Abstract
Blockade of cannabinoid type 1 (CB(1))-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 CB(1) antagonists. Negative allosteric modulators (NAMs) represent a novel and indirect approach to attenuate CB(1) signaling by decreasing affinity and/or efficacy of CB(1) ligands. We hypothesized that a CB(1)-NAM would block opioid reward while avoiding the unwanted effects of orthosteric CB(1) antagonists. GAT358, a CB(1)-NAM, failed to elicit cardinal signs of direct CB(1) activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB(1) agonist CP55,940, suggesting that a CB(1)-NAM blocked cardinal signs of CB(1) 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 CB(1) positive allosteric modulator (CB(1)-PAM), and absent in CB(1)-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 CB(1)-NAMs as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side-effects.