mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism

Scientific Reports
Xia LiZheng-Xiong Xi

Abstract

Metabotropic glutamate receptor 5 (mGluR5) antagonism inhibits cocaine self-administration and reinstatement of drug-seeking behavior. However, the cellular and molecular mechanisms underlying this action are poorly understood. Here we report a presynaptic glutamate/cannabinoid mechanism that may underlie this action. Systemic or intra-nucleus accumbens (NAc) administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) dose-dependently reduced cocaine (and sucrose) self-administration and cocaine-induced reinstatement of drug-seeking behavior. The reduction in cocaine-taking and cocaine-seeking was associated with a reduction in cocaine-enhanced extracellular glutamate, but not cocaine-enhanced extracellular dopamine (DA) in the NAc. MPEP alone, when administered systemically or locally into the NAc, elevated extracellular glutamate, but not DA. Similarly, the cannabinoid CB1 receptor antagonist, rimonabant, elevated NAc glutamate, not DA. mGluR5s were found mainly in striatal medium-spiny neurons, not in astrocytes, and MPEP-enhanced extracellular glutamate was blocked by a NAc CB1 receptor antagonist or N-type Ca++ channel blocker, suggesting that a retrograde endocannabinoid-signaling mechanism underlie...Continue Reading

References

Jan 1, 1997·Annual Review of Pharmacology and Toxicology·P J Conn, J P Pin
Apr 27, 2002·Nature Neuroscience·G L GerdemanD M Lovinger
Jun 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·David RobbeOlivier J Manzoni
Jun 5, 2003·Nature Neuroscience·David A BakerPeter W Kalivas
Aug 20, 2003·The European Journal of Neuroscience·Nathalie Rouach, Roger A Nicoll
Dec 20, 2003·Annals of the New York Academy of Sciences·David RobbeOliver J Manzoni
Aug 6, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Lawrence FourgeaudOlivier J Manzoni
Jul 1, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ping Jun Zhu, David M Lovinger
Sep 27, 2005·Pharmacology & Therapeutics·Charles P O'Brien, Eliot L Gardner
Aug 18, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Zheng-Xiong XiEliot L Gardner
Apr 17, 2007·Molecular and Cellular Neurosciences·Diego CentonzeMauro Maccarrone
Feb 19, 2008·Nature Neuroscience·Sharon M AndersonR Christopher Pierce
Jan 23, 2009·Current Opinion in Pharmacology·Lori A Knackstedt, Peter W Kalivas
Jun 4, 2010·Neurochemical Research·Hanqing LiuZhifeng Liu
Apr 27, 2011·Molecular Psychiatry·P W Kalivas, N D Volkow
Jul 26, 2011·Nature Neuroscience·Zheng-Xiong XiEliot L Gardner
Oct 14, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·James E McCutcheonKuei Y Tseng

❮ Previous
Next ❯

Citations

May 28, 2019·Molecular Neurobiology·Julianna KardosLászló Héja
Aug 26, 2019·Psychopharmacology·Christina Gobin, Marek Schwendt
Aug 28, 2020·British Journal of Pharmacology·Chloe J JordanAmy Hauck Newman
Mar 13, 2019·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Amy Hauck NewmanZheng-Xiong Xi
Nov 25, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Ani GasparyanJorge Manzanares
Apr 11, 2021·Molecular Psychiatry·Junshi WangYan Dong
Jul 3, 2021·Cells·Miguel A Gonzalez-LozanoKa Wan Li
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ishtiaq AhmedQingyou Liu
Aug 23, 2021·Psychoneuroendocrinology·Heng-Ai ChangSherry Shu-Jung Hu

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
sedation

Related Concepts

Related Feeds

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Astrocytes & Neurodegeneration

Astrocytes are important for the health and function of the central nervous system. When these cells stop functioning properly, either through gain of function or loss of homeostatic controls, neurodegenerative diseases can occur. Here is the latest research on astrocytes and neurodegeneration.

Basal Ganglia

Basal Ganglia are a group of subcortical nuclei in the brain associated with control of voluntary motor movements, procedural and habit learning, emotion, and cognition. Here is the latest research.