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

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. [Display omitted] • CB 1 negative allosteric modulator GAT358 does not produce cannabimimetic effects. • GAT358 decreases CB 1 agonist-induced catalepsy, hypothermia but not antinociception. • GAT358 eliminates morphine-induced phasic dopamine release in the NAc shell. • GAT358 blocks conditioned place preference to morphine via a CB 1 mechanism. • GAT358 reduces oral oxycodone but not water intake in a two-bottle choice assay. [ABSTRACT FROM AUTHOR]