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

Abstract

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.

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…Further modifications and optimizations gener- ated more membrane-permeable and PDE-resistant EPACspecific agonists (838,1075). While these 2'-O-alkyl-based cAMP analogs have been widely employed as pharmacological tools to probe EPAC-specific functions (191,290,451,627), extensive studies also document that these EPACspecific cAMP analogs, as well as their cellular metabolites, display activity towards multiple cellular targets, thereby leading to cross-target activities and off-target effects (275-277, 413, 414, 624, 838, 902). These findings raise significant concerns over the specificity of 8-CPT-cAMP analogs as cAMP mimetics and the applications of 8-CPT-2'-O-Me-cAMP class compounds as EPAC selective activators.…”

The Epac-Phospholipase Cε Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons

“…It is thus likely that endocannabinoid signaling contributes to cocaine-induced reduction of GABAergic inhibition and the increase in action potential firing. Cocaine exposure in vivo in rats or mice led to increases in insertion of GluA2-lacking AMPARs (Bellone and Lüscher, 2006;Good and Lupica, 2010;Liu et al, 2016) and in AMPAR/NMDAR ratio (Ungless et al, 2001;Borgland et al, 2004;Bellone and Lüscher, 2006;Mameli et al, 2007;Argilli et al, 2008). We have shown that Epac2 is required for both effects of cocaine .…”

Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance

“…Consistent with these results, we found that Epac2 -/neurons had an increased density of GluA2/3containing AMPA receptors, specifically at synapses. EPAC proteins and EPAC2 have been shown to be required for cAMP-dependent long-term depression (LTD) as well as cocaine induced switching of AMPA receptor subunit composition (Liu et al, 2016;Ster et al, 2009). The consequence of increased synaptic expression of GluA2/3cotnaining AMPA receptors would potentially impact the ability of neurons to undergo plasticity-induced functional changes.…”