Differential cocaine‐induced changes in striatal glutamate receptor phosphorylation in low and high cocaine responding rats

Abstract

Locomotor sensitization induced by repeated exposure to cocaine has been linked to increases in glutamate α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole propionic acid receptor (AMPAR) and N‐methyl D‐aspartate receptor (NMDAR) phosphorylation. Such changes may help to explain why outbred male Sprague‐Dawley rats initially classified as low cocaine responders (LCRs) more readily develop cocaine‐induced locomotor sensitization than those classified as high cocaine responders (HCRs). We used western blots to investigate LCR/HCR changes in AMPAR and NMDAR phosphorylation in the ventral tegmental area (VTA), dorsal striatum (dSTR), and nucleus accumbens (NAc) 40 min after either acute (10 mg/kg, i.p.) or repeated (10 mg/kg, i.p., once daily for 7 days) cocaine. Significant increases in phosphorylation over controls were observed only in LCRS: after acute cocaine at NMDAR NR2B‐Y1472 by 39% and 31% in NAc and dSTR, respectively, and after repeated cocaine at AMPAR GluR1‐Ser845 by 30% in dSTR. No differences were observed in VTA. Our results suggest that increased striatal NMDAR NR2B‐Y1472phosphorylationin LCRs after acute cocaine may contribute to their development of locomotor sensitization and increased AMPAR GluR1‐Ser845 phosphorylation in LCRs may help to maintain their increased locomotor response to a cocaine challenge after repeated dosing. Supported by DA004216, GM007635, DA015050.