Faculty Collaboration Database

Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects. J Neurosci 2011 Aug 03;31(31):11244-55

Date

08/05/2011

Pubmed ID

21813685

Pubmed Central ID

PMC3153072

DOI

10.1523/JNEUROSCI.1040-11.2011

Scopus ID

2-s2.0-79961216486 (requires institutional sign-in at Scopus site)   57 Citations

Abstract

Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation (LTP) in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning, and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I-LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I-LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg; four pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB(1) antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB(1) and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine.

Author List

Pan B, Zhong P, Sun D, 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

Analysis of Variance
Animals
Animals, Newborn
Benzoxazines
Biophysics
Calcium Channel Blockers
Cocaine
Conditioning, Operant
Dopamine Uptake Inhibitors
Electric Stimulation
Enzyme Inhibitors
Excitatory Amino Acid Antagonists
Extracellular Signal-Regulated MAP Kinases
GABA Antagonists
In Vitro Techniques
Male
Morpholines
Naphthalenes
Neuronal Plasticity
Patch-Clamp Techniques
Picrotoxin
Piperidines
Pyrazoles
Rats
Rats, Sprague-Dawley
Reward
Signal Transduction
Synapses
Ventral Tegmental Area