Daily Cocaine Self-administration Under Long-access Conditions Augments Restraint-induced Increases in Plasma Corticosterone and Impairs Glucocorticoid Receptor-mediated Negative Feedback in Rats

Document Type

Article

Language

eng

Publication Date

9-5-2007

Publisher

Elsevier

Source Publication

Brain Research

Source ISSN

0006-8993

Original Item ID

DOI: 10.1016/j.brainres.2007.05.080

Abstract

Cocaine addiction appears to be associated with a drug-induced dysregulation of stressor responsiveness that may contribute to further cocaine use. The present study examined alterations in stressor-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis in rats provided daily access to cocaine for self-administration (SA) under long-access conditions (1.0 mg/kg/infusion; 6 h × 14 days). Cocaine self-administering rats displayed reduced basal plasma corticosterone (CORT) levels but showed an augmented restraint-induced percent increase response from baseline compared to saline self-administering controls when measured 24 days after SA testing. This augmented CORT response may have been attributable to impaired glucocorticoid receptor (GR)-mediated feedback regulation of HPA function, since cocaine self-administering rats were also less susceptible to dexamethasone (0.01 mg/kg, i.p.) suppression of plasma CORT levels. GR protein expression measured using Western blot analysis was significantly reduced in the dorsomedial hypothalamus (including the paraventricular nucleus [PVN]) but not in the pituitary gland, ventromedial hypothalamus, dorsal hippocampus, ventral subiculum, medial prefrontal cortex or amygdala in cocaine self-administering rats. Surprisingly, basal corticotropin-releasing hormone (CRH) mRNA or post-restraint increases in CRH mRNA measured at a single (90 min) time-point in the PVN using in situ hybridization did not differ between groups. The findings suggest that cocaine use produces persistent changes in individual responsiveness to stressors that may contribute to the addiction process.

Comments

Accepted version. Brain Research, Vol. 1167 (September 5, 2007): 101-111. © 2007 Elsevier. Used with permission.

NOTICE: this is the author’s version of a work that was accepted for publication in Brain Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Brain Research, VOL 1167, September 5, 2007, DOI.

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