GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice

Study Authors Yi He and Hui Shen

Hot Off the Press – April 4, 2024

Published in Translational Psychiatry by Yi He, Hui Shen and Zheng-Xiong Xi, et al. from the NIDA IRP Addiction Biology Unit and Magnetic Resonance Imaging and Spectroscopy Section.

Summary

G protein-coupled receptor 55 (GPR55) is a putative cannabinoid receptor, which has been considered as the “CB3” receptor, as multiple cannabinoids such as Δ9-THC, CP55,940, HU-210, anandamide, and 2-AG, have high binding affinities to this receptor. However, its functional role in cannabis action and substance abuse has not been explored. Through a comprehensive array of neuroimaging techniques, including RNAscope ISH, IHC, and fluorescent ligand binding assays, we found that GPR55 is highly expressed in cortical and subcortical glutamate neurons, but not in midbrain DA neurons, in mice. Based on this cellular distribution in the brain, we then conducted a series of neurochemical, physiological, and behavioral assays. We found that GPR55 activation augments glutamate release in the nucleus accumbens without affecting extracellular dopamine levels. Systemic administration of O-1602, a potent GPR55 agonist, neither altered Δ9-THC-induced triad effects (analgesia, hypothermia, and catalepsy) nor altered optical brain-stimulation reward in DAT-cre mice. Unexpectedly, systemic administration of O-1602 dose-dependently inhibited cocaine-enhanced brain-stimulation reward and intravenous cocaine and nicotine self-administration under fixed-ratio and/or progressive-ratio reinforcement schedules in rats, wild-type mice, but not in GPR55-KO mice. These groundbreaking findings revealed a pivotal role of glutamatergic GPR55 mechanisms in the reward processes associated with cocaine and nicotine addiction, and therefore, GPR55 deserves further studies as a promising therapeutic target for treating substance use disorders.

Publication Information

He, Yi; Shen, Hui; Bi, Guo-Hua; Zhang, Hai-Ying; Soler-Cedeño, Omar; Alton, Hannah; Yang, Yihong; Xi, Zheng-Xiong

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice Journal Article

In: Transl Psychiatry, vol. 14, no. 1, pp. 101, 2024, ISSN: 2158-3188.

Abstract | Links

@article{pmid38374108,

title = {GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice},

author = {Yi He and Hui Shen and Guo-Hua Bi and Hai-Ying Zhang and Omar Soler-Cedeño and Hannah Alton and Yihong Yang and Zheng-Xiong Xi},

url = {https://pubmed.ncbi.nlm.nih.gov/38374108/},

doi = {10.1038/s41398-024-02820-3},

issn = {2158-3188},

year  = {2024},

date = {2024-02-01},

urldate = {2024-02-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {101},

abstract = {G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}