Faculty Collaboration Database

Metabotropic glutamate receptor I (mGluR1) antagonism impairs cocaine-induced conditioned place preference via inhibition of protein synthesis. Neuropsychopharmacology 2013 Jun;38(7):1308-21

Date

01/26/2013

Pubmed ID

23348064

Pubmed Central ID

PMC3656374

DOI

10.1038/npp.2013.29

Scopus ID

2-s2.0-84878621407 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB1 receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.

Author List

Yu F, Zhong P, Liu X, Sun D, Gao HQ, Liu QS

Author

Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Cycloheximide
Dopaminergic Neurons
Drug Interactions
Extracellular Signal-Regulated MAP Kinases
Glycine
Inhibitory Postsynaptic Potentials
Long-Term Synaptic Depression
Male
Microinjections
Nerve Tissue Proteins
Peptide Chain Elongation, Translational
Protein Synthesis Inhibitors
Quinolines
Rats
Receptor, Cannabinoid, CB1
Receptors, Metabotropic Glutamate
Resorcinols
Signal Transduction
Synapses
TOR Serine-Threonine Kinases
Ventral Tegmental Area