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

Abstract

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.

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Fig. 1: Escalation of ethanol drinking and somatic signs of withdrawal following CIE exposure.
Fig. 2: Chemogenetic inhibition of the LHb does not alter ethanol dependence-induced escalation of drinking or somatic signs of withdrawal.
Fig. 3: The LHb is activated during withdrawal from chronic ethanol exposure.
Fig. 4: Lesioning the FR does not alter the acquisition of somatic withdrawal symptoms or escalated ethanol intake in ethanol dependence.
Fig. 5: Lesioning the fasciculus retroflexus does not alter withdrawal-induced cFos expression in the RMTg.

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Funding

This work was supported by funding from the National Institutes on Alcohol Abuse and Alcoholism grants AA019967 and AA027706 (LJC), T32 AA007474 (TBN), and F31 AA029622 (TBN), P50 AA010761 (JJW), and from the National Institute of Drug Abuse grant F31 DA045485 (KMB). The authors have nothing to disclose.

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TBN and LJC designed the experiments and co-wrote the manuscript. TBN performed the experiments, carried out the statistical analysis, and graphed the data. DTV assisted with behavioral experiments. KMB performed slice electrophysiology experiments and analysis with oversight by JJW. BDB assisted with the immunofluorescence experiments.

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Correspondence to L. Judson Chandler.

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Nentwig, T.B., Vaughan, D.T., Braunscheidel, K.M. et al. The lateral habenula is not required for ethanol dependence-induced escalation of drinking. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01357-7

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  • DOI: https://doi.org/10.1038/s41386-022-01357-7

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