Positive Allosteric Modulation of the 5-HT1A Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans

Yano H, Adhikari P, Naing S, Hoffman AF, Baumann MH, Lupica CR and Shi L

ACS Chem Neurosci (2020) 11: 1400-1405

Link to abstract

The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem. When compared to cannabis, the misuse of SCs is associated with a higher incidence of serious adverse effects, suggesting the possible involvement of noncannabinoid sites of action. Here, we find that, unlike the phytocannabinoid Δ⁹-tetrahydrocannabinol, the indole-moiety containing SCs, AM2201 and JWH-018, act as positive allosteric modulators (PAMs) at the 5-HT_1A receptor (5-HT_1AR). This suggests that some biological effects of SCs might involve allosteric interactions with 5-HT_1ARs. To test this hypothesis, we examined effects of AM2201 on 5-HT_1AR agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons in vitro and on the hypothermic response to 5-HT_1AR stimulation in mice lacking the cannabinoid receptor 1. We found that both 5-HT_1AR effects were potentiated by AM2201, suggesting that PAM activity at 5-HT_1AR may represent a novel noncannabinoid receptor mechanism underlying the complex profile of effects for certain SCs.