Sex differences in the effect of the FKBP5 inhibitor SAFit2 on anxiety and stress-induced reinstatement following cocaine self-administration

Krista L Connelly; Cassandra C Wolsh; Jeffrey L Barr; Michael Bauder; Felix Hausch; Ellen M Unterwald

doi:10.1016/j.ynstr.2020.100232

Sex differences in the effect of the FKBP5 inhibitor SAFit2 on anxiety and stress-induced reinstatement following cocaine self-administration

Neurobiol Stress. 2020 Jun 1:13:100232. doi: 10.1016/j.ynstr.2020.100232. eCollection 2020 Nov.

Authors

Krista L Connelly¹, Cassandra C Wolsh¹, Jeffrey L Barr¹, Michael Bauder², Felix Hausch², Ellen M Unterwald^{1

3}

Affiliations

¹ Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA.
² Clemens Schöpf Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss Str. 4, 64287, Darmstadt, Germany.
³ Department of Pharmacology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St. Philadelphia, PA, 19140, USA.

Abstract

Cocaine use and withdrawal prompt stress system responses. Stress and the negative affective state produced by cocaine withdrawal are major triggers for relapse. FKBP5 is a co-chaperone of the glucocorticoid receptor and regulates HPA axis negative feedback. The role of FKBP5 in cocaine-related behaviors has not been studied. The FKBP5 inhibitor SAFit2 was used to examine the role of FKBP5 in anxiety-like behavior during early cocaine withdrawal and in stress-induced reinstatement following cocaine self-administration in male and female rats. Withdrawal from cocaine self-administration resulted in heightened anxiety-like behavior in female rats, which was significantly attenuated by SAFit2 administration. SAFit2 pretreatment prior to stress-induced reinstatement to cocaine seeking significantly reduced active lever presses of males. In female rats, SAFit2 administration prevented stress-induced reinstatement for rats in metestrus or diestrus, but not proestrus or estrus phases at the time of reinstatement. These data suggest an important role for FKBP5 in stress-related behaviors following cocaine self-administration, particularly in females.

Keywords: Anxiety; Cocaine; FKBP51; Reinstatement; Sex differences.