Background/Aims: Allopregnanolone or 3α-hydroxy-5α-pregnan-20-one (AlloP) is normally sedative and anxiolytic, but can under provoking circumstances paradoxically induce aggressive behavior. Therefore, it is of particular interest to determine if there is a relationship between an anxiolytic effect and aggressive behavior following AlloP administration. Method: Male Wistar rats were housed in triads comprising of 1 young rat (35 days) and 2 older rats (55 days), with the intent of producing a social hierarchy. The triads were sampled for total serum testosterone and submitted to a social challenge in the form of a food competition test (FCT), where the rats competed for access to drinking sweetened milk. At baseline, the younger rats were identified as subordinates. To test for the behavioral effect of AlloP, the subordinate rats were given intravenous AlloP injections of 0.5 and 1 mg/kg. To assess the optimal AlloP effect, 6 intervals (5, 10, 15, 20, 30 and 40 min) between injection and the FCT were used. In separate studies, AlloP was also given by subcutaneous and intraperitoneal administration at 10 and 17 mg/kg. Results: AlloP (1 mg/kg, i.v.) increased drinking time and aggressive behavior in subordinate rats, with a positive correlation between these behaviors. The subcutaneous injection (17 mg/kg) also increased drinking time in subordinate animals. Serum testosterone concentration was higher in dominant compared to subordinate rats, and correlated with drinking time and weight. Conclusions: AlloP increased drinking time and aggressive behavior, and the correlation indicates a relationship between an anxiolytic effect and aggressive behavior.

Finn DA, Roberts AJ, Lotrich F, Gallaher EJ: Genetic differences in behavioral sensitivity to a neuroactive steroid. J Pharmacol Exp Ther 1997;280:820-828.
Carboni E, Wieland S, Lan NC, Gee KW: Anxiolytic properties of endogenously occurring pregnanediols in two rodent models of anxiety. Psychopharmacology (Berl) 1996;126:173-178.
Bitran D, Hilvers RJ, Kellogg CK: Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 1991;561:157-161.
Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A, Costa E: Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice. Neurochem Res 2008;33:1990-2007.
Fish EW, Faccidomo S, DeBold JF, Miczek KA: Alcohol, allopregnanolone and aggression in mice. Psychopharmacology (Berl) 2001;153:473-483.
Fish EW, DeBold JF, Miczek KA: Escalated aggression as a reward: corticosterone and GABA(A) receptor positive modulators in mice. Psychopharmacology (Berl) 2005;182:116-127.
Taylor GT, Moore S: Social position and competition in laboratory rats. J Comp Physiol Psychol 1975;88:424-430.
Baenninger LP: Social dominance orders in the rat: ‘spontaneous' food and water competition. J Comp Physiol Psychol 1970;71:202-209.
Malatynska E, Goldenberg R, Shuck L, Haque A, Zamecki P, Crites G, Schindler N, Knapp RJ: Reduction of submissive behavior in rats: a test for antidepressant drug activity. Pharmacology 2002;64:8-17.
Gentsch C, Lichtsteiner M, Feer H: Competition for sucrose pellets in triads of male Wistar rats: the individuals' performances are differing but stable. Behav Brain Res 1988;27:37-44.
Joly D, Sanger DJ: Social competition in rats: a test sensitive to acutely administered anxiolytics. Behav Pharmacol 1991;2:205-213.
Pucilowski O, Overstreet DH, Rezvani AH, Janowsky DS: Effect of verapamil on submissive behavior in genetically bred hypercholinergic rats in a water competition test. Eur J Pharmacol 1990;187:507-511.
Tomkiewicz M, Steinberg H: Proceedings: amylobarbitone abolishes social dominance hierarchies in laboratory rats. Br J Pharmacol 1972;44:351P.
Albert DJ, Petrovic DM, Walsh ML: Competitive experience activates testosterone-dependent social aggression toward unfamiliar males. Physiol Behav 1989;45:723-727.
Albert DJ, Petrovic DM, Walsh ML: Female rats in a competitive situation: medial hypothalamic lesions increase and ovariectomy decreases success and aggression. Physiol Behav 1989;46:379-386.
Ruskin RS, Davis GG, DePeralta A Jr: The relationship between emotionality and dominance in the hooded rat. J Gen Psychol 1975;92:53-58.
Askew A, Gonzalez FA, Stahl JM, Karom MC: Food competition and social experience effects on V1a receptor binding in the forebrain of male Long-Evans hooded rats. Horm Behav 2006;49:328-336.
Chance MR, Silverman AP: The structure of social behaviour and drug action; in Steinberg HE (ed): Animal Behaviour and Drug Action. London, Churchill, 1964, pp 65-79.
Miller NE: The analysis of motivational effects illustrated by experiments on amylobarbitone sodium; Ciba Foundation Symposium - Animal Behaviour and Drug Action. Wiley, 2008, pp 1-22.
