Childhood and adolescent adversity are associated with a wide range of psychiatric disorders, including an increased risk for substance abuse. Despite this, the mechanisms underlying the ability of chronic stress during adolescence to alter reward signaling remains largely unexplored. Understanding how adolescent stress increases addiction-like phenotypes could inform the development of targeted interventions both before and after drug use. The current study examined how prolonged isolation stress, beginning during adolescence, affected behavioral and neuronal underpinnings to the response to cocaine in male and female mice. Adolescent-onset social isolation did not alter the ability of mice to learn an operant response for food, nor influence food self-administration or motivation for food on a progressive ratio schedule. However, male and female social isolation mice exhibited an increase in motivation for cocaine and cocaine seeking during a cue-induced reinstatement session. Additionally, we demonstrated that adolescent-onset social isolation increased cocaine-induced neuronal activation, as assessed by c-Fos expression, within the nucleus accumbens core and shell, ventral pallidum, dorsal bed nucleus of the stria terminalis, lateral septum and basolateral amygdala. Taken together, the present studies demonstrate that social isolation stress during adolescence augments the behavioral responses to cocaine during adulthood and alters the responsiveness of reward-related brain circuitry.

Drug addiction is a major public health concern in the United States costing taxpayers billions in health care costs, lost productivity and law enforcement. However, the availability of effective treatment options remains limited. The development of novel therapeutics will not be possible without a better understanding of the addicted brain. Studies in both clinical and preclinical models indicate that chronic drug use leads to alterations in the body and brain’s response to stress. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may shed light on the ability of stress to increase vulnerability to relapse. Further, within both the HPA axis and limbic brain regions, corticotropin-releasing factor (CRF) is critically involved in the brain’s response to stress. Alterations in both central and peripheral CRF activity seen following chronic drug use provide a mechanism by which substance use can alter stress reactivity, thus mediating addictive phenotypes. While many reviews have focused on how stress alters drug-mediated changes in physiology and behavior, the goal of this review is to focus on how substance use alters responses to stress.

Addiction is associated with changes in synaptic plasticity mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors at synapses within the nucleus accumbens. Exposure to cocaine can lead to protein kinase C–mediated phosphorylation of GluA2 AMPA subunits and this phosphorylation event leads to the internalization of GluA2-containing AMPARs, which are calcium-impermeable. However, it is not clear whether this internalization is necessary for the expression of addictive phenotypes. Utilizing a mouse with a point mutation within the GluA2 subunit c-terminus, the current study demonstrates that disrupting PKC-mediated GluA2 phosphorylation potentiates reinstatement of both cue-induced cocaine seeking and cocaine conditioned reward without affecting operant learning, food self-administration or cocaine sensitization. Electrophysiological recordings revealed increased GluA2-mediated AMPA transmission as evidenced by increased sEPSC amplitude without any changes in sEPSC frequency or rectification. In support of this increase in GluA2 activity mediating the augmented cocaine reinstatement, we found that accumbal overexpression of GluA2 recapitulated this behavioral effect in wildtype mice while not altering reinstatement behavior in the GluA2 K882A knock-in mice. In addition, disrupting GluA2 phosphorylation was associated with blunted long-term depression in the nucleus accumbens, mimicking the anaplasticity seen following cocaine self-administration. Taken together these results indicate that disrupting GluA2 phosphorylation and increasing GluA2-mediated transmission in the nucleus accumbens leads to increased vulnerability to cocaine relapse. Further, these results indicate that modulating GluA2-containing AMPAR trafficking can contribute to addictive phenotypes in the absence of alterations in GluA2-lacking receptors. These results highlight the GluA2 phosphorylation site as a novel target for the development of cocaine addiction therapeutics.

Cocaine addiction is characterized by persistent craving and addicts frequently relapse even after long periods of abstinence. Exposure to stress can precipitate relapse in humans and rodents. Stress and drug use can lead to common alterations in synaptic plasticity and these commonalities may contribute to the ability of stress to elicit relapse. These common changes in synaptic plasticity are mediated, in part, by alterations in the trafficking and stabilization of AMPA receptors. Exposure to both cocaine and stress can lead to alterations in protein kinase C-mediated phosphorylation of GluA2 AMPA subunits and thus alter the trafficking of GluA2-containing AMPARs. However, it is not clear what role AMPAR trafficking plays in the interactions between stress and cocaine. The current study utilized a mouse with a point mutation within the GluA2 subunit c-terminus resulting in a disruption of PKC-mediated GluA2 phosphorylation to examine stress responsivity. Although no differences were seen in the response to a forced swim stress in naïve mice, GluA2 K882A knock-in mice exhibited an increased stress response following cocaine self-administration. Furthermore, we demonstrated that disrupting GluA2 phosphorylation increases vulnerability to stress-induced reinstatement of both cocaine seeking and cocaine-conditioned reward. Finally, GluA2 K882A knock-in mice exhibit an increased vulnerability to social defeat as indicated by increased social avoidance. Taken together these results indicate that disrupting GluA2 phosphorylation leads to increased responsivity to acute stress following cocaine exposure and increased vulnerability to chronic stress. These results highlight the GluA2 phosphorylation site as a novel target for the stress-related disorders.