DOPAMINE AND SPATIAL WORKING-MEMORY IN RATS AND MONKEYS - PHARMACOLOGICAL REVERSAL OF STRESS-INDUCED IMPAIRMENT

The anxiogenic benzodiazepine inverse agonist FG7142 increases dopamin e turnover in rodent prefrontal cortex but not in other dopamine termi nal field areas. FG7142-induced increases in prefrontal cortical dopam ine receptor stimulation impair prefrontal-dependent, but not nonprefr ontal-dependent, cognitive tasks in rats and monkeys. The degree of im pairment correlates with levels of prefrontal cortical dopamine turnov er in rats and can be blocked in rats and monkeys with dopamine recept or antagonists, suggesting that increased dopamine turnover is directl y related to the cognitive deficits. The current study examined nondop aminergic drug effects On FG7142-perturbed biochemistry and cognition. Both the noradrenergic alpha-2 agonist clonidine and the glycine/NMDA antagonist (+)HA966 prevented the FG7142-induced increase in dopamine turnover in rodent prefrontal cortex. infusion of (+)HA966 into the v entral tegmental area (VTA) also blocked this increase in dopamine tur nover, indicating that critical modulatory effects of (+)HA966 on FG71 42-induced changes in dopamine turnover are occurring at the level of mesoprefrontal dopamine neuron cell bodies, Systemic (+)HA966 and clon idine, but not propranolol or D-cycloserine, prevented FG7142-associat ed spatial working memory deficits in rats and monkeys. These results support the idea of a critical range of dopamine turnover for optimal prefrontal cortical cognitive functioning, with excessive dopamine tur nover leading to cognitive impairment. These studies also provide evid ence for the regulation of prefrontal cortical dopamine turnover and c ognition by multiple neurotransmitter systems and suggest that the VTA is an important regulatory site for these effects.