Arnsten A F, Cai J X, Murphy B L, Goldman-Rakic P S
Section of Neurobiology, Yale Medical School, New Haven, CT 06510-8001.
Psychopharmacology (Berl). 1994 Oct;116(2):143-51. doi: 10.1007/BF02245056.
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.
研究了多巴胺（DA）D1受体化合物对猴子前额叶皮质工作记忆功能和初级运动皮质精细运动能力的影响。在年轻的对照猴子以及患有自然发生的儿茶酚胺耗竭的老年猴子中，对D1拮抗剂SCH23390、部分D1激动剂SKF38393和完全D1激动剂二氢麦角隐亭进行了特性研究。此外，还对经慢性利血平处理实验性耗竭儿茶酚胺的年轻猴子进行了SKF38393测试。注射SCH23390显著损害了年轻对照猴子的记忆表现，但对假定儿茶酚胺耗竭的老年猴子没有损害。相反，部分激动剂SKF38393改善了耗竭的猴子（老年或利血平处理的），但没有改善年轻对照动物。完全激动剂二氢麦角隐亭确实改善了年轻对照猴子以及一部分老年猴子的记忆表现。与D1受体机制一致，激动剂诱导的改善被SCH23390阻断。药物对记忆表现的影响独立于对精细运动表现的影响。这些结果强调了DA D1机制在认知功能中的重要性，并为老年猴子DA系统退化提供了功能证据。最后，高剂量的D1激动剂损害了老年猴子的记忆表现，表明过度的D1刺激可能对认知功能有害。
