Cocaine-induced adaptations in inhibitory signaling in VTA dopamine neurons

University Of Minnesota, Minneapolis MN

Investigators

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Abstract

? DESCRIPTION (provided by applicant): Drug addiction is a chronically relapsing disorder affecting more than 20 million people in the United States and is defined by compulsion to seek and take drug. Our ability to successfully treat addiction is hindered by our limited knowledge of the underlying biological mechanisms. A long-term goal of work in our lab is to better understand the mechanisms and relevance underlying drug-induced adaptations in key neuron populations implicated in addiction. Toward this end, we recently described a transient cocaine-induced suppression of G protein-dependent inhibitory signaling in dopamine (DA) neurons of the ventral tegmental area (VTA), a key element in the mesocorticolimbic system. This novel cocaine-induced adaptation required activation of D2/3 DA receptors (D2/3R) and involved the internalization of G protein-gated inwardly rectifying K (GIRK/Kir3) + channels, a key contributor to inhibitory feedback pathways that normally temper DA neurotransmission in the mesocorticolimbic system. The key goals of my project are to better understand the mechanisms and neurophysiological impact underlying the cocaine-induced suppression of GIRK-dependent signaling in VTA DA neurons (AIM 1), and to determine the impact of GIRK channel manipulation in DA neurons to cocaine- induced reward-related behavior (AIM 2). My working hypothesis is that the cocaine-induced increase in extracellular DA levels in the VTA leads to the acute D2R- and GIRK-dependent inhibition of VTA DA neurons, and subsequent internalization of the unique GIRK channel (GIRK2/GIRK3 heteromer) found in this cell type. The cocaine-induced suppression of GIRK-dependent signaling in VTA DA neurons then facilitates enhanced DA transmission with subsequent drug exposure, and the development of long-term adaptations that promote and support addiction-related behaviors. I propose to test key elements of this working hypothesis using an interdisciplinary approach including brain slice electrophysiology, in vitro fast scan cyclic voltammetry, and behavioral analysis, in tandem with pharmacologic and neuron-specific genetic manipulations of GIRK- dependent signaling in mice. Successful completion of this project will expand our understanding of inhibitory cell signaling mechanisms that underlie drug addiction and will provide an initial assessment of the potential utility of GIRK channel manipulation for the treatment or prevention of addiction.