The lateral habenula is not required for ethanol dependence-induced escalation of drinking.

The lateral habenula (LHb) is an epithalamic nuclei that has been shown to signal the aversive properties of ethanol. The present study tested the hypothesis that activity of the LHb is required for the acquisition and/or expression of dependence-induced escalation of ethanol drinking and somatic withdrawal symptoms. Male Sprague-Dawley rats completed 4 weeks of baseline drinking under a standard intermittent access two-bottle choice (2BC) paradigm before undergoing 2 weeks of daily chronic intermittent ethanol (CIE) via vapor inhalation. Following this CIE exposure period, rats resumed 2BC drinking to assess dependence-induced changes in voluntary ethanol consumption. CIE exposed rats exhibited a significant increase in ethanol drinking that was associated with high levels of blood alcohol and a reduction in somatic symptoms of ethanol withdrawal. However, despite robust cFos activation in the LHb during ethanol withdrawal, chemogenetic inhibition of the LHb did not alter either ethanol consumption or somatic signs of ethanol withdrawal. Consistent with this observation, ablating LHb outputs via electrolytic lesions of the fasciculus retroflexus (FR) did not alter the acquisition of somatic withdrawal symptoms or escalation of ethanol drinking in CIE-exposed rats. The LHb controls activity of the rostromedial tegmental nucleus (RMTg), a midbrain nucleus activated by aversive experiences including ethanol withdrawal. During ethanol withdrawal, both FR lesioned and sham control rats exhibited similar cFos activation in the RMTg, suggesting that RMTg activation during ethanol withdrawal does not require LHb input. These data suggest that, at least in male rats, the LHb is not necessary for the acquisition or expression of escalation of ethanol consumption or expression of somatic symptoms of ethanol withdrawal. Overall, our findings provide evidence that the LHb is dispensable for some of the negative consequences of ethanol withdrawal.