Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self‐administration and relapse in mice

• DOI: 10.1111/adb.13429
• Publication Date: 2024-08-07T12:25:27Z
• Authors: Idaira Oliva; Fezaan Kazi; Lucas N. Cantwell; Ganesh A. Thakur; Jonathon D. Crystal; Andrea G. Hohmann
• Keywords: Self-administration; Allosteric modulator

The endocannabinoid system interacts with the reward to modulate responsiveness natural reinforcers, as well drugs of abuse. Previous preclinical studies suggested that direct blockade CB1 cannabinoid receptors (CB1R) could be leveraged a potential pharmacological approach treat substance use disorder, but this strategy failed during clinical trials due severe psychiatric side effects. Alternative strategies have emerged circumvent effects binding through development allosteric modulators. We hypothesized negative modulation CB1R signalling would reduce reinforcing properties morphine and decrease behaviours associated opioid misuse. By employing intravenous self-administration in mice, we studied GAT358, functionally-biased modulator (NAM), on intake, relapse-like behaviour motivation work for infusions. GAT358 reduced infusion intake maintenance phase under fixed ratio 1 schedule reinforcement. also decreased morphine-seeking after forced abstinence. Moreover, dose dependently obtain infusions progressive Strikingly, did not affect food rewards an identical task, suggesting effect decreasing was specific. Furthermore, GAT58 produce motor ataxia rotarod test. Our results suggest NAMs represent viable therapeutic route safely misuse opioids.