Deleterious Interaction between the Neurosteroid and the Mu-Opioid System Activation during Forced Swim Stress in Rats

The neurosteroid 3α,5α-THP is a potent GABA[sub.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...

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Bibliographic Details
Published inBiomolecules (Basel, Switzerland) Vol. 13; no. 8
Main Authors Boero, Giorgia, McFarland, Minna H, Tyler, Ryan E, O’Buckley, Todd K, Chéry, Samantha L, Robinson, Donita L, Besheer, Joyce, Morrow, A. Leslie
Format Journal Article
LanguageEnglish
Published MDPI AG 01.08.2023
Subjects
GABA
Health aspects
Medical research
Medicine, Experimental
Opioids
Receptors
Steroids
Stress (Physiology)
United States
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Summary:The neurosteroid 3α,5α-THP is a potent GABA[sub.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.
ISSN:2218-273X
2218-273X
DOI:10.3390/biom13081205