Abstract
Withdrawal from cocaine regulates expression of distinct glutamate re-uptake transporters in the nucleus accumbens (NAc). In this study, we examined the cumulative effect of glutamate re-uptake by multiple excitatory amino acid transporters (EAATs) on drug-seeking at two different stages of withdrawal from self-administered cocaine. Rats were trained on fixed ratio 1 (FR1), progressing to FR5 schedule of reinforcement. After one day of withdrawal, microinfusion of a broad non-transportable EAAT antagonist, DL-threo-beta-benzyloxyaspartate (DL-TBOA), into the NAc shell dose-dependently attenuated self-administration of cocaine. Sucrose self-administration was not affected by DL-TBOA, indicating an effect specific to reinforcing properties of cocaine. The attenuating effect on cocaine seeking was not due to suppression of locomotor response, as DL-TBOA was found to transiently increase spontaneous locomotor activity. Previous studies have established a role for EAAT2-mediated re-uptake on reinstatement of cocaine seeking following extended withdrawal and extinction training. We found that blockade of NAc shell EAATs did not affect cocaine-primed reinstatement of cocaine seeking. These results indicate that behavioral history of withdrawal influences the effect of re-uptake mediated glutamate clearance on cocaine seeking. Dynamic regulation of glutamate availability by re-uptake mechanisms may impact other glutamate signaling pathways to account for such differences.
Highlights
Repeated cocaine has been linked to changes in glutamate signaling in the nucleus accumbens (NAc) that may contribute to both maintenance of cocaine self-administration and reinstatement of cocaine seeking following extinction training [1,2,3,4,5]
We have recently demonstrated that short withdrawal from limited (2 hr) access cocaine self-administration is associated with increased excitatory amino acid transporters (EAATs) activity that offsets the impact of altered NMDA receptor distribution in the NAc shell [13]
We found that bilateral infusion of a broad spectrum EAAT-antagonist, DL-TBOA, into the NAc shell attenuated maintenance of cocaine self-administration following a short period of withdrawal, but did not affect cocaine-primed reinstatement of cocaine seeking following long withdrawal combined with extinction training
Summary
Repeated cocaine has been linked to changes in glutamate signaling in the NAc that may contribute to both maintenance of cocaine self-administration and reinstatement of cocaine seeking following extinction training [1,2,3,4,5]. After both short (1–2 days) and long (10–30 days) withdrawal from repeated cocaine, reduced basal NAc glutamate levels are observed [1,6,7]. Following long withdrawal combined with extinction training, glutamate has been observed to recover to baseline levels [8] or remain suppressed [9]. Long periods of withdrawal or extinction training have been associated with reduced activity of EAAT2 ( known as GLT-1) and xCT1 [10,11,12]. Combined with increased EAAT binding of glutamate [8] and reduced NAc glutamate levels [1,7,9], these findings support a net increase in glutamate re-uptake in early withdrawal
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