Increased encoding of aversive stimuli by lateral habenula neurons during Δ9-tetrahydrocannabinol withdrawal

The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input and is implicated in negative affective states, but its involvement in negative affect associated with cannabis withdrawal is unknown. Here, effects of withdrawal from the psychoactive cannabis constituent, Δ9-tetrahydrocannabinol (Δ9-THC), on fear conditioning (FC) and LHb function were measured in rats using calcium photometry and electrophysiology. FC-associated LHb calcium signals, freezing behavior, and LHb excitatory-inhibitory (E-I) ratios were increased during Δ9-THC withdrawal, and local GABA release was impaired, indicating disinhibition of LHb output neurons.

GABA release was also impaired at optogenetically activated BF-LHb axons, and not from ventral tegmental area-LHb inputs. The results indicate that Δ9-THC withdrawal increases LHb excitability through disinhibition, contributing to increased fear of primary and conditioned aversive stimuli. Our findings implicate the LHb in cannabis withdrawal-associated negative affect and offer insight into the neural mechanisms of cannabis use disorder.

This research was supported by the NIH (NIDA) Intramural Research Program. The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S.

Department of Health and Human Services. This work is supported by Grant 1ZIA-DA000643 (to CRL) from the National Institute on Drug Abuse. Present address: Department of Behavioral Neuroscience, Oregon Health & Sciences University, Portland, OR, USA These authors contributed equally: Eun-Kyung Hwang, Deborah Daphne.

National Institutes of Health, National Institute on Drug Abuse Intramural Research Program, Cellular and Neurocomputational Systems Branch, Electrophysiology Research Section, Baltimore, MD, USA Eun-Kyung Hwang, Deborah Daphne, Charlie J. Maddox, Agustin Zapata, Alexander F. Lupica The Lewis Katz School of Medicine, Center for Substance Abuse Research, Temple University, Philadelphia, PA, USA The authors declare no competing interests.

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