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Abstract
Behavioral sensitization to cocaine is associated with increased AMPA receptor (AMPAR)
surface expression in the nucleus accumbens (NAc). This upregulation is withdrawal-dependent,
as it is not detected on withdrawal day (WD) 1, but is observed on WD7-21. Its underlying
mechanisms have not been clearly established. Nitric oxide (NO) regulates AMPAR trafficking
in the brain by S-nitrosylation of the AMPAR auxiliary subunit, stargazin, leading
to increased AMPAR surface expression. Our goal was to determine if stargazin S-nitrosylation
contributes to AMPAR upregulation during sensitization. First, we measured stargazin
S-nitrosylation in NAc core and shell subregions on WD14 after 8 daily injections
of saline or 15 mg/kg cocaine. Stargazin S-nitrosylation was markedly increased in
NAc shell but not core. To determine if this is associated with AMPAR upregulation,
rats received 8 cocaine or saline injections followed by twice-daily treatments with
vehicle or the nitric oxide synthase inhibitor l-NAME (50 mg/kg) on WD1-6, the time
when AMPAR upregulation is developing in cocaine-exposed rats. Cocaine/vehicle rats
showed elevated stargazin and GluA1 surface expression on WD7 compared to saline/vehicle
rats; the GluA1 increase was more robust in core, while stargazin increased more robustly
in shell. These effects of cocaine were attenuated in shell but not core when cocaine
injections were followed by l-NAME treatment on WD1-6. Together, these results indicate
that elevated S-nitrosylation of stargazin contributes to AMPAR upregulation during
sensitization selectively in the NAc shell. It is possible that AMPAR upregulation
in core involves a different TARP, γ4, which also upregulates in the NAc of sensitized
rats.