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.