PITUITARY-ADRENAL AXIS RESPONSES TO ACUTE AMPHETAMINE IN THE RAT

After acute administration of amphetamine (AMPH), a characteristic behavioral response occurs in the rat, involving increased locomotion and stereotyped licking, grooming, and biting. AMPH administration also activates several neuroendocrine systems, including the pituitary-adrenal axis. Because recent evidence has supported a role for glucocorticoids in modulating the behavioral response to AMPH, the purpose of the present study was to examine the relationship between behavioral and hypothalamic-pituitary-adrenal (HPA) responses to AMPH and determine the physiological substrates responsible for the AMPH-induced release of adrenal steroids. AMPH administration produced the often-reported ''inverted-U'' shaped behavioral response. Specifically, locomotion was increased by low doses (0.5-1.0 mg/kg, SC) significantly more so than by the highest dose (5.0 mg/kg, SC), which instead elicited intense focused stereotyped movements. Plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone were increased by AMPH in a monotonic dose-response function, with highest levels measured in rats exhibiting the most intense stereotyped behaviors. Plasma ACTH levels then declined 10-30 min after AMPH administration, while AMPH-induced locomotion and stereotyped behavior persisted well beyond this period. In a parallel study, AMPH failed to elevate plasma levels of vasopressin, an important ACTH secretagogue, and AMPH reduced levels of corticotropin-releasing factor (CRF) immunoreactivity in the median eminence, providing indirect evidence of CRF release from this region. AMPH-stimulated ACTH and corticosterone release were prevented by immunoneutralization of CRF. These results show that the ''nonlinear'' behavioral response to AMPH is accompanied by activation of adrenocorticoids mediated by AMPH-stimulated CRF release from the median eminence and suggest that the stereotyped movements do not represent an active coping response to the stress-enhancing actions of amphetamine.