The effects of repeated corticosterone exposure on the interoceptive effects of alcohol in rats

Abstract

Rationale and objective: Repeated and/or heightened elevations in glucocorticoids (e.g., repeated stress) can promote escalated drug-taking behaviors and induce compromised HPA axis function. Given that interoceptive/subjective drug cues are a fundamental factor in drug-taking behavior, we sought to determine the effects of exposure to repeated elevations in the glucocorticoid corticosterone (CORT) on the interoceptive effects of alcohol in rats using drug discrimination techniques.

Methods: Male Long Evans rats trained to discriminate alcohol (1 g/kg, IG) vs. water were exposed to CORT (300 μg/ml) in the home cage drinking water for 7 days. The interoceptive effects of experimenter- and self-administered alcohol were assessed and HPA axis function was determined.

Results: The interoceptive effects of experimenter- and self-administered alcohol were blunted following CORT. Control experiments determined that this decreased sensitivity was unrelated to discrimination performance impairments or decreased CORT levels at the time of testing and was dependent on repeated CORT exposure. Susceptibility to compromised HPA axis function following CORT exposure was suggested by an altered pattern of CORT secretion and blunted CORT response following injection of the synthetic glucocorticoid dexamethasone.

Conclusions: These findings present a possible behavioral mechanism for escalated alcohol drinking during episodes of heightened elevations in glucocorticoids (e.g., stress). That is, during these episodes, individuals may consume more alcohol to achieve the desired interoceptive effects. Understanding these behavioral mechanisms may lead to a better understanding of factors that promote alcoholism and alcohol abuse in at risk populations.

Fig. 1

Corticosterone exposure (7 days) produces elevations in CORT and blunts response to dexamethasone. a On the seventh day of CORT exposure (300 μg/ml), plasma CORT levels were significantly higher than the Water group at 10 pm, and significantly lower than the Water group at 10 am (n=8/group). Asterisk signifies significant difference from the Water group (p<0.05). b CORT exposure (300 μg/ml; 7 days) resulted in significantly less suppression of plasma CORT levels in the CORT group after dexamethasone (0.1 mg/kg, SC) administration (blood collected 4 h after dexamethasone administration at 11 am; n=9/group). Asterisk signifies significant difference from the respective vehicle group (p<0.05); number sign signifies significant difference from the respective Water groups. Values on graphs represent mean ± S.E.M.

Fig. 2

Corticosterone exposure (7 days in drinking water) blunts the interoceptive effects of experimenter-administered alcohol. a Corticosterone exposure (CORT; 300 μg/ml; 7 days; n=8) significantly reduced the percentage of alcohol-appropriate responding relative to Water controls (n=8), and prevented full expression of the discriminative stimulus effects of alcohol (1 and 1.7 g/kg, IG), without altering b response rate. c One day of CORT exposure (300 μg/ml) did not alter the discriminative stimulus effects of alcohol or d response rate. Horizontal dashed line (>80%) represents full expression of the discriminative stimulus effects of alcohol. Asterisk signifies significant difference from Water group (p<0.05). Values on graphs represent mean ± S.E.M.

Fig. 3

Inhibition of CORT synthesis by metyrapone does not alter the interoceptive effects of alcohol. a Metyrapone pretreatment (25 or 50 mg/kg, SC) did not alter the percentage of alcohol-appropriate responding, but induced b an overall reduction in response rate at the highest (50 mg/kg) dose (n=7). Horizontal dashed line (>80%) represents full expression of the discriminative stimulus effects of alcohol. c Plasma CORT levels were reduced by metyrapone pretreatment. Asterisk signifies significant difference from vehicle group (p<0.05). Values on graphs represent mean ± S.E.M.

Fig. 4

Corticosterone exposure (7 days) blunts the interoceptive effects of self-administered alcohol. a In the Water controls (n=6), alcohol-appropriate responding increased across time as greater alcohol was consumed, indicating sensitivity to the discriminative stimulus effects of the consumed sweetened alcohol reinforcer (10% w/v sucrose/10% v/v alcohol). CORT exposure (300 μg/ml; 7 days; n=8) blunted the full expression of the discriminative stimulus effects of the consumed alcohol, and b did not alter alcohol intake (g/kg). c In the Water controls, alcohol-appropriate responding remained low throughout the session when sucrose (10% w/v) was the reinforcer, indicating accurate discrimination performance. CORT exposure (300 μg/ml; 7 days) did not alter this pattern of responding, or d sucrose intake (ml; n=7/group). Horizontal dashed line (>80%) represents full expression of the discriminative stimulus effects of alcohol. Asterisk signifies significant difference from Water group (p<0.05). Values on graphs represent mean ± S.E.M.