RESERPINE IMPAIRS SPATIAL WORKING-MEMORY PERFORMANCE IN MONKEYS - REVERSAL BY THE ALPHA-2-ADRENERGIC AGONIST CLONIDINE

Repeated daily treatment with the catecholamine-depleting agent, reser pine, dramatically reduced performance on the delayed response task, a test of spatial working memory that depends upon the integrity of the prefrontal cortex. Delayed response performance fell from an average of 27.2/30 trials correct before reserpine treatment to an average of 20.4/30 trials correct after repeated reserpine administration. Inject ion of the alpha2-adrenergic agonist, clonidine (0.0001-0.05 mg/kg), t o chronic reserpine-treated monkeys significantly restored performance on the delayed response task; performance after an optimal dose avera ged 27.8/30 trials correct. Clonidine's beneficial effects on delayed response performance were longlasting; monkeys remained improved for m ore than 24 h after a single clonidine injection. The finding that clo nidine is efficacious in reserpinized animals supports the hypothesis that alpha2-adrenergic agonists improve cognitive function through act ions at postsynaptic, alpha2-adrenergic receptors on non-adrenergic ce lls. In contrast to the delayed response task, reserpine had little ef fect on performance of a visual discrimination task, a reference memor y task which does not depend on the prefrontal cortex. These results e mphasize the importance of postsynaptic alpha2-adrenergic mechanisms i n the regulation of working memory,