Disruption of GluA2 phosphorylation potentiates stress responsivity

Abstract

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.

Cocaine-Induced Impulsivity is Differentially Expressed in Male and Female Mice Exposed to Maternal Separation and is Associated with Alterations in AMPA Receptors Subunits

“…433 Caffino et al (2015) report that a single cocaine exposure in adolescent rats can reduce the 434 number of dendritic spines without any changes of GluA1 or GluA2 in the total mPFC 435 homogenate. Other studies employing the cocaine SA paradigm reported that disruption of 436 the GluA2 phosphorylation potentiated the acquisition of cocaine SA (Ellis et al 2017). In 437 the current work, the biochemical analysis yielded a sex × rearing interaction for the 438 GluA1, but any alteration induced per se by the drug exposure ( Figure 5A).…”

Cocaine-seeking behaviour is differentially expressed in male and female mice exposed to maternal separation and is associated with alterations in AMPA receptors subunits in the medial prefrontal cortex.

“…Caffino et al (2015) report that a single cocaine exposure in adolescent rats can reduce the number of dendritic spines without any changes of GluA1 or GluA2 in the total mPFC homogenate. Other studies employing the cocaine SA paradigm reported that disruption of the GluA2 phosphorylation potentiated the acquisition of cocaine SA (Ellis et al 2017). In was not certified by peer review) is the author/funder.…”

“…Epidemiologic studies showed that childhood adversity increased the risk of depression by 28.4% but also to illicit drug use by 16.5% (Anda et al 2006). Animal studies exploring how stressful situations influence addiction-like behaviours described that acute and chronic stress alters the phosphorylation of GluA2, affecting the function of the AMPA receptor but no the GluA1/GluA2 ratio in the nucleus accumbens and hippocampus (Ellis et al 2017;Caudal et al 2010;Caudal et al 2016). This evidence could explain why we not able to find differences in the GluA1/GluA2 ratio.…”

Resilience to the effects of social stress on vulnerability to developing drug addiction

“…Stress and drug use can lead to common alterations in synaptic plasticity that may contribute to the ability of stress to elicit relapse. For example, disruption of PKC-mediated GluA2 phosphorylation increases vulnerability to both SD-induced enhancement of social avoidance and stress-induced reinstatement of cocaine AA and CPP[ 258 ]. Study of resilience to the reinstating effects of SD stress may help to identify therapies that prevent stress-induced relapse.…”