Repeated administration of amphetamine-like stimulants to rats results in enhanced behavioral responsiveness to subsequent administration of these drugs. Recent evidence suggests corticosterone may play a role in the development of sensitization perhaps through the down-regulation of glucocorticoid receptor (GR). To test this hypothesis further we examined the effects of five daily injections of amphetamine (AMPH) (2.5 mg/kg) on GR mRNA of adult Sprague-Dawley rats. Two other groups received saline for 4 days and then either saline or AMPH on the fifth day. All animals were killed 24 h after the last treatment and in situ hybridization was performed with an antisense mRNA GR probe. Quantification of hippocampal GR was accomplished by computer analysis of digitized images of CA1 and dentate gyrus. Acute AMPH produced a significant up-regulation of GR mRNA in CA1 and a nonsignificant trend towards up-regulation in the dentate gyrus. Repeated exposure to AMPH resulted in a significant down-regulation in CA1, and a nonsignificant trend towards down-regulation in dentate gyrus. These data support a role for hippocampal GR mRNA in the development of behavioral sensitization.