Sg. Birnbaum et al., Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats, PHARM BIO B, 67(3), 2000, pp. 397-403
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.