Measuring and Manipulating Reward Circuit Plasticity in Opiate Addition Models

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Opiate addiction is a major health concern, and its chronic relapsing nature is perhaps its most insidious aspect. Preceding relapse, addicts often experience intense craving when exposed to drug or drug-associated stimuli. An essential step in confronting addiction is understanding the neurochemical and cellular mechanisms responsible for the resumption of drug use long after cessation of drug use. The nucleus accumbens (NAc) is a key target of addictive drugs in the mammalian brain and provides a motive force behind drug-seeing behavior. Although drug-induced plasticity in NAc AMPA-type glutamate receptors (AMPARs) has been studied extensively in psychostimulant relapse, the temporal and anatomical dynamics of opiate-induced plasticity and how these adaptations function to promote relapse is unknown. Here, I examine morphine-induced adaptations in synaptic strength and glutamate-related plasticity within corticostriatal brain circuits by combining whole-cell electrophysiological approaches with viral-mediated expression of light sensitive opsins (optogenetics), and fluorescent reporter mice in operant models of drug-administration. Pilot data from our lab indicate that MSN glutamatergic synaptic strength is potentiated in the NAc shell region following abstinence (10-14 days) from both contingent and non-contingent morphine administration. In the K99 Aims, I propose to delineate the time course of development and persistence of changes in synaptic strength, glutamate receptor signaling and subunit composition in subpopulations of NAc medium spiny neurons (MSNs) containing either the dopamine D1-(D1-MSN) or D2-(D2-MSN) receptor subtype using an extended-access operant model of addiction. Next, I propose to selectively activate channelrhodopsin2- expressing cortical or amygdalar afferents onto MSNs using optical stimulation delivered directly to the NAc to evaluate pathway-specific alterations in plasticity. Training in the K99 phase will be under the guidance of Dr. Mark Thomas, an expert in measuring glutamatergic synaptic function in reward circuits, whose lab has recently incorporated the use of optogenetics tools for in vitro and in vivo study. We have recruited additional expertise from Drs. Tim Ebner (optogenetics/ mentorship), Antonello Bonci (optogenetics and behavior) and David Self (mouse drug self-administration) as part of my advisory committee. With the training in electrophysiology and optogenetic modulation of neural networks I receive during the K99 period, I will employ these techniques to further determine the functional role persistent opiate-induced plasticity plays in context-, cue-, and drug-induced relapse. Using in vivo optogenetic stimulation to depotentiate cortical and/or limbic afferents onto NAc MSNs, I predict that restoring "basal" neurotransmission prior to relapse testing using an established long-term depression protocol will prevent a subsequent return to opiate-seeking. Finally, I will use a novel model addiction model recently shown to promote compulsive-like drug-seeking in a subpopulation of mice to explore changes in excitatory and inhibitory neurotransmission neurons of the medial prefrontal cortex and dorsal striatum, two brain regions that have generally been overlooked in studies of opiate plasticity. These experiments will provide significant contributions to opiate addiction literature as well as potential pharmacotherapeutic targets to mitigate relapse.