Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys

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Abstract
Dopamine (DA) D1 receptor compounds were examined in monkeys for effects on the working memory functions of the prefrontal cortex and on the fine motor abilities of the primary motor cortex. The D1 antagonist, SCH23390, the partial D1 agonist, SKF38393, and the full D1 agonist, dihydrexidine, were characterized in young control monkeys, and in aged monkeys with naturally occurring catecholamine depletion. In addition, SKF38393 was tested in young monkeys experimentally depleted of catecholamines with chronic reserpine treatment. Injections of SCH23390 significantly impaired the memory performance of young control monkeys, but did not impair aged monkeys with presumed catecholamine depletion. Conversely, the partial agonist, SKF38393, improved the depleted monkeys (aged or reserpine-treated) but did not improve young control animals. The full agonist, dihydrexidine, did improve memory performance in young control monkeys, as well as in a subset of aged monkeys. Consistent with D1 receptor mechanisms, agonist-induced improvements were blocked by SCH23390. Drug effects on memory performance occurred independently of effects on fine motor performance. These results underscore the importance of DA D1 mechanisms in cognitive function, and provide functional evidence of DA system degeneration in aged monkeys. Finally, high doses of D1 agonists impaired memory performance in aged monkeys, suggesting that excessive D1 stimulation may be deleterious to cognitive function.