Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes.

Methods and Findings in Experimental and Clinical Pharmacology
Doodipala S Reddy, Y-C Zeng

Abstract

Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by the interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the noncompetitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone-induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the no...Continue Reading

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Citations

Feb 10, 2016·The Journal of Pharmacology and Experimental Therapeutics·Chase Matthew Carver, Doodipala Samba Reddy
Mar 25, 2014·Expert Opinion on Therapeutic Targets·Giovana BristotAdriane R Rosa
Apr 12, 2015·American Journal of Physiology. Heart and Circulatory Physiology·Ronald E PachonStephen F Vatner
Oct 11, 2020·International Journal of Molecular Sciences·Berthold DrexlerJulia Grenz

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