Multifunctional aspects of allopregnanolone in stress and related disorders

Abstract

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one) is a major cholesterol-derived neurosteroid in the central nervous system and is synthesized from progesterone by steroidogenic enzymes, 5α-reductase (the rate-limiting enzyme) and 3α-hydroxysteroid dehydrogenase. The pathophysiological role of allopregnanolone in neuropsychiatric disorders has been highlighted in several investigations. The changes in neuroactive steroid levels are detected in stress and stress-related disorders including anxiety, panic and depression. The changes in allopregnanolone in response to acute stressor tend to restore the homeostasis by dampening the hyper-activated HPA axis. However, long standing stressors leading to development of neuropsychiatric disorders including depression and anxiety are associated with decrease in the allopregnanolone levels. GABAA receptor complex has been considered as the primary target of allopregnanolone and majority of its inhibitory actions are mediated through GABA potentiation or direct activation of GABA currents. The role of progesterone receptors in producing the late actions of allopregnanolone particularly in lordosis facilitation has also been described. Moreover, recent studies have also described the involvement of other multiple targets including brain-derived neurotrophic factor (BDNF), glutamate, dopamine, opioids, oxytocin, and calcium channels. The present review discusses the various aspects of allopregnanolone in stress and stress-related disorders including anxiety, depression and panic.

Keywords: 3α-HSD; 3α-hydroxysteroid dehydrogenase; AlloP; Allopregnanolone; Anxiety; BDNF; Brain-derived neurotrophic factor; CRF; Corticotropin releasing factor; Depression; GABA; HPA; HVA; Homovanillic acid; Hypothalamus-pituitary- adrenal axis; MAPK; Msitogen-activated protein kinases; N-methyl-D-aspartate; NKCC1; NMDA; NTS; Na(+)-K(+)-Cl(-) co-transporter; Nucleus tractus solitaries; PBR; PKA; PVN; Panic; Paraventricular nucleus; Peripheral benzodiazepine receptors; Protein kinase A; SBBS; SON; Spontaneous excitatory postsynaptic current; Steroidogenic stimulant; Stress; Supraoptic nucleus; TSPO; TSST; Translocator protein; Trier Social Stress test; VMH; Ventromedial hypothalamus; mPFC; median prefrontal cortex; sEPSCs.