Deleterious Interaction between the Neurosteroid (3α,5α)3-Hydroxypregnan-20-One (3α,5α-THP) and the Mu-Opioid System Activation during Forced Swim Stress in Rats
Giorgia Boero,
Minna H. McFarland,
Ryan E. Tyler,
Todd K. O’Buckley,
Samantha L. Chéry,
Donita L. Robinson,
Joyce Besheer,
A. Leslie Morrow
Affiliations
Giorgia Boero
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Minna H. McFarland
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Ryan E. Tyler
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Todd K. O’Buckley
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Samantha L. Chéry
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Donita L. Robinson
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
Joyce Besheer
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
A. Leslie Morrow
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA
The neurosteroid 3α,5α-THP is a potent GABAA receptor-positive modulator and its regulatory action on the HPA axis stress response has been reported in numerous preclinical and clinical studies. We previously demonstrated that 3α,5α-THP down-regulation of HPA axis activity during stress is sex-, brain region- and stressor-dependent. In this study, we observed a deleterious submersion behavior in response to 3α,5α-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3α,5α-THP might affect behavioral coping strategies engaged in by the animal. Given the well-established involvement of the opioid system in HPA axis activation and its interaction with GABAergic neurosteroids, we explored the synergic effects of 3α,5α-THP/opiate system activation in this behavior. Serum β-endorphin (β-EP) was elevated by FSS and enhanced by 3α,5α-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3α,5α-THP + FSS. Pretreatment with the MOP antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP; 2 mg/kg, IP) reversed submersion behavior in males. Moreover, in both males and females, CTAP pretreatment decreased immobility episodes while increasing immobility duration but did not alter swimming duration. This interaction between 3α,5α-THP and the opioid system in the context of FSS might be important in the development of treatment for neuropsychiatric disorders involving HPA axis activation.
