Rationale Rats raised in isolation self-administer more amphetamine than rats raised in enrichment. Objective This study examined whether differential rearing alters basal and amphetamine-stimulated corticosterone and whether blocking glucocorticoid receptors alters amphetamine self-administration in differentially reared rats. Methods The rats were raised from 21 to 51 days of age in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Following the repeated collection of basal blood samples, the rats were administered amphetamine (0.5 or 2.0 mg/kg, i.p.) or saline, and blood samples were collected again. In another experiment, EC and IC rats were trained to i.v. self-administer amphetamine (0.003 or 0.03 mg/kg/infusion) and then were pretreated with the glucocorticoid receptor antagonist RU-486 (5, 10, or 20 mg/kg; i.p.) or vehicle prior to the session. Results Basal-free corticosterone levels were ~4 times higher in IC rats than in either EC or SC rats with the first blood collection, but not with repeated collections. IC rats showed a more rapid amphetamine-induced increase in corticosterone levels than EC and SC rats. RU-486 pretreatment decreased amphetamine self-administration dose-dependently in both EC and IC rats; however, using an amphetamine unit dose of 0.03 mg/kg/infusion, the effect of RU-486 was blunted in IC rats (maximal decrease of ~40% in IC and ~90% in EC), suggesting an environment-induced difference in the role of glucocorticoid receptors in stimulant reinforcement. Conclusion The increase in stimulant self-administration produced by social isolation may involve enhanced reactivity of the hypothalamo-pituitary-adrenal stress axis.
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