Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area. J Neurosci 2016 Apr 27;36(17):4802-15
Date
04/29/2016Pubmed ID
27122037Pubmed Central ID
PMC4846675DOI
10.1523/JNEUROSCI.3186-15.2016Scopus ID
2-s2.0-84966577646 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
UNLABELLED: Exchange protein directly activated by cAMP (Epac) and protein kinase A (PKA) are intracellular receptors for cAMP. Although PKA and its downstream effectors have been studied extensively in the context of drug addiction, whether and how Epac regulates cellular and behavioral effects of drugs of abuse remain essentially unknown. Epac is known to regulate AMPA receptor (AMPAR) trafficking. Previous studies have shown that a single cocaine exposure in vivo leads to an increase in GluA2-lacking AMPARs in dopamine neurons of the ventral tegmental area (VTA). We tested the hypothesis that Epac mediates cocaine-induced changes in AMPAR subunit composition in the VTA. We report that a single cocaine injection in vivo in wild-type mice leads to inward rectification of EPSCs and renders EPSCs sensitive to a GluA2-lacking AMPAR blocker in VTA dopamine neurons. The cocaine-induced increase in GluA2-lacking AMPARs was absent in Epac2-deficient mice but not in Epac1-deficient mice. In addition, activation of Epac with the selective Epac agonist 8-CPT-2Me-cAMP (8-CPT) recapitulated the cocaine-induced increase in GluA2-lacking AMPARs, and the effects of 8-CPT were mediated by Epac2. We also show that conditioned place preference to cocaine was impaired in Epac2-deficient mice and in mice in which Epac2 was knocked down in the VTA but was not significantly altered in Epac1-deficient mice. Together, these results suggest that Epac2 is critically involved in the cocaine-induced change in AMPAR subunit composition and drug-cue associative learning.
SIGNIFICANCE STATEMENT: Addictive drugs, such as cocaine, induce long-lasting adaptions in the reward circuits of the brain. A single intraperitoneal injection of cocaine leads to changes in the composition and property of the AMPAR that carries excitatory inputs to dopamine neurons. Here, we provide evidence that exchange protein directly activated by cAMP (Epac), a cAMP sensor protein, is required for the cocaine-induced changes of the AMPAR. We found that the effects of cocaine were mimicked by activation of Epac but were blocked by genetic deletion of Epac. Furthermore, cocaine-cue associative learning was impaired in mice lacking Epac. These findings uncovered a critical role of Epac in regulating the cellular and behavioral actions of cocaine.
Author List
Liu X, Chen Y, Tong J, Reynolds AM, Proudfoot SC, Qi J, Penzes P, Lu Y, Liu QSAuthors
Qing-song Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinJiaqing Tong PhD Postdoctoral Researcher 3 in the Neurology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
8-Bromo Cyclic Adenosine MonophosphateAnimals
Cocaine
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases
Dopamine
Excitatory Postsynaptic Potentials
Female
Male
Mice
Mice, Knockout
Neurons
Patch-Clamp Techniques
Receptors, AMPA
Reward
Synapses
Thionucleotides
Ventral Tegmental Area
