Role of allopregnanolone biosynthesis in acute stress-induced anxiety-like behaviors in mice

Abstract

The neurosteroid allopregnanolone (3α, 5α-tetra-hydroprogesterone: ALLO) elicits anxiolytic, anticonvulsant, and hypnotic anesthetic effects in vivo similar to those induced by other positive allosteric modulators of the GABA receptor. Endogenous ALLO has been shown to be rapidly elevated in the brain by acute stress paradigms, such as immobilization, in animal models. The present study was designed to ascertain the role of neurosteroid biosynthesis in the anxiety-like behavior induced by immobilization stress. Mice were exposed to an immobilization stressor for 2 h. After 24 h, the mice that had been immobilized did not behave significantly differently in the elevated plus maze (EPM) test and in the elevated open platform (EOP) test than the mice that had not been immobilized. In contrast, finasteride-pretreated immobilization stressed mice did behave significantly differently in the EPM and EOP tests. These findings suggest that ALLO biosynthesis contributes to stress resistance. Furthermore, the ALLO mimetic drug alfaxalone appeared to antagonize the effects of finasteride by significantly changing the behavior in the EPM test or in the EOP test in finasteride (10 mg kg )-pretreated immobilized mice. In addition, alfaxalone, unlike diazepam, did not affect the muscle tone of the mice, as measured by the grip strength test. These results suggest that alfaxalone is a promising anxiolytic candidate lacking benzodiazepine-like muscle-relaxant effects.

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

“…Sexually dimorphic behavioral deficits could arise from different baseline levels of gonadal hormones, neurosteroids and synthesis enzymes in females. These could modulate tonic GABA A currents and make females more vulnerable to GABA A deletion (Schüle et al, 2014;Ströhle et al, 2002;Yoshizawa et al, 2017). The observations that baseline tonic currents are larger in females but THIP-evoked currents are of equal amplitude are consistent with this hypothesis (Figure S1 G, H).…”

A novel therapeutic approach for treatment of catamenial epilepsy

“…We propose that excitatory action of progesterone receptors counterbalances the memory impairing effect of allopregnanolone. Progesterone derivative allopregnanolone has a sedative anxiolytic action (Yoshizawa et al, 2017; Pinna, 2010). However, it also impairs spatial memory performance on Morris water maze task without impairing non-spatial learning (Johansson et al, 2002; Matthews et al, 2002).…”

Yokukansankachimpihange Improves the Social Isolation-Induced Sleep Disruption and Allopregnanolone Reduction in Mice

“…ALLO is a neuroactive steroid derived from progesterone, and acts as positive allosteric modulator of GABA A receptor action. As a positive allosteric modulator of the GABA A receptor, ALLO has been reported to be an anxiolytic, anesthetic, and anticonvulsant agent (28)(29)(30). In addition, ALLO treatment has been reported to improve memory impairment and BPSDlike behavior in Alzheimer's disease mouse models (22,31,32).…”