Contrasting the role of xCT and GLT-1 upregulation in the ability of ceftriaxone to attenuate the cue-induced reinstatement of cocaine-seeking and normalize AMPA receptor subunit expression

Chronic treatment with ceftriaxone attenuates reinstatement of cocaine-seeking while increasing the function of the glutamate transporter GLT-1 and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of non-synaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (catalytic subunit of Sxc), in order to determine the relative importance of both proteins in mediating ceftriaxone's ability to prevent cue-induced reinstatement of cocaine-seeking and normalize glutamatergic proteins in the NAc of rats. Intra-NAc xCT knockdown prevented ceftriaxone from attenuating reinstatement and from upregulating GLT-1, and resulted in increased surface expression of AMPA receptor subunits GluA1 and GluA2. Intra-NAc GLT-1 knockdown also prevented ceftriaxone from attenuating reinstatement and from upregulating xCT expression, without affecting GluA1 and GluA2 expression. In the absence of cocaine or ceftriaxone treatment, xCT knockdown in the NAc increased expression of both GluA1 and GluA2 without affecting GLT-1 expression while GLT-1 knockdown had no effect. PCR and immunoprecipitation of GLT-1 revealed that ceftriaxone does not upregulate GLT-1 and xCT through a transcriptional mechanism and their co-regulation by ceftriaxone is not mediated by physical interaction. These data support important and distinct roles for xCT and GLT-1 in the actions of ceftriaxone and add to a body of literature finding evidence for co-regulation of these transporters. Our results also point to xCT expression and subsequent basal glutamate levels as a key mediator of AMPA receptor expression in the NAc.