Blockade of cocaine-induced increases in adrenocorticotrophic hormone and cortisol does not attenuate the subjective effects of smoked cocaine in humans.

Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of cocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective effects of smoked cocaine in humans. To examine whether attenuation of HPA function at the pituitary level reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced order under each pre-treatment condition. Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocorticotrophic hormone and cortisol release. Maximal heart rate following cocaine administration was significantly increased by dexamethasone. However, the subjective effects of cocaine were not affected by dexamethasone pre-treatment. These results extend our earlier findings with humans, indicating that the role of the HPA axis in mediating the effects of cocaine is limited. These data are concordant with findings in non-human primates, but contrast with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans.