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

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 Δ-tetrahydrocannabinol, the indole-moiety containing SCs, AM2201 and JWH-018, act as positive allosteric modulators (PAMs) at the 5-HT receptor (5-HTR). This suggests that some biological effects of SCs might involve allosteric interactions with 5-HTRs. To test this hypothesis, we examined effects of AM2201 on 5-HTR agonist-activated G protein-coupled inwardly rectifying potassium channel currents in neurons and on the hypothermic response to 5-HTR stimulation in mice lacking the cannabinoid receptor 1. We found that both 5-HTR effects were potentiated by AM2201, suggesting that PAM activity at 5-HTR may represent a novel noncannabinoid receptor mechanism underlying the complex profile of effects for certain SCs.