Positive Allosteric Modulation of the 5-HT<sub>1A</sub> Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans
Hideaki Yano, Pramisha Adhikari, Sett Naing, Alexander F. Hoffman, Michael H. Baumann, Carl R. Lupica, Lei Shi
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-HT1A receptor (5-HT1AR). This suggests that some biological effects of SCs might involve allosteric interactions with 5-HT1ARs. To test this hypothesis, we examined effects of AM2201 on 5-HT1AR agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons in vitro and on the hypothermic response to 5-HT1AR stimulation in mice lacking the cannabinoid receptor 1. We found that both 5-HT1AR effects were potentiated by AM2201, suggesting that PAM activity at 5-HT1AR may represent a novel noncannabinoid receptor mechanism underlying the complex profile of effects for certain SCs.