Synthetic Cannabinoid Receptor Agonist ‘JWH-018’ does not mimic Serotonin

Synthetic cannabinoid receptor agonists (SCRAs) are popular recreational drugs. It has been suggested that indole-containing SCRAs may have activity at several serotonergic targets, owing to their structural similarity to the neurotransmitter serotonin (5-HT). This similarity may be responsible for features of toxicity similar to serotonin syndrome observed in cases of SCRA intoxication. To determine whether indole-SCRAs have activity at serotonergic targets we investigated the effect of JWH-018, an indole-containing SCRA, with a non-indole-containing SCRA (CP55,940) and an endocannabinoid (anandamide) on 5-HT neuronal functions in rat brain slices; 5-HT neuronal activity was examined using in vitro extracellular single-unit electrophysiology in the dorsal raphe nucleus and 5-HT presynaptic uptake was examined using radiolabeled 5-HT(3[H] 5-HT) in the hippocampus. 5-HT (50M) inhibited the 5-HT neuronal firing rate but JWH-018 (50M) had no effect on the basal or NMDA (30M) augmented firing rate. In contrast, anandamide (10uM) increased the NMDA-augmented firing rate of 5-HT neurons, but not the basal rate. The selective serotonin reuptake inhibitor fluoxetine (0.001 10 M) inhibited 5-HT reuptake but JWH-018 (0.001 10 M) had no effect on serotonin uptake. Our data suggest that indole-SCRAs and non-indole SCRAs do not directly interact with serotonergic targets in either the dorsal raphe nucleus or hippocampus. Further mechanistic studies are needed to determine if SCRAs affect serotonergic neurotransmission through modulation of afferents to 5-HT neurons.