Enhanced psychostimulant response, but not social avoidance, depends on GluA1 AMPA receptors in VTA dopamine neurons following intermittent social defeat stress in rats.

Megan L Rudolph,Ella M Nikulina,Ronald P Hammer,Racheal L Neve

doi:10.1111/ejn.14884

Abstract

Evidence from both human and animal studies demonstrates the importance of social stress in the development of addiction‐related behaviour. In rats, intermittent social defeat stress causes long‐lasting psychostimulant cross‐sensitization. Our recent data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunit in rat ventral tegmental area (VTA), which occurs concurrently with social stress‐induced amphetamine (AMPH) cross‐sensitization. In addition, social stress in rats induced social avoidance behaviour. The present study evaluated the effects of intermittent social defeat stress on GluA1 expression in VTA dopamine (DA) neurons, then utilized Cre‐dependent virus‐mediated gene transfer to determine the functional role of homomeric GluA1‐AMPARs in these neurons. Social defeat stress exposure induced GluA1 expression in VTA DA neurons, as demonstrated by a greater density of GluA1/tyrosine hydroxylase (TH) double‐labelling in VTA neurons in stressed rats. Additionally, functional inactivation of VTA GluA1 AMPARs in DA neurons prevented stress‐induced cross‐sensitization, or augmented locomotor response to low dose AMPH challenge (1.0 mg/kg, i.p.), but had no effect on social stress‐induced social avoidance behaviour. Furthermore, wild‐type overexpression of GluA1 in VTA DA neurons had the opposite effect; locomotor‐activating effects of AMPH were significantly augmented, even in the absence of stress. Taken together, these results suggest that stress‐induced GluA1 expression in VTA DA neurons is necessary for psychostimulant cross‐sensitization, but not for social avoidance. This differential effect suggests that different neural pathways are implicated in these behaviours. These findings could lead to novel pharmacotherapies to help prevent stress‐induced susceptibility to substance abuse.

Highlights

Stress is an influential factor that impacts the transition from recreational drug use to addiction and has been correlated with increased substance abuse susceptibility and relapse (Sinha, 2001, 2008, 2011)
The present results demonstrate that virus-mediated functional inactivation of GluA1 expression in ventral tegmental area (VTA) DA neurons prevents social stressinduced AMPH cross-sensitization, and overexpression of wild-type AMPA receptor (AMPAR) GluA1 in VTA DA neurons augments locomotor response to AMPH, mimicking the effect of social stress
In rats, repeated social defeat stress enhances glutamatergic synaptic plasticity in the VTA (Stelly et al, 2016), and GluA1 AMPARs play an essential role in the induction of drug sensitization and self-administration (Carlezon & Nestler, 2002; McCutcheon, Wang, Tseng, Wolf, & Marinelli, 2011)

Summary

| INTRODUCTION

Stress is an influential factor that impacts the transition from recreational drug use to addiction and has been correlated with increased substance abuse susceptibility and relapse (Sinha, 2001, 2008, 2011). Converging evidence from human and animal studies demonstrates that repeated social stress augments the locomotor effect of psychostimulants in a phenomenon referred to as “cross-sensitization” (Covington & Miczek, 2001; Nikulina, Covington, Ganschow, Hammer, & Miczek, 2004; Nikulina, Lacagnina, Fanous, Wang, & Hammer, 2012) and leads to social avoidance behaviour (Berton et al, 2006; Fanous, Terwilliger, Hammer, & Nikulina, 2011; Komatsu et al, 2011) These social stress-induced behavioural effects are long-lasting (Covington et al, 2005; Nikulina et al, 2004) and induce prolonged activation of mesocorticolimbic pathways, which are comprised of dopaminergic neurons that originate in the ventral tegmental area (VTA; Swanson, 1982). To reveal the behavioural specificity of VTA GluA1 signalling for the sensitized response to psychostimulants, we studied the effect of intra-VTA GluA1 manipulation on intermittent social stress-induced social avoidance behaviour

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION

| Concluding remarks