA, and serotonin in animals that have received chronic neuroleptic treatment. Studies will be performed at rest, engaged in a working memory task, or a control visually guided task.
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