Cannabinoid CB1 and CB2 receptors and drug abuse

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

During this review period (from October 2021 to August 2022), we published 3 original research papers (2 cannabinoid research papers + 1 glutamate research paper) and 3 review articles. In the first cannabinoid research paper (Zhang et al., APS, 2022), we investigated why brain CB2R level is very low in normal healthy subjects, while CB2R agonists are highly effective in the treatment of cocaine use disorder as we reported previously. We found that a single injection of cocaine failed to alter, while repeated cocaine injections or self-administration dose-dependently upregulated CB2R gene expression in both brain (cortex and striatum) and periphery (spleen). In contrast, repeated administration of heroin produced a dose-dependent reduction in striatal CB2 mRNA expression. We then used 3 transgenic mouse lines to purify striatal microglia, D1-MSNs, and D2-MSNs, respectively. We found that CB2R upregulation occurred mainly in D1-MSNs, not in D2-MSNs or microglia, in the nucleus accumbens rather than the dorsal striatum. These findings indicate that CB2R is highly inducible and dynamic. Chronic cocaine administration may upregulate CB2R expression in both brain and spleen, which may well explain why CB2R agonists are effective in reducing drug taking and drug-seeking behavior in the experimental animals. In the second cannabinoid research paper (Galaj et al., Translational Psychiatry, 2022), we evaluated the therapeutic potential of PIMSR, a novel neutral CB1R antagonist lacking an inverse agonist profile, against cocaine's behavioral effects in experimental animals. We found that PIMSR dose-dependently inhibited cocaine self-administration and decreased incentive motivation for cocaine seeking. Unlike rimonabant, a CB1R antagonist with inverse agonist profile, PIMSR alone is neither rewarding nor aversive, suggesting that it may have less rimonabant-like unwanted effects. Thus, the neutral CB1R antagonist PIMSR deserves further research as a potential pharmacotherapeutic for cocaine use disorder. In the third glutamate research paper (Yang et al., JNS, 2022), we investigate the role of glutamate in brain reward function. We found that elevating extracellular glutamate level in the NAc by TFB-TBOA, a selective astrocyte glutamate transporter inhibitor, inhibits cocaine self-administration and brain-stimulation reward by a NMDA (GluN2B subtype) receptor mechanism. In contrast, elevating extracellular glutamate levels in the NAc, ventral tegmental area (VTA), or ventral pallidum by TFB-TBOA reinstates extinguished cocaine-seeking behavior. These findings demonstrate that glutamate plays an opposite role in drug reward versus relapse reducing cocaine reward, while potentiating relapse to cocaine seeking. In a book chapter (Hempel and Xi, Advance in Pharmacology, 2022), we systemically reviewed recent progress in cannabinoid receptor mechanism research using advanced techniques including transgenics, optogenetics and RNAscope ISH. The use of such advanced techniques and tools has led to a series of new discoveries about the receptor mechanisms underlying cannabinoid actions and increased our understanding on how cannabis and cannabinoids alter brain function and behavior. In the second review article (Jordan and Xi, Front in Neurosci, 2022), we reviewed recent progress in identifying candidate genes contributing to drug use and addiction using transgenic approaches. A central hypothesis was if a particular gene variant (e.g., transgenic mutation or deletion of a gene) is associated with increases in drug taking and drug seeking, this gene variant may be considered a risk factor for drug use and addiction. Accordingly, we identified several candidate genes such as those that encode D2 and D3 , mGluR2, M4 and 5 receptors, which appear to meet the above risk-gene criteria. In the last minireview article (Hempel and Xi, APS, 2022), we briefly reviewed how a mitochondrial enzyme (clock 1, Clk1) modulates methamphetamine reward by regulating intracellular iron content and DAT expression.