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

Featured Paper of the Month – October 2021

Published in Neuropharmacology by Agustin Zapata and Carl R Lupica in the NIDA IRP Electrophysiology Research Section.

Summary

Studies show that cannabis increases relapse to cocaine seeking following withdrawal, and in humans cannabis and cocaine use are associated with impulse control deficits. We showed previously that an area of the brain known as the lateral habenula (LHb) is involved in inhibiting operant responses for cocaine in rat self-administration studies. Therefore, the present study was conducted to determine if the LHb controls impulsivity caused by acute cocaine or the primary psychoactive component of cannabis know as Δ9-tetrahydrocannabinol (Δ9-THC). Using a task to measure impulsivity, attention, and motivation, known as the 5 choice serial reaction time task (5CSRTT) in rats, we found that both cocaine and Δ9-THC, at select systemic doses, selectively increased impulsive behavior without affecting attention and motivation. Then, using the 5CSRTT we found that the pro-impulsive effects of both drugs were prevented by blocking cannabinoid CB1 receptors with an antagonist in the LHb. This provides the first evidence that the LHb endogenous cannabinoid system may be involved in drug-associated impulsive behavior. Finally, we also found that Δ9-THC increased impulsive cocaine seeking during self-administration and this was also prevented by blocking LHb CB1Rs. Together these experiments show that CB1Rs in the LHb are involved in impulsive drug-related behavior and that the LHb endocannabinoid system could represent a viable target for therapies to decrease drug seeking in humans.

Publication Information

Zapata, Agustin; Lupica, Carl R

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

In: Neuropharmacology, vol. 192, pp. 108604, 2021, ISSN: 1873-7064.

Abstract | Links

@article{pmid33965396,

title = {Lateral habenula cannabinoid CB1 receptor involvement in drug-associated impulsive behavior},

author = {Agustin Zapata and Carl R Lupica},

url = {https://pubmed.ncbi.nlm.nih.gov/33965396/},

doi = {10.1016/j.neuropharm.2021.108604},

issn = {1873-7064},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Neuropharmacology},

volume = {192},

pages = {108604},

abstract = {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, Δ-tetrahydrocannabinol (Δ-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 Δ-THC-evoked premature responses. Systemic Δ-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 Δ-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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}