Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area.
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.



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.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Xiaojie
X
Liu
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Yao
Y
Chen
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
Jiaqing
J
Tong
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Ashley M
0000-0003-3895-3926
AM
Reynolds
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
Sarah C
SC
Proudfoot
Department of Physiology, Shanxi Medical University, Taiyuan 030001, China.
Jinshun
J
Qi
Departments of Physiology and Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Peter
0000-0001-5449-1640
P
Penzes
Neuroscience Center of Excellence and Department of Neurology, Louisiana State University School of Medicine, New Orleans, Louisiana 70112, and Department of Pathophysiology, Tongji Medical College and Institute for Brain Research, Huazhong University of Science and Technology, Wuhan 430030, China.
Youming
Y
Lu
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, qsliu@mcw.edu.
Qing-Song
0000-0003-1858-1504
QS
Liu
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D018091:Receptors, AMPA / Q000187:drug effects*; D012201:Reward; D013569:Synapses; D013873:Thionucleotides; D017557:Ventral Tegmental Area / Q000166:cytology / Q000378:metabolism*
D018091:Receptors, AMPA; D013873:Thionucleotides; D015124:8-Bromo Cyclic Adenosine Monophosphate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003042:Cocaine; C104722:glutamate receptor ionotropic, AMPA 2; D004298:Dopamine
AMPAR trafficking; Epac signaling; cocaine; conditioned place preference (CPP); inward rectification