Cannabinoid CB1 and CB2 receptors and drug abuse

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

During the period from September 2022 to the present, our research efforts have resulted in 3 original research papers, including 2 cannabinoid-related research papers and 1 exercise reward-related paper. Additionally, we have collaborated on 3 research papers and authored 2 review articles. In our recent cannabinoid research paper (Hempel et al., Mol Psychiatry, 2023), we explored the roles of putative cannabinoid receptors peroxisome proliferator-activated receptors (PPARs) in cannabinoid CNS effects. PPAR and PPAR were detected in around 70% of midbrain dopamine (DA) neurons, 60% of amygdala glutamatergic neurons, and 60% of GABA neurons, but not detected in nucleus accumbens GABA neurons. Behavioral assays indicated that optogenetic stimulation of midbrain DA neuron is rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Both 9-THC and a PPAR agonist (not PPAR) dose-dependently inhibited oICSS, while PPAR/ antagonists mitigated 9-THC-induced aversive and anxiogenic effects. These findings provide pioneering anatomical and functional evidence supporting an important role of PPAR/ in DA-dependent behavior and cannabinoid actions. In our second cannabinoid research paper (Han et al., JNS, 2022), we investigated CB1 receptor (CB1R) expression and function in midbrain dopamine (DA) neurons. We found that CB1Rs are not only expressed in GABA neurons but also in a specific subset of dopamine neurons co-releasing glutamate. These CB1R-expressing DA neurons are primarily located in the middle portion of the VTA, with CB1-TH colocalization gradually declining from the medial to lateral VTA. Optogenetic activation of this population of DA neurons is rewarding, as assessed by oICSS. 9-THC and ACEA, a selective CB1R agonist, dose-dependently inhibited oICSS in DAT-Cre control mice, but not in conditional CB1-KO mice where the CB1R gene was absent in DA neurons. In addition, removing CB1R from DA neurons attenuated 9-THC-induced reductions in DA release in the NAc, locomotion and anxiety. These findings suggest that dopaminergic CB1R mechanisms also contribute to the CNS effects of cannabinoids. In the third paper (He et al., Sci Adv, 2022), we explored the neural circuitry underlying the rewarding effects of physical exercise. Our findings reveal that prolonged wheel-running produced a robust increase in c-fos expression in the midbrain red nucleus (RN), predominantly in RN magnocellular glutamate neurons. Electrophysiological assays indicate that wheel-running activates RN glutamate neurons that project to nearby VTA DA neurons. Optogenetic stimulation of this pathway produces rewarding effects as assessed by oICSS and CPP. Conversely, optogenetically inhibiting RN glutamate neurons attenuates wheel-running behavior. Additionally, wheel running reduces cocaine self-administration and cocaine-seeking, while optogenetic stimulation of the RN-to-VTA glutamate pathway suppresses cocaine intake. These findings highlight an important role of a RN-to-VTA glutamate pathway in producing exercise reward and reducing cocaine consumption. In three collaborative research papers with Drs. Newman and Ferre, our focus was on exploring the therapeutic potential of novel D3 antagonists or partial agonists in treatment of cocaine and opioid use disorders. My specific contribution involved utilizing our behavioral models to assess the impact of these novel compounds on cocaine or opioid self-administration and reinstatement of drug-seeking behavior. In a review article by Newman et al. (2023), we reviewed the recent progress in D3 receptor-based medication development for treating psychostimulant and opioid use disorders in humans and experimental animals. In another review by Soler-Cedeno and Xi (Cells, 2022), we comprehensively outlined the reasoning, advancements, and obstacles in developing neutral CB1R neutral antagonists as potential treatments for substance use disorders.