Dexamethasone suppression of the effects of cocaine on adrenocortical secretion in Lewis and Fischer rats.

There is evidence to suggest that cocaine acts centrally to enhance adrenocortical secretory activity and this effect may be associated with the reinforcing properties of this drug. Lewis (LEW) and Fischer (F344) rats are inbred strains which differ in their responses to the reinforcing effects of cocaine. Previous findings from this laboratory have demonstrated differences in the hypothalamic-pituitary-adrenocortical (HPA) responses to cocaine between these strains. To determine whether strain differences in glucocorticoid responsiveness play a role in the differential effects of cocaine on plasma corticosterone (CS) secretion in these strains, experiments were designed to suppress the HPA response to cocaine in these two rat strains. HPA activity was attenuated by central administration of the glucocorticoid agonist dexamethasone (DEX) using osmotic minipumps. A constant infusion of artificial cerebrospinal fluid or DEX (50, 100 or 500 ng/h) was delivered into the lateral ventricle of LEW and F344 rats. Four days later, the rats were challenged with cocaine HCl (0, 20 and 40 mg/kg, i.p.), and the plasma CS response 15 min later was quantified. Cocaine-induced alterations in circulating plasma CS were reduced in a dose-related manner by centrally administered DEX in both strains. Significant strain differences in the effects of DEX on the plasma CS response to cocaine were observed, suggesting that LEW rats were more sensitive to DEX suppression of HPA activity than F344 rats. DEX also produced dose-related effects on body weight in both strains and decreased adrenal weight at the highest dose in F344 rats. Blood collected on the final day of the experiment demonstrated that central infusions of DEX decreased plasma ACTH concentrations in both strains compared to control rats. These studies indicate that central administration of DEX produces a feedback inhibition of cocaine-induced glucocorticoid release and that LEW rats are more sensitive to DEX suppression than F344 rats.