Canna~Fangled Abstracts

Neurosteroid biosynthesis downregulation and changes in GABAA receptor subunit composition: A biomarker axis in stress-induced cognitive and emotional impairment.

By April 29, 2017 No Comments
Br J Pharmacol. 2017 Apr 29. doi: 10.1111/bph.13843.
[Epub ahead of print]

Author information

1
The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Str., Chicago, IL, 60612, USA.

Abstract

pm-2-site-207By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed “high” dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced downregulation of neurosteroid biosynthesis and changes in GABAA receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABAAreceptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABAA receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients.

KEYWORDS:

Aggressive behaviour; Allopregnanolone; Anxiety; Biomarkers; Contextual fear; GABAA receptors; PTSD; Selective brain steroidogenic stimulants (SBSSs)

PMID: 28456011

 

DOI: 10.1111/bph.13843

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twin memes II

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