Region-specific alterations in glutamate receptor expression and subcellular distribution following extinction of cocaine self-administration

Abstract

A role for glutamatergic signaling in the nucleus accumbens (NA) in both the expression and extinction of cocaine seeking has been suggested. The effects of extinction following cocaine self-administration on the expression and synaptosomal distribution of GluR1 and NMDAR1 glutamate receptor subunits in the NA shell and core and the dorsolateral striatum were examined. Rats self-administered cocaine or had access to saline for 14 days followed by a period of extinction training, home-cage exposure, or placement in the self-administration chambers with levers retracted in the absence of discrete cues. Self-administration followed by home-cage exposure reduced GluR1 expression in the NA shell and NMDAR1 expression in the dorsolateral striatum without affecting expression in the NA core. These effects were not observed following extinction. Extinction training increased synaptosomal GluR1 in the NA shell and core and NMDAR1 in the dorsolateral striatum while decreasing synaptosomal NMDAR1 in the shell. Extinction but not home-cage exposure was associated with altered expression and synaptosomal content of the scaffolding proteins PICK1 and PSD95. Following extinction, synaptosomal PICK1 decreased in the dorsolateral striatum while total PICK1 expression was increased in the shell. The synaptosomal PSD95 was decreased in the NA shell, while total PSD95 expression was increased in the core. These data suggest that extinguished cocaine seeking is associated with changes in GluR1 and NMDAR1 expression and subcellular distribution that are region-specific and consist of both a reversal of cocaine-induced adaptations and emergent extinction-related alterations that include receptor subunit redistribution and may involve alterations in scaffolding proteins.