Cannabinoid CB1 and CB2 receptors and drug abuse

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

During this review period, we have carried out a series of experiments in our cannabinoid research, which has led to 5 original research papers, 3 review articles, and 1 article in print. The major findings include: 1) both phytocannabinoids (Delta9-THC, beta-caryophyllene) and synthetic cannabinoids (WIN55212-2, ACEA, AM2201) are not rewarding, but aversive, as assessed by optogenetic intracranial self-stimulation (oICSS) in DAT-cre mice (Humburg et al., Addiction Biology, 2021); 2) cannabinoid CB2 receptor is found in red nucleus glutamate neurons and functionally modulate locomotion behavior (Zhang et al., Neuropharmacology, 2021); 3) Beta-caryophyllene, a FDA-approved food additive and also a natural CB2R agonist, is effective in attenuation of cocaine (and methamphetamine)-taking and -seeking behavior in both rats and mice (Galaj et al., NPP, 2021; He et al., Frontiers in Pharmacol, 2021); 4) Chronic cocaine administration up-regulates CB2 receptor expression in cortical glutamate neurons and striatal D1-expressing GABA neurons (Zhang et al., Acta Pharmacologica Sinica, 2021); 5) Using both CB1-KO and CB2-KO mice as controls, we recently found that CB1 and CB2 receptors play functionally opposite roles in regulating cannabinoid reward and aversion. Specifically, activation of the CB1 receptor is rewarding, while CB2R activation is aversive. The final outcome of cannabinoid action depends on the balance of both opposite actions, while the CB2-mediated effects are predominant in mice (Li et al., Eur NPP, 2021). The different cellular distributions of CB1 and CB2 receptors in the brain may in part explain cannabis reward versus aversion observed in humans and experimental animals (Humburg et al., Addiction Biology, 2021). There is a comprehensive review published in the past fiscal year that summarizes our major findings in this research area over the past decade (Briana and Xi, Advance in Pharmacology, 2021). To determine whether such cell type-specific CB1/CB2 receptor mechanisms of cannabinoid reward and aversion can be generalized to other substrates of abuse, we further investigated the role of mu opioid receptors (MOR) in different phenotypes of neurons in opioid reward. We found that MORs expressed in GABAergic neurons in the substantia nigra pars reticulata (SNr) play a more important role than MORs in VTA GABAergic neurons (Galaj et al., JNS, 2021; Galaj and Xi, Int J Mol Sci, Dec 2020). These findings challenge a long-held view for over a half century that MORs within VTA GABAergic neurons play an essential role in opioid reward and addiction-related behavior.