REPEATED AMPHETAMINE ADMINISTRATION ALTERS THE EXPRESSION OF MESSENGER-RNA FOR AMPA RECEPTOR SUBUNITS IN RAT NUCLEUS-ACCUMBENS AND PREFRONTAL CORTEX

Recent evidence suggests that behavioral sensitization to amphetamine is associated with alterations in excitatory amino acid (EAA) transmis sion in perikarya (ventral tegmental area) and terminal regions (nucle us accumbens [NAc]) of the mesoaccumbens dopamine system. The present study determined whether repeated amphetamine administration alters ex pression of mRNAs for AMPA receptor subunits. We studied the NAc, beca use it is the site of expression of amphetamine sensitization, and the prefrontal cortex (PFC), because it is the origin of EAA projections that regulate the mesoaccumbens dopamine system. Rats were treated for 5 days with 5 mg/kg/day amphetamine sulfate or vehicle (controls) and perfused 3 or 14 days after the last injection. We used a novel in si tu hybridization method that allows quantification of mRNA levels [Lu et al. (1996) J. Neurosci. Methods, 65:69-76]. Repeated amphetamine ad ministration decreased levels of GluR1 and GluR2 but not GluR3 mRNAs i n both core and shell subregions of the NAc at the 14 day withdrawal t ime; no changes were observed after 3 days of withdrawal. In contrast, levels of GluR1 mRNA in the PFC were increased at 3 but not 14 days o f withdrawal, while GluR2 and 3 mRNAs were unchanged. Levels of GluR4 mRNA were very low in both NAc and PFC. Functional properties of heter omeric AMPA receptors are determined by subunit composition. Thus, the observed changes in mRNAs for AMPA receptor subunits may result in al tered AMPA transmission in NAc and PFC. This, in turn, may influence t he responsiveness of the mesoaccumbens DA system to psychomotor stimul ants and potentially contribute to behavioral sensitization. (C) 1997 Wiley-Liss, Inc.