1. The Epac-Phospholipase Cε Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons
- Author
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Qing-song Liu, Youming Lu, Tong Jiaqing, Yan Li, Alan V. Smrcka, Xiaojie Liu, Laikang Yu, and Casey R. Vickstrom
- Subjects
Male ,0301 basic medicine ,Agonist ,medicine.drug_class ,Neurotransmission ,Mice ,03 medical and health sciences ,Phosphoinositide Phospholipase C ,0302 clinical medicine ,Cocaine ,Dopamine ,medicine ,Animals ,Research Articles ,Mice, Knockout ,Chemistry ,Dopaminergic Neurons ,General Neuroscience ,Ventral Tegmental Area ,Neural Inhibition ,Endocannabinoid system ,Mice, Inbred C57BL ,Ventral tegmental area ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Synaptic plasticity ,Second messenger system ,Retrograde signaling ,Female ,Neuroscience ,030217 neurology & neurosurgery ,Endocannabinoids ,Signal Transduction ,medicine.drug - Abstract
Exchange protein directly activated by cAMP (Epac) is a direct effector for the ubiquitous second messenger cAMP. Epac activates the phospholipase Cε (PLCε) pathway. PLCβ has been linked to the synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Here, we report that Epac facilitates endocannabinoid-mediated retrograde synaptic depression through activation of PLCε. Intracellular loading of a selective Epac agonist 8-CPT-2Me-cAMP into ventral tegmental area (VTA) dopamine neurons enabled previously ineffective stimuli to induce depolarization-induced suppression of inhibition (DSI) and long-term depression of IPSCs (I-LTD) in the VTA. DSI and I-LTD are mediated by 2-AG since they were blocked by a diacylglycerol lipase inhibitor. The effects of 8-CPT-2Me-cAMP on DSI and I-LTD were absent in Epac2 and PLCε knock-out mice, but remained intact in Epac1 knock-out mice. These results identify a novel mechanism for on-demand synthesis of retrograde signaling 2-AG by the Epac2-PLCε pathway. We investigated the functional significance of Epac2-PLCε-2-AG signaling in regulating inhibitory synaptic plasticity in VTA dopamine neurons induced byin vivococaine exposure. We showed that cocaine place conditioning led to a decrease in the frequency and amplitude of spontaneous IPSCs and an increase in action potential firing in wild-type mice, but not in Epac2 or PLCε knock-out mice. Together, these results indicate that the Epac2-PLCε-2-AG signaling cascade contributes to cocaine-induced disinhibition of VTA dopamine neurons.SIGNIFICANCE STATEMENT2-arachidonoylglycerol (2-AG) is an endogenous cannabinoid that depresses synaptic transmission through stimulation of CB1receptors. Among the six isoforms of phospholipase C (PLC; PLCβ, PLCγ, PLCδ, PLCε, PLCζ, PLCη), only PLCβ has been linked to 2-AG synthesis. Here we demonstrate that 8-CPT-2Me-cAMP, a selective agonist of the cAMP sensor protein Epac, enhances 2-AG-mediated synaptic depression in ventral tegmental area (VTA) dopamine neurons via activation of PLCε. These results identify a novel mechanism for 2-AG synthesis via activation of the Epac-PLCε pathway. Furthermore, we show that cocaine-induced conditioned place preference and disinhibition of VTA dopamine neurons were impaired in mice lacking Epac or PLCε. Thus, the Epac-PLCε signaling pathway contributes to cocaine-induced disinhibition of VTA dopamine neurons and formation of drug-associated memories.
- Published
- 2017