Lateral habenula cannabinoid CB1 receptor involvement in drug-associated impulsive behavior

Animal and human studies show that cannabis or its derivatives can increase relapse to cocaine seeking following withdrawal. Moreover, cannabis use in humans is associated with impulse control deficits and animal studies implicate endogenous cannabinoids (eCB) in several impulsivity constructs. However, the brain areas where cannabinoids might control impulsivity or cocaine seeking are largely unknown. Here, we assess Lateral Habenula (LHb) involvement on performance in the 5-choice serial reaction time task (5CSRTT) in rats and investigate whether LHb cannabinoid CB1 receptors (CB1R) are involved in these effects. Systemic cocaine increased premature responding, a measure of impulsivity, at a dose (5 mg/kg) that did not alter other measures of task performance. Intra-LHb infusion of the CB1R antagonist AM251 blocked this effect. Systemic injection of the psychoactive constituent of cannabis, Δ⁹-tetrahydrocannabinol (Δ⁹-THC, 1 mg/kg), also increased 5CSRTT premature responding at a dose that did not otherwise disrupt task performance. This was blocked by intra-LHb infusion of AM251 in a subgroup of rats showing the largest increases in Δ⁹-THC-evoked premature responses. Systemic Δ⁹-THC also prompted impulsive cocaine seeking in a Go/NoGo cocaine self-administration task and this was blocked by intra-LHb AM251. These data show that LHb CB1Rs are involved in deficits in impulse control initiated by cocaine and Δ⁹-THC, as assessed by the 5CSRTT, and play a role in impulsive cocaine seeking during cocaine self-administration. This suggests that the LHb eCB system contributes to the control of impulsive behavior, and thus represents a potential target for therapeutic treatment of substance use disorders (SUDs) in humans.