Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex

Glutamate plays a critical role in neuroadaptations induced by drugs of abu se. This study determined whether expression of the NMDAR1 subunit of the N MDA receptor is altered by repeated amphetamine administration. We quantifi ed NMDAR1 mRNA (using in situ hybridization with S-35-labelled oligonucleot ide probes) and immunolabelling (using immunocytochemistry with S-35-labell ed secondary antibodies) in rat ventral midbrain, nucleus accumbens and pre frontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expre ssion were observed after 3 days of withdrawal, whereas significant decreas es were observed in all regions after 14 days. NMDAR1 mRNA levels in midbra in were too low for reliable quantification, but immunolabelling was decrea sed significantly in intermediate and caudal portions of the substantia nig ra. This may indicate a reduction in excitatory drive to substantia nigra d opaminergic neurons. In the nucleus accumbens, there were significant decre ases in NMDAR1 mRNA levels (74.8 +/- 7.7% of control, P < 0.05) and immunol abelling (76.7 +/- 4.4%, P < 0.05). This may account for previously-reporte d decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dys regulation of goal-directed behaviour. In prefrontal cortex, there was a si gnificant decrease in NMDAR1 mRNA levels (76.1 +/- 7.1%, P < 0.05) and a tr end towards decreased immunolabelling (89.5 +/- 7.0%). This may indicate de creased neuronal excitability within prefrontal cortex. A resultant decreas e in activity of excitatory prefrontal cortical projections to nucleus accu mbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.