Ethanol exerts effects on the brain noradrenergic system, and these are thought to contribute to the sedative/hypnotic (depressant) effects of ethanol. Recent studies suggest that the norepinephrine transporter (NET) plays an important role in modulating ethanol's depressant effects. The aim of the present study was to further characterize this role. Transporter blockers with varying affinity for NET versus the serotonin transporter (desipramine>fluoxetine>citalopram) were tested for their ability to alter ethanol's depressant effects, and for comparison, hypothermic effects. Effects of desipramine on another depressant, pentobarbital, were examined. Desipramine potentiation of ethanol's depressant effects was assessed following depletion of brain norepinephrine via N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4) treatment, or depletion of brain 5-HT via para-chlorophenylalanine methyl ester hydrochloride (PCPA) treatment. The effects of co-administration of either the selective alpha2-adrenoreceptor agonist (dexmedetomidine) or the selective alpha2-adrenoreceptor antagonist (atipamezole) on desipramine's effect on ethanol's depressant effects were examined. Given the close link between stress, ethanol and norepinephrine, desipramine potentiation of ethanol's depressant effects was tested following repeated forced swim stress. Results showed that desipramine, but not SERT-selective doses of citalopram or fluoxetine, strongly potentiated the depressant (not hypothermic) effects of ethanol. These effects were mimicked by dexmedetomidine and blocked by atipamezole, but not by depletion of either norepinephrine or 5-HT. Desipramine potentiation of ethanol's depressant effects was abolished following repeated stress. Present findings further support a major role for NET and the alpha2-adrenoreceptor in modulating the depressant effects of ethanol, with possible implications for understanding the role of noradrenergic dysfunction in stress-related alcoholism.