Featured Paper of the Month – August 2022
It is well known that glutamate plays an important role in relapse to drug seeking. However, the role of glutamate in drug reward is unclear. In this report, we found that elevating extracellular glutamate level in the nucleus accumbens (NAc) by TFB-TBOA, a selective astrocyte glutamate transporter inhibitor, dose-dependently inhibits cocaine self-administration and brain-stimulation reward. Mechanistic assays indicate that prolonged cocaine self-administration selectively upregulates NMDA-GluN2B receptor subtype expression in striatal dopaminoceptive neurons. Transgenic downregulation or pharmacological blockade of GluN2B in the NAc blocked TFB-TBOA or glutamate-induced reduction in cocaine self-administration, suggesting a GluN2B receptor mechanism underlying glutamate modulation of drug reward. In contrast, elevating extracellular glutamate levels in the NAc, ventral tegmental area (VTA), or ventral pallidum (VP) by TFB-TBOA reinstates extinguished cocaine-seeking behavior. These findings demonstrate that glutamate plays an opposite role in drug reward versus relapse – reducing cocaine reward, while potentiating relapse to cocaine seeking.
In: J Neurosci, vol. 42, no. 11, pp. 2327–2343, 2022, ISSN: 1529-2401.