Evaluating mGlu5 knockout mice as a model of morphine addiction susceptibility

Abstract

Globally, opioid addiction causes significant health, social and economic costs. There has been an increasing trend of opioid dependence and abuse in high-income countries, and long term opioid use is associated with significant health costs. Additionally, there are substantial sex differences in opioid addiction as men report higher lifetime use of opioids; however, women are more likely to relapse during abstinence. Opioid addiction is also accompanied by significant neural adaptations that drive an abstinence-relapse cycle and the development of opioid addiction-relevant behaviours. Current treatments are limited and do not address these biological processes. The metabotropic glutamate 5 receptor (mGlu5) receptor is a potential target for treating addiction. Mice with a genetic deletion (i.e. knockout, KO) of mGlu5 exhibit addiction-like behaviour for psychostimulants and ethanol, but their response to opioids has yet to be examined. Assessing opioid addiction-like behaviour in these mice, and testing for potential sex-differences in their reward and locomotor response to morphine, will determine if mGlu5 could be a treatment target for opioid abuse. The effects of mGlu5 deletion on morphine conditioned place preference (CPP) were assessed. Male and female WT-like and mGlu5 KO mice acquired morphine CPP for 5 and 10 mg/kg morphine. Female mice had a higher preference for 5 mg/kg morphine than male mice. There were no sex-differences in preference for 10 mg/kg morphine. Female mGlu5 KO had a persistent preference for a morphine-paired environment for 5 mg/kg morphine. mGlu5 KO mice, regardless of sex, showed morphine-induced hypolocomotion for 5 mg/kg morphine and hyperlocomotion for 10 mg/kg morphine. Both 5 and 10 mg/kg morphine induced hyperlocomotion in WT-like mice. Female mGlu5 KO mice developed locomotor sensitisation to 5 mg/kg morphine while all mice showed locomotor sensitisation to 10 mg/kg morphine. mGlu5 modulation of morphine reward was sex-specific and dose-dependent. These results suggest that mGlu5 deletion did not affect morphine reward in male mice, but female mGlu5 KO mice are more sensitive to the rewarding effects of morphine than female WT-like mice. mGlu5 mediates sensitivity to morphine-induced locomotion in both male and female mice. These findings emphasise the importance of considering sex effects in opioid addiction research.

Date of Award	2022
Original language	English