Objective: Preclinical animal studies show that cannabinoid CB1 receptor (CB1R) orthosteric antagonists/inverse agonists have strong anti-addiction effects against many addictive drugs. However, development of CB1R orthosteric antagonists/inverse agonists was terminated in 2008 due to significant side-effects (anxiety, depression, suicidal ideation) in clinical trials and use in Europe of the lead CB1R orthosteric antagonist/inverse agonist SR141716 (rimonabant). We propose that neutral CB1R antagonists (lacking inverse agonism) or CB1R negative allosteric modulators (binding to transmembrane allosteric sites rather than extracellular orthosteric sites) may have therapeutic anti-addiction potential without unwanted effects.
Methods: We evaluated the effects of these three types of CB1R ligand in animal models relating to drug addiction – including intravenous drug self-administration and drug-enhanced electrical brain-stimulation reward (BSR).
Results: We found that 1) the inverse CB1R agonist SR141716 (3, 10 mg/kg, i.p.) significantly inhibited cocaine, heroin, or nicotine self-administration and cocaine-enhanced BSR in laboratory rats; but SR141716 itself produced dysphoric effects in the BSR model; 2) the CB1R neutral antagonists AM4113 and PIMSR1 (3, 10 mg/kg) significantly attenuated cocaine, nicotine, or heroin self-administration and cocaine-enhanced brain-stimulation reward; by themselves, the two compounds had no effect on basal BSR functions; 3) the CB1R negative allosteric modulators (NAMs) GAT358 and GAT369 (10, 20 mg/kg) altered neither nicotine-enhanced BSR nor basal BSR functions.
Conclusions: Neutral CB1R antagonists appear more promising than CB1R orthosteric antagonists/inverse agonists or CB1R NAMs in medication development for treatment of drug abuse and addiction.