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Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure

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Abstract

Rationale

Women represent a vulnerable and growing population with respect to alcohol abuse. Elevated glucocorticoid exposure in adolescence increases addiction risk and stress sensitivity in adulthood. However, little is known about sex differences in ethanol craving-like behavior.

Objective

This study characterized sex differences in ethanol-motivated behavior following ethanol-paired cues and/or acute stimulation of the HPA axis in male and female rats with or without exposure to chronically elevated glucocorticoids in adolescence.

Methods

Adolescent corticosterone-treated (Experiment 1) or naïve (Experiment 2) male and female rats were trained as adults to self-administer ethanol paired with a cue, and tested for the effects of this cue, alone or in combination with yohimbine, on the reinstatement of ethanol seeking.

Results

Females showed elevated ethanol self-administration and seeking compared to males. In Experiment 1, corticosterone exposure in adolescence augmented cue-induced reinstatement of ethanol seeking in females only, and females were more sensitive to yohimbine in promoting reinstatement. Experiment 2 replicated these findings and showed that exposure to both yohimbine and alcohol-related cues enhanced the reinstatement of alcohol seeking, producing additive effects in females. Corticosterone levels were higher in females and in yohimbine-treated rats, and corticosterone and estradiol correlated with responding during reinstatement.

Conclusions

Chronic manipulations in adolescence and acute manipulations in adulthood of the HPA axis increase cue-induced reinstatement of ethanol seeking to a greater degree in females than in males. Elucidating the mechanisms that underlie these effects may lead to the development of sex-specific interventions aimed at mitigating alcohol relapse risk in females.

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Acknowledgments

This research was supported by the NIH grant K01DA071345, the American Heart Association grant AHA13BGIA16850030, the Pennsylvania Department of Health (all to MMT), and the DSF Charitable Foundation 132RA03 (training fellowship to MLB). The authors would like to thank Bryan McElroy, Hayley Busch, and Jenna Hebert for their skilled technical assistance.

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Correspondence to Mary M. Torregrossa.

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All procedures were conducted in accordance with the policies set forth by University of Pittsburgh Institutional Animal Care and Use Committee and the National Institutes of Health Guidelines on the Care and Use of Laboratory Animals.

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The authors report no conflicts of interest.

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Bertholomey, M.L., Nagarajan, V. & Torregrossa, M.M. Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure. Psychopharmacology 233, 2277–2287 (2016). https://doi.org/10.1007/s00213-016-4278-x

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  • DOI: https://doi.org/10.1007/s00213-016-4278-x

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