The overall purpose of this two-part project is to examine drug interactions in human and nonhuman primates with particular reference to cognitive function. In Part A, monkeys will be the subjects of inquiry whereas in Part B, the initial studies will be conducted to normal human adults. Although higher cortical functions are disturbed in schizophrenia, little is known about how these transmitters influence cortical circuitry in the primate. The proposed research will use behavioral pharmacological techniques to examine the effects of dopaminergic, serotonergic and glutamatergic compounds on higher cortical function. Experiments in rhesus monkeys will focus on the cognitive abilities of the prefrontal, inferior temporal and parietal association cortices, as well as assessing fine and gross motor function and general behavioral changes. The ability of D1 receptor stimulation to enhance cognition will be studied using the newly available, full D1 agonist, dihydrexidine. The D2 agonist, quinpirole, has recently been found to have multiple effects on behavior, including improvement in working memory performance and the production of """"""""hallucinatory-like"""""""" behavior. The receptor mechanisms underlying these behavioral changes will be examined using antagonists with varying affinities for cloned, dopamine receptor subtypes (eg D2 vs D3 receptors). In addition, D1 and D2 agonists will be co-administered to observe whether excessive DA stimulation can lead to cognitive dysfunction. Results with dopamine compounds will be compared to those with serotonergic drugs which act at the 5HT2 and 5HT1c receptors. Agonists at these receptors produce hallucinations in humans; they may also produce """"""""hallucinatory-like"""""""" behavior and cognitive changes in monkeys. The receptor subtype responsible for hallucinatory-like behaviors will be identified using a new, selective 5HT2 antagonist. As many D1 compounds bind at 5HT2/5HT1c receptors, these experiments will also serve as important controls. The studies of Part B, like those planned in monkeys, will focus on tests of frontal lobe function, particularly the Wisconsin Card Sort Test, but also delayed recall of object names and verbal fluency, among other tests. These studies will examine the relative efficacy of the typical and atypical neuroleptics, haloperiodol and clozapine, to block the deficit producing effects of ketamine in healthy subjects. Comparative studies of dopamine interactions with glutamate receptors will be carried out on rhesus monkeys in Part A. These studies are expected to lead to an understanding of the pharmacological interactions in the primate prefrontal cortex that are relevant to schizophrenia.
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