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

Abstract

Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of proges-terone 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 chromatographymass 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 5α-dihydroprogesterone (5α-DHP: immediate precursor for Allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-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 (ρ = −0.74, p = 0.006)and CAPS-IV derived Simms dysphoria cluster (ρ = −0.71, p = 0.01) scores. The allo + pregnan to DHEA ratio

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

“…While it is important that these findings will be confirmed also in blood and post-mortem brain of PTSD patients [101], this observation provides support to the involvement of the PPAR-allopregnanolone axis dysfunction in PTSD. Together with the findings that allopregnanolone has been found decreased in cerebrospinal fluid (CSF) and plasma of both male and female PTSD and MDD patients [95,[97][98][99]102], these clinical data provide a translational example with PTSD animal models [103].…”

Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

“…It is interesting to note, that ALLO levels have been found to be decreased relative to controls in the CSF of women with chronic stress disorders, such as PTSD (75). A subsequent study from this group observed a negative correlation between CSF levels of total GABAergic neurosteroids levels (ALLO plus pregnanolone) and PTSD symptoms in men (76). This study also found an association between PTSD and reduced 5α-reductase mediated biosynthesis of ALLO in men, which is in contrast to the block at 3α-HSD previously observed in women with PTSD.…”

Progesterone and anxiety during the oestrus cycle in rats genetically selected for high and low active avoidance

“…The neurophysiological role of allopregnanolone in permitting the finetuning and regulation of the strength of GABA A receptors to agonists, positive allosteric modulators, and GABAmimetic agents, was also unveiled (Pinna et al 2000). By affecting GABA A receptors, allopregnanolone also regulates emotional animal behaviour in rodent stress models and humans with posttraumatic stress disorder and major unipolar depression (Rasmusson et al 2019;Pineles et al 2018).…”