GABAA receptor modulating steroid antagonists (GAMSA) are functional in vivo

Abstract

GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAA receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents. Allopregnanolone and THDOC have both negative and positive actions. Allopregnanolone can impair encoding/consolidation and retrieval of memories. Chronic administration of a physiological allopregnanolone concentration reduces cognition in mice models of Alzheimer's disease. In humans an allopregnanolone challenge impairs episodic memory and in hepatic encephalopathy cognitive deficits are accompanied by increased brain ammonia and allopregnanolone. Hippocampal slices react in vitro to ammonia by allopregnanolone synthesis in CA1 neurons, which blocks long-term potentiation (LTP). Thus, allopregnanolone may impair learning and memory by interfering with hippocampal LTP. Contrary, pharmacological treatment with allopregnanolone can promote neurogenesis and positively influence learning and memory of trace eye-blink conditioning in mice. In rat the GAMSA UC1011 inhibits an allopregnanolone-induced learning impairment and the GAMSA GR3027 restores learning and motor coordination in rats with hepatic encephalopathy. In addition, the GAMSA isoallopregnanolone antagonizes allopregnanolone-induced anesthesia in rats, and in humans it antagonizes allopregnanolone-induced sedation and reductions in saccadic eye velocity. 17PA is also an effective GAMSA in vivo, as it antagonizes allopregnanolone-induced anesthesia and spinal analgesia in rats. In vitro the allopregnanolone/THDOC-increased GABA-mediated GABAA receptor activity is antagonized by isoallopregnanolone, UC1011, GR3027 and 17PA, while the effect of GABA itself is not affected.

Isoallopregnanolone reduces tic‐like behaviours in the D1CT‐7 mouse model of Tourette syndrome

“…The effects of AP on these receptors are antagonised by its 3β‐epimer, isoallopregnanolone (isoAP; 3β,5α, tetrahydroprogesterone) . Similar to other GABA A receptor modulating steroid antagonists, isoAP opposes the positive modulation of this receptor and does not inhibit GABA‐evoked currents . Recently, a randomised clinical trial validated that isoAP is a highly effective therapy for premenstrual dysphoric disorder, with optimal safety and tolerability profiles .…”

Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis

“…ALLO may modulate other ionotropic neurotransmitter receptors (5-HT3 and NMDA; Frye et al, 2014) or act at nonclassical steroid receptors (membrane progesterone and pregnane xenobiotic; Porcu et al, 2016). In addition, local availability of metabolic enzymes could convert ALLO into its precursor, dihydroprogesterone, which acts at intracellular progesterone receptors (Rupprecht et al, 1993), or its 3β epimer, isoallopregnanolone, which can antagonize ALLO-mediated potentiation of GABARs (Johansson et al, 2016). …”

Neurosteroids Involvement in the Epigenetic Control of Memory Formation and Storage

“…Some indications suggest that ALLO may impair learning and memory by interfering with hippocampal LTP; some others suggest opposite effects. Pharmacological doses of ALLO promote neurogenesis and positively influence learning and memory [77]. In a mouse model of ammonia hepatic encephalopathy, cognitive deficits are paralleled by increased brain levels of ALLO; the treatment with the 5 α -reductase inhibitor, finasteride, blocks the synthesis of ALLO and LTP can be reinduced [78].…”