Negative allosteric modulation of CB₁ cannabinoid receptor signaling suppresses opioid-mediated reward

Blockade of cannabinoid type 1 (CB₁)-receptor signaling decreases the rewarding properties of many drugs of abuse and has been proposed as an anti-addiction strategy. However, psychiatric side-effects limit the clinical potential of orthosteric CB₁ antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB₁ signaling by decreasing affinity and/or efficacy of CB₁ ligands. We hypothesized that a CB₁-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB₁ antagonists. GAT358, a CB₁-NAM, failed to elicit cardinal signs of direct CB₁ activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB₁ agonist CP55,940, suggesting that a CB₁-NAM blocked cardinal signs of CB₁ activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB₁ positive allosteric modulator (CB₁-PAM), and absent in CB₁-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm. Our results support the therapeutic potential of CB₁-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.