Anxiolytic Effect of Progesterone is Mediated by the Neurosteroid Allopregnanolone at Brain GABA<sub>A</sub> Receptors

Journal of Neuroendocrinology - Tập 7 Số 3 - Trang 171-177 - 1995
Daniel Bitran1, Michael Shiekh1, Michael K. McLeod1
1Department of Psychology, College of the Holy Cross, Worcester, MA 01610 USA

Tóm tắt

AbstractPrevious studies from this laboratory have shown that progesterone (PROG) treatment in ovariectomized rats produces an anti‐anxiety response similar to that observed after the administration of prototypical anxiolytic benzodiazepine (BDZ) compounds. The PROG‐induced anxiolytic response was highly correlated with an increased level of 3α‐hydroxy‐5α‐pregnan‐20‐one (allopregnanolone) in the blood and brain, and was also associated with a facilitation of GABA‐stimulated chloride ion (Cl−) influx in cortical synaptoneurosomes. This correlative evidence suggested that the anxiolytic effect of PROG was a result of its in vivo reduction to the neuroactive steroid, allopregnanolone. In this report, a series of studies was conducted to determine the mechanism(s) by which PROG alters behavior in animal models of anxiety. In the first experiment, ovariectomized rats were injected with PROG (1 mg/0.2 ml, SC) 4 h prior to a test in the elevated plus‐maze. Some animals also received an injection of picrotoxin (0.75 mg/kg, IP), a GABAA receptor‐gated Cl− channel antagonist, whereas other animals were pretreated with RU 38486 (5 mg/0.2 ml, SC), a progestin receptor antagonist. PROG elicited anxiolytic behavior in the plus‐maze, an effect that was blocked by picrotoxin administration. Pretreatment with RU 38486 was not effective in altering PROG‐induced anxiolytic behavior in the plus‐maze. In a second experiment, the effect of PROG on behavior in the plus‐maze was determined in the presence of N,N‐diethyl‐4‐methyl‐3‐oxo‐4‐aza‐5α‐androstane‐17β‐carboxamide (4‐MA; 10 mg/0.2 ml, SC), a 5α‐reductase inhibitor. The enzyme inhibitor was potent in preventing the anxiolytic effect observed in the plus‐maze after PROG administration. In the defensive burying paradigm, PROG treatment also produced anxiolysis by reducing the duration of burying behavior, and this effect was prevented by 4‐MA pretreatment, but not by RU 38486 administration. After the completion of the behavioral assays, analysis of blood allopregnanolone levels revealed a marked increase in PROG‐treated females. The PROG‐induced elevation in circulating allopregnanolone was blocked by pretreatment with 4‐MA. In cortical synaptoneurosomes, the sensitivity (inverse of the EC50) and the maximal response (Emax) in GABA‐stimulated 36Cl− uptake were increased in PROG‐treated females. The potentiation of PROG on both of these neurochemical measures was not observed in animals pretreated with 4‐MA. Together, these studies provide evidence that the anxiolytic effect of PROG is not associated with an intracellular steroid receptor that initiates genomic‐mediated responses. The evidence is consistent with a nongenomic mechanism whereby PROG is metabolized to allopregnanolone, a neuroactive steroid that potentiates GABAA receptor‐mediated responses.

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Tài liệu tham khảo

10.1001/jama.268.14.1908

10.1111/j.1365-2125.1992.tb04038.x

10.1136/bmj.290.6482.1617

10.1016/B978-0-08-040698-5.50012-0

10.1016/0306-4530(84)90008-8

Fernandez‐Guasti A, 1991, Behavioral Biology: Neuroendocrine Axis, 105

10.1016/0306-4530(92)90027-5

10.1016/0091-3057(93)90260-Z

10.1016/0091-3057(93)90219-J

Treit D., 1991, 5‐HT, Agonists, 5‐HT3 Antagonists and Benzodiazepines: Their Comparative Behavioural Pharmacology, 107

10.1002/9780470513989.ch2

10.1016/0301-0082(92)90025-A

10.1016/0006-8993(91)90761-J

10.1016/0006-8993(91)91658-N

10.1016/0014-2999(89)90077-0

10.1111/j.1748-1716.1987.tb08202.x

10.1016/0006-8993(87)90228-9

10.1016/0091-3057(90)90008-6

10.1016/0031-9384(87)90013-8

10.1111/j.1471-4159.1991.tb08293.x

10.1016/0006-8993(90)91792-F

10.1111/j.1600-0773.1987.tb01770.x

Patel JB, 1983, Anxiolytics: Neurochemical, Behavioral, and Clinical Perspectives, 173

10.1210/endo-119-4-1610

10.1210/endo-109-3-830

10.1016/0896-6273(93)90156-L

10.1096/fasebj.6.6.1347506

Corpechot C, 1993, Neurosteroids: 3r‐hydroxy‐5a‐pregnan‐20‐one and its pre‐cursors in the brain, plasma, and steroidogenic glands of male and female rats, Endocrinology., 133, 1003, 10.1210/endo.133.3.8365352

Papadopoulos V., 1993, Peripheral‐type benzodiazepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function, Endocrine Rev., 14, 222

Morrow AL, 1990, Characterization of steroid interactions with the GABA receptor‐gated chloride ion channel: Evidence for multiple steroid recognition sites, Mol Pharmacol., 37, 263

10.1016/0896-6273(90)90202-Q

10.1007/BF00249916

10.1016/0006-8993(89)90955-4

Canonaco M, 1993, Steroid hormones and receptors of the GABA, supramolecular complex. I. Benzodiazepine receptor level changes in some extrahypothalamic brain areas of the female rat following sex steroid treatment, Neuroendocrinology., 57, 365

10.1016/0006-8993(87)90728-1

10.1159/000126462

10.1016/0091-3057(90)90044-I

10.1037/0735-7044.105.5.653

Finn DA, 1993, The influence of estrus cycle on neuros‐teroid potency at the 7‐aminobutyric acid, receptor complex, J Pharmacol Exp Ther., 265, 1374

10.1111/j.1476-5381.1991.tb09830.x

10.1016/0165-0270(85)90031-7

10.1016/0091-3057(81)90219-7

Schwartz RD, 1986, y‐Aminobutyric acid (GABA)‐and barbiturate‐mediated CI‐ uptake in rat brain synaptoneu‐rosomes: evidence for rapid desensitization. of the GABA receptor‐coupled chloride ion channel, Mol Pharmacol., 30, 419

10.1016/0039-128X(90)90031-6

10.1016/S0076-6879(81)72018-4

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Journal of Neuroendocrinology

Tập 7 Số 3

171-177

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