Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats

Performance on working memory tasks, a measure of prefrontal cortical funct ion, is impaired by exposure to mild stress as well as the anxiogenic drug, FG7142. Previous studies have shown that like stress, FG7142 increases cat echolamine release in the prefrontal cortex (PFC) and that high levels of d opamine (DA) D-1 and norepinephrine (NE) alpha -1 receptor stimulation unde rlie the FG7142 - induced cognitive impairment. Both the FG7142-induced DA turnover and working memory deficit can be blocked by pretreatment with the nonselective NE alpha -2/imidazoline II receptor agonist, clonidine. The p resent study examined the alpha -2 adrenoceptor subtype underlying this rev ersal in FG7142-induced working memory deficits by comparing the efficacy o f clonidine with the more selective alpha -2A adrenoceptor agonist, guanfac ine. The anxiogenic drug, FG7142 (0, 10, 20, or 30 mg/kg), dose-dependently impaired delayed alternation performance. Clonidine pretreatment (0.1 mg/k g, 30 min prior to FG7142) partially reversed the FG7142-induced impairment while guanfacine pretreatment (0.11 mg/kg) completely blocked the FG7142-i nduced impairment. Neither clonidine nor guanfacine had any effect on perfo rmance when administered alone. This study suggests that stimulation of the NE alpha -2A receptor subtype is sufficient to ameliorate the cognitive de ficit induced by FG7142. Clonidine's sedative and hypotensive side effects limit its therapeutic usefulness; however, selective alpha -2A receptor ago nists may be effective in treating prefrontal cognitive deficits in stress- related neuropsychiatric disorders with fewer side effects. (C) 2000 Elsevi er Science Inc. All rights reserved.