Cocaine-induced ACTH secretion: dependence of plasma levels of the drug and mode of exposure

To determine whether changes in pituitary responsiveness might account for the lack of corticotropin (ACTH) stimulation following 6 consecutive days of continuous cocaine administration (5 or 25 mg/kg/day, via osmotic minipumps), the hormonal response of vehicle- or cocaine-pretreated male rats was compared. Intravenous injections of synthetic corticotropin-releasing factor (CRF) (0.2, 1, or 5 μg/Kg) elicited dose-dependent increases in ACTH secretion irrespective of whether rats had been previously exposed to cocaine or not. Similarly, in both vehicle- and cocaine-pretreated rats ACTH response to acute injections of the drug was identical, indicating that pituitary corticotrophs remained responsive following continuous administration of cocaine. To determine and compare plasma concentrations of cocaine and its metabolites after continuous or acute administration of the drug, pharmacokinetics analysis of concentration vs. time was ascertained. Circulating concentrations of cocaine from rats continuously exposed to the drug were relatively low throughout the 6 days of exposure. In contrast, intravenous injections of cocaine produced peak concentrations of the drug that were significantly higher than those measured during continuous cocaine infusion. Such peak concentrations in cocaine correlated with marked increases in plasma ACTH levels. Plasma concentrations of the metabolites benzoylecgonine and methyl ester ecgonine followed a pharmacokinetic clearance similar to that of the parent compound, with low concentrations detected during continuous exposure whereas high concentrations were observed following intravenous injections of the drug. Our results suggest two nonmutually exclusive conclusions. First, there may be a critical threshold of cocaine plasma concentrations (as indicated by our results as being over 800 ng/ml) that are necessary for activation of the hypothalamic-pituitary-adrenal axis to occur. Second, stimulation of ACTH secretion may only occur during rapid systemic increases in drug concentrations.