Dopamine and spatial working memory in rats and monkeys: pharmacological reversal of stress-induced impairment.
The anxiogenic benzodiazepine inverse agonist FG7142 increases dopamine turnover in rodent prefrontal cortex but not in other dopamine terminal field areas. FG7142-induced increases in prefrontal cortical dopamine receptor stimulation impair prefrontal-dependent, but not nonprefrontal-dependent, cognitive tasks in rats and monkeys. The degree of impairment correlates with levels of prefrontal cortical dopamine turnover in rats and can be blocked in rats and monkeys with dopamine receptor antagonists, suggesting that increased dopamine turnover is directly related to the cognitive deficits. The current study examined nondopaminergic 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 ventral tegmental area (VTA) also blocked this increase in dopamine turnover, indicating that critical modulatory effects of (+)HA966 on FG7142-induced changes in dopamine turnover are occurring at the level of mesoprefrontal dopamine neuron cell bodies. Systemic (+)HA966 and clonidine, but not propranolol or D-cycloserine, prevented FG7142-associated 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 turnover leading to cognitive impairment. These studies also provide evidence for the regulation of prefrontal cortical dopamine turnover and cognition by multiple neurotransmitter systems and suggest that the VTA is an important regulatory site for these effects.
Murphy
B L
BL
Department of Pharmacology, Yale Medical School, New Haven, Connecticut 06510-8001, USA.
Arnsten
A F
AF
Jentsch
J D
JD
Roth
R H
RH
D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D003523:Cycloserine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008253:Macaca mulatta / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000502:physiology*; D013312:Stress, Physiological / Q000523:psychology*
D002243:Carbolines; D018690:Excitatory Amino Acid Agonists; D011760:Pyrrolidinones; C035874:FG 7142; D003523:Cycloserine; D011433:Propranolol; C001369:1-hydroxy-3-amino-2-pyrrolidone; D003000:Clonidine; D004298:Dopamine; D009638:Norepinephrine