Sensitizing exposure to amphetamine increases AMPA receptor phosphorylation without increasing cell surface expression in the rat nucleus accumbens.

Exposure to psychostimulants like cocaine or amphetamine leads to long-lasting sensitization of their behavioral and neurochemical effects. Here we characterized changes in AMPA receptor distribution and phosphorylation state in the rat nucleus accumbens (NAcc) weeks after amphetamine exposure to assess their potential contribution to sensitization by this drug. Using protein cross-linking, biochemical, subcellular fractionation, and slice electrophysiological approaches in the NAcc, we found that, unlike cocaine, previous exposure to amphetamine did not increase cell surface levels of either GluA1 or GluA2 AMPA receptor subunits, redistribution of these subunits to the synaptic or perisynaptic cellular membrane domains, protein-protein associations required to support the accumulation and retention of AMPA receptors in the PSD, or the peak amplitude of AMPA receptor mediated mEPSCs recorded in NAcc slices. On the other hand, exposure to amphetamine significantly slowed mEPSC decay times and increased levels in the PSD of PKA and CaMKII as well as phosphorylation by these kinases of the GluA1 S845 and S831 residues selectively in this cellular compartment. As the latter effects are known to respectively regulate channel open probability and duration as well as conductance, they provide a novel mechanism that could contribute to the long-lasting AMPA receptor dependent expression of sensitization by amphetamine. Rather than increase the number of surface and synaptic AMPA receptors as with cocaine, this mechanism could increase NAcc medium spiny neuron reactivity to glutamate afferents by increasing the phosphorylation state of critical regulatory sites in the AMPA receptor GluA1 subunit in the PSD.

Going retro: ancient viral origins of cognition.

In this issue of Neuron, Zhang et al. (2015) provide the first crystal structure of a domain Arc. These results confirm prior computational approaches that suggested Arc, a master regulator of vertebrate synaptic plasticity, was "domesticated" from Ty3/Gypsy retrotransposons.

Stress-induced changes in nucleus accumbens glutamate synaptic plasticity.

Stress hormones released in the CNS following exposure to unavoidable, aversive stimuli have been shown to alter the physiology of neurons in multiple brain regions including hippocampus, amygdala, prefrontal cortex, and ventral tegmental area. The nucleus accumbens (NAc), a motor-limbic interface linked to motivation and reward, receives inputs from each of these stress-affected brain regions, raising the possibility that its function might also be altered in response to stress. To assess potential stress-induced plasticity in the NAc, we exposed adult mice to daily cold water forced swim for 2 consecutive days and conducted electrophysiological experiments assessing glutamate receptor function in brain slices taken 18-24 h following the second swim. We found that AMPA receptor (AMPAR)/N-methyl-d-aspartate receptor (NMDAR) ratios, a measure of synaptic strength, were increased in the NAc shell but not core medium spiny neurons (MSNs) in stressed animals relative to controls. This effect was blocked by preadministration of glucocorticoid receptor (GR) antagonist RU486, suggesting that the observed changes are dependent on corticosteroid signaling. The role of corticosterone (CORT) in the observed plasticity was confirmed, because exogenous administration of 10 mg/kg CORT also enhanced AMPAR/NMDAR ratios in the NAc shell. The synaptic changes in NAc shell MSNs reflect an enhancement of AMPAR-mediated currents, as we observed increased AMPAR miniature postsynaptic current (mEPSC) amplitude following stress but no change in NMDAR mEPSCs. We hypothesize that altered information processing via plasticity of excitatory inputs might contribute to reward-related behaviors such as stress-induced reinstatement of drug seeking in animals and relapse in humans.