Cannabinoid CB1 and CB2 receptors and drug abuse

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

During the annual review period from September 2024 to October 2025, my research team published a cannabis-related original research paper and one review article. In addition, we collaborated with Drs. Amy Newman and Yihong Yang and shared co-corresponding authors on five additional research papers on brain dopamine D3 receptor and DAT research. In our first cannabinoid research paper (Soler-Cedeno et al., Neuropsychopharmacology, October 2024), we explored the potential use of a new compound called AM6527, a neutral CB1 receptor antagonist without inverse agonist profile, in treatment of opioid and cannabinoid use disorders. Our findings revealed that AM6527 did not affect cocaine self-administration under fixed-ratio reinforcement schedules but dose-dependently inhibited it under progressive-ratio reinforcement schedules. Additionally, AM6527 dose-dependently inhibited heroin self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and oral sucrose self-administration under a fixed-ratio reinforcement schedule, as well as cocaine- or heroin-triggered reinstatement of drug-seeking behavior in rats. However, chronic AM6527 administration for five consecutive days significantly inhibited heroin self-administration only during the initial two days, indicating tolerance development. Notably, AM6527 did not produce rewarding or aversive effects by itself in classical electrical intracranial self-stimulation and conditioned place preference tests. However, in optical intracranial self-stimulation (oICSS) maintained by optogenetic stimulation of midbrain dopamine neurons in DAT-cre mice, both AM6527 and rimonabant dose-dependently inhibited dopamine-dependent oICSS behavior. These findings suggest that AM6527 effectively reduces drug-taking and seeking behaviors without rimonabant-like adverse effects. Thus, AM6527 warrants further investigation as a potential pharmacotherapy for opioid and cocaine use disorders. In a review article (Xi ZX and Galag E, Biomedicine and Pharmacotherapy, August, 2025), we discussed the use of a number of cannabinoid ligands and other novel compounds in treating eating disorders comorbid with substance use disorders. Eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED), frequently co-occur with substance use disorders (SUDs), affecting 20–30 % of individuals with either condition. This significant overlap is driven by shared neurobiological mechanisms, such as disruptions in dopamine, opioid, and cannabinoid systems, as well as by psychological traits including impulsivity, anxiety, and stress. While AN is often characterized by restrictive behaviors, BN and BED involve compulsive binge episodes, mirroring addiction patterns observed in SUDs. The current lack of FDA-approved treatments for co-occurring EDs and SUDs highlights the urgent need for innovative pharmacotherapies targeting overlapping neural pathways and behaviors. This article reviews the epidemiology and neurobiology of three major EDs, explores their behavior and metabolic commonalities, and examined recent advances in pharmacotherapy for EDs with comorbid SUDs. Promising treatments include dronabinol, olanzapine and ketamine, which improve compulsive behaviors and mood in AN and SUDs, as well as glucagon-like peptide 1 (GLP-1) receptor agonists, which reduce binge episodes and cravings in BED and SUDs. Hormonal agents such as leptin, ghrelin, and oxytocin are emerging as potential treatments due to their effects on appetite, reward systems, and stress regulation. Additionally, beta-caryophyllene and lisdexamfetamine demonstrate potential for binge-related disorders. Future research should prioritize large-scale clinical trials, integrated pharmacotherapeutic and psychological approaches, and a personalized medical treatment based on genetic and neurobiological profiles. In a collaboration study with Dr. Amy Newman (Soler-Cedeno et al., Br. J. Pharmacol, July 2025), we examined the effects of ESG-1-60 and ESG-1-61 (cariprazine analogs), novel D3 receptor-preferring partial agonist or D3 receptor-preferring antagonist/inverse agonist, in treating cocaine use disorder in rodents. We found that both the compounds are highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioral effects. (See Dr. Amy Newman's annual report for more details). In a second collaboration study with Dr. Amy Newman (Soler-Cedeno et al., Translational Psychiatry, May, 2025), we explored the potential use of RDS-04-010, a novel atypical DAT inhibitor in treating cocaine use disorder. We found that systemic administration of RDS-04-010 dose-dependently inhibited cocaine self-administration, shifted the cocaine self-administration dose-response curve downward, decreased motivation for cocaine seeking under progressive-ratio reinforcement conditions, and inhibited cocaine-primed reinstatement of drug-seeking behavior. RDS-04-010 alone neither altered optical brain-stimulation reward nor evoked reinstatement of drug-seeking behavior. RDS-04-010 substitution for cocaine was not able to maintain self-administration in rats trained to self-administer cocaine. These findings suggest that RDS-04-010 has favorable therapeutic potential in reducing cocaine-taking and -seeking behavior with low addictive liability. (See Dr. Amy Newman's annual report for more details). In a third collaboration study with Dr. Amy Newman (Xi et al., Biological Psychiatry, Nov. 2024), we employed multiple advanced techniques including Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1 receptor (D1R)-expressing neurons in mice, NAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics and behavioral assays to functionally characterize the roles of presynaptic versus postsynaptic D3 receptors in cocaine and opioid actions. We found that D2 and D3 receptors are expressed in different populations of midbrain dopamine neurons, regulating dopamine release, while in the mesolimbic system, D3R are critically involved in the actions of opioids but not cocaine. (See Dr. Amy Newman's annual report for more details). In other two collaboration studies with Dr. Yihong Yang (Shen et al., Neuropharmacology, Oct, 2024; eNeuro, March 2025), we investigated the functional role of dopamine D3 receptor in impulsive choice decision-making in rats and the effects of chronic cocaine use on impulsive behavior in rats. We found that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, holds therapeutic potentials for mitigating impulsivity in high-impulsive subjects. In addition, we also found, unexpectedly, that there is no difference in cocaine-taking and -seeking between low-impulsive and high-impulsive rats. In contrast, chronic cocaine use selectively increases impulsive choice decision-making in normally low-impulsive rats, which is associated with reduced functional connectivity and DA receptor expression in the mesocorticolimbic DA network.(See Dr. Yihong Yang's annual report for more details).