Traumatic stress-enhanced ethanol drinking: Sex, but not stress responsivity, alters sensitivity to the effects of a CRF-R1 antagonist and a GPR39 agonist in mice.

Abstract

Background: Predator stress (PS) is used to model trauma leading to post-traumatic stress disorder, and it increases ethanol drinking in a proportion of male and female rodents. The goals of the present studies were to identify male and female mice with prior binge drinking experience that exhibited sensitivity and resilience to PS-enhanced drinking and then to test two target molecules (corticotropin releasing factor receptor 1 [CRF-R1] antagonist NBI-27914 [NBI] and G-protein coupled receptor 39 [GPR39] agonist TC-G 1008 [TC-G]) for their ability to selectively reduce PS-enhanced drinking.

Methods: Adult male and female C57BL/6J mice received seven binge ethanol sessions, a period of abstinence, and acclimation to lickometer chambers to examine the effects of NBI or TC-G on stress-associated drinking. Following establishment of stable baseline (BL) drinking and four intermittent PS exposures, mice were classified into "Sensitive" and "Resilient" subgroups, based on the change in ethanol drinking from BL after PS2-4. Then, mice received injections of vehicle or drug (NBI or TC-G) in a within-subjects design. Control studies examined the effects of NBI or TC-G on binge drinking, locomotor activity, and saccharin intake.

Results: NBI and TC-G significantly suppressed binge drinking in male and female mice in the control studies. However, sensitivity to the ability of the compounds to decrease PS-enhanced drinking did not differ between animals in the "PS-sensitive" versus "PS-resilient" subgroups, and female mice were insensitive to TC-G in the traumatic stress drinking model. Specifically, NBI doses of 5 and 10 mg/kg (males) and 12.5 mg/kg (females) significantly decreased PS-associated drinking in both subgroups. TC-G (7.5 mg/kg) significantly decreased PS-associated drinking in both subgroups of male mice but not in female mice.

Conclusions: The present findings suggest that stress sensitivity and subsequent enhanced ethanol drinking in the "Sensitive" subgroup may not increase sensitivity to CRF-R1 antagonism or GPR39 agonism.