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 FG7142. To investigate the functional relevance of elevated levels of dopamine turnover in the prefrontal cortex, the current study examined the effects of FG7142 on the performance of spatial working memory tasks in the rat and monkey. FG7142 selectively increased prefrontal cortical dopamine turnover in rats and significantly impaired performance on spatial working memory tasks in both rats and monkeys. Spatial discrimination, a task with similar motor and motivational demands (rats), or delayed response performance following zero-second delays (monkeys) was unaffected by FG7142. Further, biochemical analysis in rats revealed a significant positive correlation between dopamine turnover in the prefrontal cortex and cognitive impairment on the delayed alternation task. 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 findings indicate that excessive dopamine activity in the prefrontal cortex is detrimental to cognitive functions mediated by the prefrontal cortex.
Murphy
B L
BL
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510-8001, USA.
Arnsten
A F
AF
Goldman-Rakic
P S
PS
Roth
R H
RH
D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006220:Haloperidol / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception; D013315:Stress, Psychological
D001552:Benzazepines; D002243:Carbolines; D018492:Dopamine Antagonists; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D005442:Flumazenil; C035874:FG 7142; D003024:Clozapine; D006220:Haloperidol; D004298:Dopamine