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 hypotharamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of c ocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective eff ects of smoked cocaine in humans. To examine whether attenuation of HPA fun ction at the pituitary level reduces the effects of cocaine in humans, eigh t 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoi d, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses o f smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced ord er under each pre-treatment condition. Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocor ticotrophic hormone and cortisol release. Maximal heart rate following coca ine administration was significantly increased by dexamethasone. However, t he subjective effects of cocaine were not affected by dexamethasone pre-tre atment. These results extend our earlier findings with humans, indicating t hat 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 contra st with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans. (C) 1999 Li ppincott Williams & Wilkins.