Biomolecules

2218-273X1382023Aug01BiomoleculesBiomoleculesDeleterious 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.120510.3390/biom13081205The neurosteroid 3α,5α-THP is a potent GABA_A 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.BoeroGiorgiaG0000-0001-7328-3943Bowles 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.Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.McFarlandMinna HMHBowles 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.TylerRyan EREBowles 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.O'BuckleyTodd KTK0000-0001-8723-734XBowles 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.ChérySamantha LSLBowles 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.RobinsonDonita LDL0000-0001-7540-3363Bowles 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.Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.BesheerJoyceJBowles 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.Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.MorrowA LeslieALBowles 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.Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.engF31 DA054781DANIDA NIH HHSUnited StatesR01 AA024095AANIAAA NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, N.I.H., Extramural20230801