The intraventricular administration of 6-hydroxydopamine before chronic ethanol exposure prevented the development of tolerance to the hypnotic and hypothermic effects of ethanol as well as cross-tolerance to barbiturates. The injection of 6-hydroxydopamine depleted brain norepinephrine but had little effect on levels of dopamine and serotonin. Although mice pretreated with 6-hydroxydopamine did not develop tolerance to ethanol, they exhibited signs of physical dependence after chronic treatment with ethanol. If 6-hydroxydopamine was administered after tolerance to ethanol was established, the destruction of noradrenergic neurons had little effect in disrupting the tolerance. Noradrenergic systems may be necessary for the consolidation but not the expression of tolerance.