The proposed experiments will determine whether improvements in delayed response performance produced by DA D1 or D2 agonists result from drug actions in the prefrontal cortex (PFC) enhancing the spatial working memory abilities of this cortex, or whether improvement results from nonspecific changes in performance variables. These issues are particularly important for D2 compounds, currently thought to have little influence on PFC function. Two methods will be used to address these questions: 1. D1 and D2 agonists (dihydrexidine and quinpirole, respectively) will be characterized in a thorough, dose-response manner in aged monkeys on the delayed response task, a task whose performance deteriorates with age, and on a battery of nonPFC tasks with different cognitive demands but similar motivational and motor requirements such as delayed response. These additional tasks will include delayed non-matching to sample, visual discrimination, route finding, and fine motor skills. Any effects of the agonists will be challenged with the antagonist of the same receptor subtype. The principal investigator will attempt to identify D1/D2 interactions by countering agonist effects with the antagonist at another subtype, and also by combining the D1 and D2 agonist to determine whether the combination will result in greater improvement than either agonist alone. 2. D1 or D2 compounds will be infused directly into the prefrontal cortex and control sites (premotor cortex, caudate) in young monkeys performing the delayed response task of a fine motor task. Agonist responses will also be examined after the monkeys have received chronic treatment with reserpine. Research on NE mechanisms continues to examine the hypothesis that alpha-2 agonists selectively improve the cognitive functions of the PFC through actions at a subtype of post-synaptic, alpha-2 receptor in that cortical region. Three related issues are addressed: (1.) Characterization of the alpha-2 agonist response will be continued, including an examination of drug effects on a test of parietal (area 7) function, an NE-rich area that shows age-related deficits. The response of young vs. aged animals to alpha-2 agonist treatment will be compared on a battery of cognitive tasks. (2.) Receptor mechanisms will be further defined by relating drug effects on cognitive function, hypotension and sedation to actions at the cloned alpha-2 subtypes (alpha-2A, alpha-2B, and alpha-2C). Optimal parameters for chronic, oral dosing of the alpha-2A selective agonist, guanfacine, will be determined to identify an appropriate dose regimen for clinical trials in human patients. (3.) The site of cognitive-enhancing effects of alpha-2-agonists in brain will be examined using two different methodologies: (a.) a study will be completed in which alpha-2 agonists are infused into the PFC vs premotor cortex of aged monkeys performing the delayed response test, and (b.) SPECT technology will be utilized to observe clonidine's effects on regional blood flow in aged monkeys performing the delayed response task.
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