INCREASED DOPAMINE TURNOVER IN THE PREFRONTAL CORTEX IMPAIRS SPATIAL WORKING-MEMORY PERFORMANCE IN RATS AND MONKEYS

The selective activation of the prefrontal cortical dopamine system by mild stress can be mimicked by anxiogenic beta-carbolines such as FG7 142. To investigate the functional relevance of elevated levels of dop amine turnover in the prefrontal cortex, the current study examined th e effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortic al dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discri mination, a task with similar motor and motivational demands (rats), o r delayed response performance following zero-second delays (monkeys) was unaffected by FG7142, Further, biochemical analysis in rats reveal ed a significant positive correlation between dopamine turnover In the prefrontal cortex and cognitive impairment on the delayed alternation Bask, The cognitive deficits in both rats and monkeys were prevented by pretreatment with the benzodiazepine receptor antagonist, RO15-1788 , which blocked the increase in dopamine turnover and by the dopamine receptor antagonists, haloperidol, clozapine, and SCH23390, These find ings indicate that excessive dopamine activity in the prefrontal corte x is detrimental to cognitive functions mediated by the prefrontal cor tex.