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

作者：Idaira Oliva, Fezaan Kazi, Lucas Cantwell, Ganesh A. Thakur, Jonathon D. Crystal, Andrea G. Hohmann · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.01.16.575900 · 被引用次数：2 · 研究领域：Cannabis and Cannabinoid Research、Neurotransmitter Receptor Influence on Behavior、Neuroscience and Neuropharmacology Research

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that pharmacological inhibition of CB1R signaling through negative allosteric modulation (NAM) would reduce the reinforcing properties of morphine and decrease opioid addictive behaviors. By employing i.v. self-administration in mice, we studied the effects of the CB1-biased NAM GAT358 on morphine intake, relapse-like behavior, and motivation to work for morphine infusions. Our data revealed that GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under fixed ratio 1 schedule of reinforcement. GAT358 decreased morphine-seeking behavior after forced abstinence. Moreover, GAT358 dose-dependently decreased the motivation to obtain morphine infusions in a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-...