Conditioned release of corticosterone by contextual stimuli associated with cocaine is mediated by corticotropin-releasing factor.

Elevated blood concentrations of corticosterone (CORT), an adrenal steroid associated with stress responses, is one of the endocrine correlates of cocaine treatment. Experiment 1 confirmed and extended previous findings that chronic cocaine treatment does not alter corticosteroid responses to cocaine. In Experiment 2, conditioned endocrine effects of cocaine were examined in three groups of rats after 7 consecutive days of treatment. Cocaine-induced conditioning was achieved using a simple contextual design. In group 1 (paired), rats were injected with cocaine (30 mg/kg), then immediately placed into a locomotor activity chamber for 30 min. One hour after the rats were returned to their home cages, they received an injection of saline. In group 2 (unpaired), rats were injected with saline, then immediately placed into a locomotor activity chamber for 30 min. One hour after the rats were returned to their home cages, they received an injection of cocaine (30 mg/kg). Rats in group 3 (control) received only saline injections, but otherwise were treated as animals in the other treatment groups. On the test day (Day 8), all rats were placed immediately into the locomotor apparatus for 30 min prior to collection of a blood sample. Blood CORT concentrations and locomotor activity in the paired group were significantly higher than in the unpaired and control groups. However, pretreatment of the rats in Experiment 3 with the corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF9-41 (1 microg, i.c.v.), on the test day, prior to exposure to cocaine-associated contextual cues, attenuated the subsequent conditioned increase in blood CORT concentrations. These data represent the first demonstration of classical conditioning of a steroid hormone response to stimuli associated with a psychoactive drug in rats and suggest that the effect is mediated by endogenous CRF. Because the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in modulating the actions of cocaine, it is plausible that such conditioned increases in CORT release by cocaine-associated cues may further predispose an organism to the reinforcing effects of the drug or enhance the susceptibility to drug-taking behavior. Alternatively, such conditioned effects may be related to the anxiogenic properties of cocaine. Further understanding of the conditioned effects of hormones in the development and expression of addictive behaviors may provide new insights into treatment of drug addiction. Copyright 1998 Elsevier Science B.V.