Conditioned activity to amphetamine in transgenic mice expressing an antisense RNA against the glucocorticoid receptor.

Glucocorticoids enhance the locomotion-stimulating and the rewarding properties of stimulant drugs. Amphetamine-induced conditioned activity was investigated in B6C3F1 (controls) and antisense transgenic mice. The latter expresses a neurofilament-promotor-driven antisense RNA complementary to a fragment of cDNA that codes for the mouse glucocorticoid receptor. This gene expression leads to approximately a 50% reduction in glucocorticoid receptor mRNA in the brain. Transgenic mice showed an increased novelty response when tested in an open field, in terms of both distance traveled and number of rearings. Moreover, they displayed enhanced amphetamine-induced conditioned activity. Behavioral sensitization was observed in controls, whereas behavioral tolerance developed in transgenic mice. These data support the concept of an enhanced stress response in these transgenic mice, rather than a general downregulation of the stress response because of impaired glucocorticoid receptor function.