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

被引:3
作者
Boero, Giorgia [1 ,2 ,3 ]
Mcfarland, Minna H. [1 ]
Tyler, Ryan E. [1 ]
O'Buckley, Todd K. [1 ]
Chery, Samantha L. [1 ]
Robinson, Donita L. [1 ,2 ]
Besheer, Joyce [1 ,2 ]
Morrow, A. Leslie [1 ,2 ,3 ]
机构
[1] Univ North Carolina Chapel Hill, Bowles Ctr Alcohol Studies, Sch Med, 3027 Thurston Bowles Bldg,CB 7178, Chapel Hill, NC 27599 USA
[2] Univ North Carolina Chapel Hill, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA
[3] Univ North Carolina Chapel Hill, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA
基金
美国国家卫生研究院;
关键词
neurosteroids; behavior; stress; forced swim stress; 3; alpha; 5; alpha-THP; allopregnanolone; opioid system; mu-opioid receptor; CTAP; brexanolone; CORTICOTROPIN-RELEASING FACTOR; GENE-TRANSCRIPTION; SIGMA-RECEPTORS; BETA-ENDORPHIN; BRAIN; ALLOPREGNANOLONE; PROGESTERONE; COCAINE; PLASMA; MICE;
D O I
10.3390/biom13081205
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The neurosteroid 3 alpha,5 alpha-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 3 alpha,5 alpha-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 3 alpha,5 alpha-THP (15 mg/kg) during forced swim stress (FSS) that led us to investigate how 3 alpha,5 alpha-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 3 alpha,5 alpha-THP/opiate system activation in this behavior. Serum fi-endorphin (beta-EP) was elevated by FSS and enhanced by 3 alpha,5 alpha-THP + FSS. Hypothalamic Mu-opiate receptors (MOP) were increased in female rats by 3 alpha,5 alpha-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 3 alpha,5 alpha-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.
引用
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页数:22
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