Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats.Spiller KJ1, Bi GH2, He Y2, Galaj E2, Gardner EL2, Xi ZX2.Author information1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3600 Spruce Street, Philadelphia, PA, 19104, USA.2Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, 251 Bayview Blvd, Baltimore, MD, 21224, USA.AbstractBACKGROUND AND PURPOSE:

Endocannabinoids are critically involved in brain reward functions. This is generally believed to be mediated by activation of CB1 receptors, in large part due to their high density in the brain. However, the recent discovery of CB2 receptors (CB2 R) in the brain, particularly in midbrain dopamine neurons, has challenged this view and inspired us to re-examine the roles of both CB1 R and CB2 R in the effects of cannabis.

EXPERIMENTAL APPROACH:

In the present study, we used the electrical intracranial self-stimulation (ICSS) paradigm to evaluate the effects of various cannabinoid drugs on brain reward in laboratory rats, and the roles of CB1 R and CB2 R activation in brain reward function(s).

KEY RESULTS:

Two mixed CB1 R/CB2 R agonists, Δ9 -tetrahydrocannabinol (Δ9 -THC) and WIN55,212-2, produced biphasic effects – mild enhancement of brain-stimulation reward (BSR) at low dose, but inhibition at higher doses. Pretreatment with a CB1 R antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB2 R antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB1 R and CB2 R agonists, and these produced significant BSR enhancement and inhibition, respectively.

CONCLUSIONS AND IMPLICATIONS:

These findings suggest that CB1 R activation produces reinforcing effects, whereas CB2 R activation is aversive. This suggests that the subjective effects of cannabis may depend on the balance of these opposing effects. Therefore, these findings may not only explain previous conflicting results in animal models of addiction, but also explain why cannabis can be either rewarding or aversive in humans, since CB1 R/CB2 R expression may differ in the brains of different subjects.

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KEYWORDS:

Addiction; CB1 Receptor; CB2 Receptor; Cannabinoid; ICSS; Reward; Δ9-THC

PMID: 30767215 DOI: 10.1111/bph.14625 Share Supplemental Content —

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