Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats

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/inf; 6 hrs × 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, ip) 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.

Requisite Role of Basolateral Amygdala Glucocorticoid Receptor Stimulation in Drug Context-Induced Cocaine-Seeking Behavior

“…In comparison, we reported in a recent study of cocaine memory reconsolidation (S. J. Stringfield and R. A. Fuchs, unpublished observations) that brief (15-minute) nonreinforced exposure to a cocaine-paired context identical to that utilized in the present study elicits a rise in blood serum corticosterone concentrations from 130ng/mL (baseline) to 250ng/mL. Further, it can be assumed that 2-hour exposure to the cocaine-paired context resulted in a similar corticosterone response, approaching levels produced by restraint stress in drug-naïve rats (Mantsch et al, 2007a; Mantsch et al, 2007b). Sensitized HPA axis function following withdrawal from cocaine, reported earlier (Mantsch et al, 2007a; Zhou et al, 2011), may contribute to similar corticosterone responses to reward-predictive stimuli and physically aversive stressors.…”

Central CRF2 receptor antagonism reduces anxiety states during amphetamine withdrawal

“…Optical density of each protein band was obtained using Odyssey software (LI-COR Biosciences), and normalized against background. Optical density for each of the CRF 1 and CRF 2 receptors from each individual sample was then corrected against actin levels, and percentage difference from un-treated control samples were calculated per individual membrane (Noshita et al, 2002; Perrotti et al, 2004; Mantsch et al, 2007; Griesbach et al, 2012). …”

Substance use modulates stress reactivity: Behavioral and physiological outcomes

“…For example, repeated experimenter-administered amphetamine administration led to augmented CORT and ACTH release following a restraint stress [119]. Similar increases in restraint-induced CORT are seen following cocaine self-administration [120]. Binge cocaine exposure during adolescence leads to exaggerated CORT responses to the elevated plus maze and forced swim stress [121, 122].…”