In Vivo Studies Identify 5a‐Pregnan‐3a‐o1‐20‐one as an Active Anesthetic Agent

Abstract

Mice were anesthetized with 5 alpha-[3H]pregnan-3 alpha-ol-20-one. Brain levels for 5 alpha-pregnan-3 alpha-ol-20-one and its five major metabolites (5 alpha-pregnanedione, k0, k1, k2, k3) were compared at behavioral endpoints that are characteristic of the anesthetized state. The results support the hypothesis that 5 alpha-pregnan-3 alpha-ol-20-one mediates the anesthetic response, and they weigh against the hypothesis that any of its metabolites is solely responsible for the onset or the maintenance of the anesthetized state. For an administered dose of 3 mg/kg, brain levels (means +/- SEM) for 5 alpha-pregnan-3 alpha-ol-20-one at the time of the loss of the righting response (n = 10) and at the time of the return of the righting response (n = 6) were 7.24 +/- 0.61 pmol/mg of brain tissue and 3.63 +/- 0.26 pmol/mg of brain tissue, respectively. No metabolite level was lower at the return of the righting response than at the loss of the righting response. 5 alpha-Pregnan-3 alpha-ol-20-one brain levels increased consistently with the percentage of anesthetized mice. This was not the case for any of the metabolites. Fifty percent of the mice were anesthetized when the 5 alpha-pregnan-3 alpha-ol-20-one level was 4.5 pmol/mg of brain tissue.

Chronopharmacological studies of ketamine in normal and NMDA Ε1 receptor knockout mice †

“…Recovery from the LORR was de®ned as having occurred when the mouse spontaneously righted itself. 18 During anaesthesia the animals were kept warm on a plate heated to 38°C. To examine the daily variation of effect, ketamine was injected at 04:00, 10:00, 16:00, and 22:00 in wild-type mice (n=12 in each group).…”

Anxiolytic Effect of Progesterone is Mediated by the Neurosteroid Allopregnanolone at Brain GABAA Receptors

“…4) PROG or allopregnanolone injection produces anxiolytic (6-8, 13, 14). anticonvulsant ( 15,16), analgesic ( 17), anti-aggressive ( 18,19) and sedative-hypnotic-anesthetic effects (20)(21)(22). Most of these effects are commonly observed after BDZ administration (23).…”

Neurosteroids Modulate Nicotinic Receptor Function in Mouse Striatal and Thalamic Synaptosomes

“…Peripheral or central administration produces a wide array of behavioral effects in laboratory animals. High doses will induce anesthesia (Mok et al, 1991 ). Lower doses have anxiolytic effects (Bitran et al, 1991(Bitran et al, , 1995Weiland et al, 1991Weiland et al, , 1995Zimmerberg et al, 1994;Fernández-Guasti and Picazo, 1995) and protect against electrically induced (Frye, 1995) and drug-induced (Luntz-Leybman et al, 1990;Finn and Gee, 1994;Kokate et al, 1994;Devaud et al, 1995;Finn et al, 1995) seizures as well as the seizures seen during withdrawal from ethanol (Finn et al, 1995).…”