Selectively bred long-sleep (LS) and short-sleep (SS) mice differ markedly in ethanol-induced adrenocortical response. Intracerebroventricular injections of saline elicited a ‘stress-induced’ adrenocortical response in both lines of mice, and intracerebroventricular infusions of noradrenergic and cholinergic compounds modulated ethanol-induced and stress-induced adrenocortical responses differentially in these mice. Clonidine, an α2-adrenergic agonist, blocked ethanol-induced elevations in plasma corticosterone in a dose-dependent manner (1 and 10 µg) in LS mice; however, only the 10-µg dose of clonidine effectively antagonized this response in SS mice. Clonidine was less effective in blocking adrenocortical activity induced by stress than that induced by ethanol. Yohimbine, an α2-adrenergic antagonist, induced a marked elevation in plasma corticosterone in LS mice but not in SS mice; however, this compound did not alter ethanol-induced adrenocortical responses in either line of mice. Yohimbine reversed the inhibitory effect of clonidine in ethanol-treated LS and SS mice. Phentolamine, a nonspecific α-adrenergic antagonist, and propranolol, a β-adrenergic antagonist at high doses (10 µg), produced slight increases in plasma corticosterone in LS mice only. Neither these compounds nor methoxamine, a nonspecific α-adrenergic agonist, altered the effect of ethanol on adrenocortical activity in LS or SS mice. Carbachol, a mixed muscarinic/nicotinic agonist, significantly increased adrenocortical response in both LS and SS mice and potentiated ethanol-induced elevation in plasma corticosterone in both lines of mice. However, atropine, a nonspecific muscarinic antagonist, or hexamethonium, a nicotinic antagonist, did not modify ethanol-induced elevations in plasma corticosterone in LS and SS mice. These results suggest that adrenocortical activation produced by ethanol may be mediated primarily through central noradrenergic systems and that differences in these systems may account for the differential ethanol-induced elevation in plasma corticosterone exhibited by LS