Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens

Background: Cue-induced cocaine craving incubates during abstinence from cocaine self-administration. Expression of incubation ultimately depends on elevation of homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in the nucleus accumbens (NAc). This adaptation requires ongoing protein translation for its maintenance. Aberrant translation is implicated in central nervous system diseases, but nothing is known about glutamatergic regulation of translation in the drug-naïve NAc or after incubation.

Methods: NAc tissue was obtained from drug-naïve rats and from rats after 1 or >40 days of abstinence from extended-access cocaine or saline self-administration. Newly translated proteins were labeled using ³⁵S-Met/Cys or puromycin. We compared basal overall translation and its regulation by metabotropic glutamate receptor 1 (mGlu1), mGlu5, and N-methyl-D-aspartate receptors (NMDARs) in drug-naïve, saline control, and cocaine rats, and we compared GluA1 and GluA2 translation by immunoprecipitating puromycin-labeled proteins.

Results: In all groups, overall translation was unaltered by mGlu1 blockade (LY367385) but increased by mGlu5 blockade (MTEP). NMDAR blockade (AVP) increased overall translation in drug-naïve and saline control rats but not in cocaine/late withdrawal rats. Cocaine/late withdrawal rats exhibited greater translation of GluA1 (but not GluA2), which was not further affected by NMDAR blockade.

Conclusions: Our results suggest that increased GluA1 translation contributes to the elevated homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels in the NAc that mediate incubation. Additional contributions to incubation-related plasticity may result from loss of the braking influence on translation normally exerted by NMDARs. Apart from elucidating incubation-related adaptations, we found a suppressive effect of mGlu5 on NAc translation regardless of drug exposure, which is opposite to results obtained in the hippocampus and points to heterogeneity of translational regulation between brain regions.