Critical role for glucocorticoid receptors in stress- and ethanol-induced locomotor sensitization

Locomotor sensitization, the augmentation of the locomotor-activating effects of stimuli with repeated exposure, is being evaluated as a partial model for several phenomena including drug addiction. Alteration of dopaminergic systems has been found in sensitized animals and dopamine neurotransmission appears to be crucial for the expression of sensitized behaviors. However, stress hormones, which are released after exposure to many of the stimuli that produce sensitization, may also be involved in the development of this phenomenon. Corticosterone appears to be important in the development of amphetamine sensitization and glucocorticoid receptors (GR) have been hypothesized to mediate this effect. The purpose of these experiments was first, to determine whether repeated restraint stress sensitizes DBA/2J mice to the activating effect of ethanol (EtOH), and second, to explore the role of GR in stress- and EtOH-induced sensitization with the GR antagonist, RU 38486. This antagonist was administered before restraint or i.p. EtOH (1.5 g/kg) on each of 10 consecutive days of pretreatment. In addition, plasma corticosterone levels were determined at various points throughout the pretreatment period and on test days. The results demonstrated that 10 consecutive days of 2-hr restraint sensitized mice to EtOH's locomotor-stimulating effect. Both stress- and EtOH-induced sensitization were attenuated by administration of RU 38486 during the pretreatment phase. Plasma corticosterone levels on the test days did not relate consistently with the degree of behavioral sensitization observed; therefore, it appears that changes in corticosteroid receptor systems and not absolute levels of corticosterone are important in the development of sensitization. These results support a critical role for GR in the development of at least some types of behavioral sensitization.