Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD

PSYCHONEUROENDOCRINOLOGY

卷:102

Article

Rasmusson, Ann M.^1,2,3  King, Matthew W.^1,2,3  Valovski, Ivan^2,4  Gregor, Kristin^2,3  Scioli-Salter, Erica^1,2,3  Pineles, Suzanne L.^1,2,3  Hamouda, Mohamed^2,4  Nillni, Yael I.^1,2,3  Anderson, George M.^5,6  Pinna, Graziano⁷ 

[1] VA Natl Ctr PTSD, Womens Hlth Sci Div, Boston, MA 02130 USA

[2] VA Boston Healthcare Syst, Boston, MA 02130 USA

[3] Boston Univ, Sch Med, Boston, MA 02118 USA

[4] Harvard Med Sch, Boston, MA 02115 USA

[5] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA

[6] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA

[7] Univ Illinois, Coll Med, Inst Psychiat, Chicago, IL 60612 USA

关键词: PTSD;    Depression;    Allopregnanolone;    Dehydroepiandrosterone;    Cerebrospinal fluid;    GABA;    Neurosteroids;    Gas chromatography-mass spectrometry;   

DOI  :  10.1016/j.psyneuen.2018.11.027

来源: Elsevier

【 摘 要 】

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of progesterone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABA(A) receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABA(A) receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatography-mass spectrometry (GC MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5 alpha-dihydroprogesterone (5 alpha-DHP: immediate precursor for allopregnanolone) suggested a block in synthesis of these neurosteroids at 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n=13) and trauma-exposed healthy controls (n=17) after an overnight fast. Individual CSF steroids were quantified separately by GC MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (rho=-0.74, p=0.006) and CAPS-IV derived Simms dysphoria cluster (rho=-0.71, p=0.01) scores. The allo + pregnan to DHEA ratio also was negatively correlated with total CAPS (rho=-0.74, p=0.006) and dysphoria cluster (rho=-0.79, p=0.002) scores. A PTSD-related decrease in the 5 alpha-DHP to progesterone ratio indicated a block in allopregnanolone synthesis at 5 alpha-reductase. This study suggests that CSF allo + pregnan levels correlate negatively with PTSD and negative mood symptoms in both men and women, but that the enzyme blocks in synthesis of these neurosteroids may be sex-specific. Consideration of sex, PTSD severity, and function of 5 alpha-reductase and 3 alpha-HSD thus may enable better targeting of neurosteroid-based PTSD treatments.

【 授权许可】

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