Neuroendocrine alterations in a high-dose, extended-access rat self-administration model of escalating cocaine use

One approach for studying cocaine addiction has been to permit escalating patterns of self-administration (SA) by rats by prolonging daily drug availability. Rats provided long access (LgA) to high cocaine doses, but not rats provided shorter cocaine access (ShA), progressively escalate their cocaine intake and display characteristics of human addiction. The purpose of the present study was to investigate the effects of 14 days of ShA or LgA, high-dose cocaine SA on plasma corticosterone (CORT), prolactin (PRL), and related mRNAs. Acutely, cocaine SA increased plasma CORT and reduced plasma PRL levels. SA training produced circadian increases in CORT that appeared to occur in anticipation of cocaine availability. With repeated LgA, high-dose SA, the daily CORT area under the curve (AUC) progressively decreased, apparently due to tolerance to cocaine's effects on CORT and a reduction in basal CORT levels. In contrast, the daily CORT AUC in ShA rats increased across testing despite constant rates of SA. When measured 12 days after SA testing, pro-opioimelanocortin and glucocorticoid receptor mRNA levels in the anterior pituitary were lower in LgA rats than in ShA rats. The effects of SA on PRL remained constant across SA testing in LgA rats, but increased in duration in ShA rats. Anterior pituitary dopamine D2 receptor mRNA levels were lower in LgA rats than in ShA rats. These findings indicate that the transition to escalating patterns of SA may be associated with altered levels of hormones and gene expression within neuroendocrine systems. Such changes may underlie the onset of human addictive disease.