Incubation of oxycodone craving and nucleus accumbens plasticity

Oregon Health & Science University, Portland OR

Investigators

Abstract

Project Summary We will use the `incubation of craving' model to study a major challenge in treating opioid addiction, namely the persistence of vulnerability to cue-induced relapse even after long periods of abstinence. In this model, rats show progressive intensification of cue-induced drug craving in the weeks after discontinuing drug self-administration (SA); craving then plateaus at a high level before declining. We will study incubation of craving for oxycodone (Oxy), an opioid with a high abuse rate. Previously, we and others found that Ca2+-permeable AMPARs (CP- AMPAR) accumulate in synapses on nucleus accumbens (NAc) medium spiny neurons (MSN) during forced abstinence from cocaine or methamphetamine SA, strengthening these synapses and mediating expression of incubated craving. Our preliminary data show that CP-AMPARs also increase in NAc during Oxy incubation and are required for its expression, but the pathways into NAc that undergo CP-AMPAR upregulation and drive incubated Oxy seeking are unknown. To address this, we propose cell type (D1 vs D2 MSN), subregion (core vs shell), and pathway specific studies comparing saline and Oxy rats in early and late withdrawal (i.e., before and after incubation). Transgenic rats with Cre in D1 or adenosine 2a (A2a) receptor-expressing cells (D2 and A2a receptors colocalize in MSN) will be used to distinguish D1 and A2a/D2 MSN. Pathway specific studies will focus on glutamate inputs from basolateral amygdala (BLA) and paraventricular nucleus of the thalamus (PVT); both are implicated in Oxy incubation by our preliminary data. We hypothesize that cues previously paired with Oxy SA activate specific BLA- and PVT-NAc MSN pathways via CP-AMPARs and thereby drive incubated Oxy seeking. This will be tested by integrating electrophysiological and chemogenetic data across Aims. In Aim 1, we will first assess excitatory synaptic transmission, including the contribution of CP-AMPARs, in D1 and A2a MSN in NAc core and shell during Oxy incubation. Preliminary data show elevated CP-AMPARs in both D1 and A2a MSN after Oxy incubation, contrasting with D1 MSN only after cocaine or methamphetamine incubation. Then, we will use chemogenetics to determine if inhibiting D1 or A2a MSN in core or shell prevents expression of Oxy incubation. Aim 2 will assess excitatory synaptic transmission in the BLA-NAc pathway (D1/A2a MSN, core/shell) and use chemogenetics to test the role of BLA inputs in incubated Oxy seeking. In Aim 3, we will perform parallel electrophysiological and chemogenetic studies for the PVT-NAc pathway. Interestingly, prior work has shown that, in morphine-dependent rodents, CP-AMPAR upregulation in PVT-shell A2a MSN synapses mediates aversive states of opioid withdrawal. Thus, to help interpret our PVT-NAc studies and potentially set the stage for future studies on the interaction between positive and negative reinforcement in driving incubation, Aim 3 will determine if negative affective states, which contribute to relapse in opioid users, are detected alongside incubation of Oxy craving. Our studies will be the first to investigate the role of NAc synaptic plasticity in Oxy incubation and the first to study negative affect following protracted withdrawal from Oxy SA.