Disrupting GluA2 phosphorylation potentiates reinstatement of cocaine seeking

Abstract

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.

PKMζ in the nucleus accumbens acts to dampen cocaine seeking

“…Despite the increase in food seeking in constitutive knockout mice, they do not demonstrate any alterations in cue-induced reinstatement of food seeking. As many studies manipulating AMPA receptors have seen specific alterations in cocaine seeking without corresponding changes in food seeking (Anderson et al, 2008;Briand et al, 2016;Briand et al, 2014;Famous et al, 2008), this supports our hypothesis that PKMζ knockout may be altering accumbal AMPA receptors.…”

“…Thus, PKMζ must play a critical role in food seeking in another brain region. (Anderson et al, 2008;Briand et al, 2016;Briand et al, 2014;Famous et al, 2008), this supports our hypothesis that PKMζ knockout may be altering accumbal AMPA receptors.…”

“…As the removal of GluA2-containing AMPARs and corresponding insertion of GluA2-lacking AMPARs plays a critical role in cocaine craving (Briand et al, 2016;Conrad et al, 2008;Famous et al, 2008;McCutcheon et al, 2011), this could provide a mechanism by which PKMζ could dampen reward. As none of the studies examining the relationship between PKMζ and GluA2 were done in the nucleus accumbens, more work is needed to determine whether PKMζ is in fact altering AMPAR subunit composition and how it functions following chronic cocaine exposure.…”

Different doses of methamphetamine alter long-term potentiation, level of BDNF and neuronal apoptosis in the hippocampus of reinstated rats

“…Emerging evidence reveals that activation of hippocampal glutamate receptors is directly implicated in reinstatement of psychostimulant seeking [9,10], which glutamate receptors are interplay with changes in synaptic plasticity [11]. Hippocampal synaptic plasticity is bi-directionally modulated by psychostimulant self-administration [12].…”

PKMζ in the nucleus accumbens acts to dampen cocaine seeking

“…Additionally, once these GluA2containing AMPARs are inserted, PKMζ may also make them harder to move out of the synapse [17]. As the removal of GluA2containing AMPARs and corresponding insertion of GluA2-lacking AMPARs plays a critical role in cocaine craving [18][19][20][21], this could provide a mechanism by which PKMζ could dampen reward. As none of the studies examining the relationship between PKMζ and GluA2 were done in the nucleus accumbens, more work is needed to determine whether PKMζ is in fact altering AMPAR subunit composition and how it functions following chronic cocaine exposure.…”