Disruption of hippocampal synaptic transmission and long‐term potentiation by psychoactive synthetic cannabinoid ‘Spice’ compounds: comparison with Δ(9)‐tetrahydrocannabinol

There has been a marked increase in the availability of synthetic drugs designed to mimic the effects of marijuana. These cannabimimetic drugs, sold illicitly as ‘Spice’ and related products, are associated with serious medical complications in some users. In vitro studies suggest that synthetic cannabinoids in these preparations are potent agonists at central cannabinoid CB1 receptors (CB1Rs), but few investigations have delineated their cellular effects, particularly in comparison with the psychoactive component of marijuana, Δ(9)‐tetrahydrocannabinol (Δ(9)‐THC). We compared the ability of three widely abused synthetic cannabinoids and Δ(9)‐THC to alter glutamate release and long‐term potentiation in the mouse hippocampus. JWH‐018 was the most potent inhibitor of hippocampal synaptic transmission (EC(50) ~15 nM), whereas its fluoropentyl derivative, AM2201, inhibited synaptic transmission with slightly lower potency (EC(50) ~60 nM). The newer synthetic cannabinoid, XLR‐11, displayed much lower potency (EC(50) ~900 nM) that was similar to Δ(9)‐THC (EC(50) ~700 nM). The effects of all compounds occurred via activation of CB1Rs, as demonstrated by reversal with the selective antagonist/inverse agonist AM251 or the neutral CB1R antagonist PIMSR1. Moreover, AM2201 was without effect in the hippocampus of transgenic mice lacking the CB1R. Hippocampal slices exposed to either synthetic cannabinoids or Δ(9)‐THC exhibited significantly impaired long‐term potentiation (LTP). We find that, compared with Δ(9)‐THC, the first‐generation cannabinoids found in Spice preparations display higher potency, whereas a recent synthetic cannabinoid is roughly equipotent with Δ(9)‐THC. The disruption of synaptic function by these synthetic cannabinoids is likely to lead to profound impairments in cognitive and behavioral function.