Increased encoding of aversive stimuli by lateral habenula neurons during Δ9-tetrahydrocannabinol withdrawal.
Eun-Kyung Hwang, Deborah Daphne, Charlie J Maddox, Agustin Zapata, Alexander F. Hoffman, Carl R. Lupica
Nature Communications September 3, 2026 DOI: 10.1038/s41467-026-77429-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats |
| Topics | Cannabis |
| Key points | Δ9-THC withdrawal increased fear-conditioning-associated LHb calcium signals, freezing behavior, and LHb excitatory-inhibitory ratios, and impaired local GABA release, indicating disinhibition of LHb output neurons. GABA release was also impaired at optogenetically activated basal forebrain-LHb axons but not at ventral tegmental area-LHb inputs. The authors propose that this LHb disinhibition contributes to increased fear of primary and conditioned aversive stimuli and to cannabis withdrawal-associated negative affect. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.