Impaired synaptic inhibition and enhanced aversion encoding by lateral habenula neurons during Δ ⁹ -tetrahydrocannabinol withdrawal

The lateral habenula (LHb) integrates cortical and basal forebrain (BF) input to control monoaminergic outflow and is implicated in depression, anxiety, impulsivity, and aversion. Although cannabis withdrawal is associated with negative affect and heightened anxiety, LHb involvement is not established. Here, effects of withdrawal from the psychoactive cannabis constituent Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) on LHb neurons were assessed with photometric calcium measurement during fear conditioning and in vitro electrophysiology. LHb calcium signals were larger during footshock, and presentation of a tone paired with footshock in Δ ⁹ -THC withdrawn rats. Fear-induced freezing to the tone was also larger during Δ ⁹ -THC withdrawal. Electrophysiology revealed larger LHb excitatory-inhibitory (E-I) ratios during Δ ⁹ -THC withdrawal, resulting from impaired synaptic GABA release. Moreover, GABA release via optogenetic activation of BF-LHb inputs was impaired during Δ ⁹ -THC withdrawal, whereas no changes occurred at ventral tegmental area-LHb inputs. Recovery of BF-LHb GABA release and cannabinoid CB1 receptor desensitization were incomplete at 30 days of Δ ⁹ -THC withdrawal. The data show that LHb responsivity to primary aversive and conditioned stimuli are increased during Δ ⁹ -THC withdrawal, and that this is likely mediated by altered E-I balance. We propose negative affect experienced during cannabis withdrawal is related to LHb hypersensitivity to aversive stimuli and this facilitates encoding of associated environmental cues.