Read GW, Cutting W, Furst A: Comparison of excited phases after sedatives and tranquilizers. Psychopharmacology 1960;1:346-350.
Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM: Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232:1004-1007.
Carl P, Högskilde S, Nielsen JW, Sorensen MB, Lindholm M, Karlen B, Bäckström T: Pregnenolone emulsion. A preliminary pharmacokinetic and pharmacodynamic study of a new intravenous anaesthetic agent. Anaesthesia 1990;45:189-197.
Landgren S, Wang MD, Bäckström T, Johansson S: Interaction between 3α-hydroxy-5α-pregnan-20-one and carbachol in the control of neuronal excitability in hippocampal slices of female rats in defined phases of the oestrus. Acta Physiol Scand 1998;162:77-88.
Kagan L, Gershkovich P, Mendelman A, Amsili S, Ezov N, Hoffman A: The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model. Eur J Pharm Biopharm 2007;67:759-765.
Lukas G, Brindle SD, Greengard P: The route of absorption of intraperitoneally administered compounds. J Pharmacol Exp Ther 1971;178:562-564.
Clarke FM, Faulkes CG: Hormonal and behavioural correlates of male dominance and reproductive status in captive colonies of the naked mole rat, Heterocephalus glaber. Proc Biol Sci 1998;265:1391-1399.
Lucion AB, De-Almeida RM, Da-Silva RS: Territorial aggression, body weight, carbohydrate metabolism and testosterone levels of wild rats maintained in laboratory colonies. Braz J Med Biol Res 1996;29:1657-1662.
Johansson IM, Birzniece V, Lindblad C, Olsson T, Bäckström T: Allopregnanolone inhibits learning in the Morris water maze. Brain Res 2002;934:125-131.
Turkmen S, Löfgren M, Birzniece V, Bäckström T, Johansson IM: Tolerance development to Morris water maze test impairments induced by acute allopregnanolone. Neuroscience 2006;139:651-659.
Fernandez-Guasti A, Picazo O: Flumazenil blocks the anxiolytic action of allopregnanolone. Eur J Pharmacol 1995;281:113-115.
Picazo O, Fernandez-Guasti A, Lemus AE, Garcia GA: A-ring reduced derivatives of two synthetic progestins induce anxiolytic effects in ovariectomized rats. Brain Res 1998;796:45-52.
Finn DA, Phillips TJ, Okorn DM, Chester JA, Cunningham CL: Rewarding effect of the neuroactive steroid 3α-hydroxy-5α-pregnan-20-one in mice. Pharmacol Biochem Behav 1997;56:261-264.
Wieland S, Lan NC, Mirasedeghi S, Gee KW: Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-o1-20-one. Brain Res 1991;565:263-268.
Reddy DS, Kulkarni SK: Sex and estrous cycle-dependent changes in neurosteroid and benzodiazepine effects on food consumption and plus-maze learning behaviors in rats. Pharmacol Biochem Behav 1999;62:53-60.
Chen SW, Rodriguez L, Davies MF, Loew GH: The hyperphagic effect of 3α-hydroxylated pregnane steroids in male rats. Pharmacol Biochem Behav 1996;53:777-782.
Turkmen S, Wahlström G, Bäckström T, Johansson IM: Persistence of tolerance to the anaesthetic effect of allopregnanolone in male rats. Eur J Pharmacol 2008;592:73-80.
Zanato VF, Martins MP, Anselmo-Franci JA, Petenusci SO, Lamano-Carvalho TL: Sexual development of male Wistar rats. Braz J Med Biol Res 1994;27:1273-1280.
Palumbo MA, Salvestroni C, Gallo R, Guo AL, Genazzani AD, Artini PG, Petraglia F, Genazzani AR: Allopregnanolone concentration in hippocampus of prepubertal rats and female rats throughout estrous cycle. J Endocrinol Invest 1995;18:853-856.
Zhu D, Birzniece V, Bäckström T, Wahlström G: Dynamic aspects of acute tolerance to allopregnanolone evaluated using anaesthesia threshold in male rats. Br J Anaesth 2004;93:560-567.
Bixo M, Bäckström T: Regional distribution of progesterone and 5α-pregnane-3,20-dione in rat brain during progesterone-induced ‘anesthesia'. Psychoneuroendocrinology 1990;15:159-162.
Nowak FV: Distribution and metabolism of 20α-hydroxylated progestins in the female rat. J Steroid Biochem Mol Biol 2002;80:469-479.
Blanchard DC, Spencer RL, Weiss SM, Blanchard RJ, McEwen B, Sakai RR: Visible burrow system as a model of chronic social stress: behavioral and neuroendocrine correlates. Psychoneuroendocrinology 1995;20:117-134.
Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy RH, Biggio G: Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J Neurochem 2000;75:732-740.
Kabbaj M, Akil H: Individual differences in novelty-seeking behavior in rats: a c-fos study. Neuroscience 2001;106:535-545.
Malatynska E, Rapp R, Harrawood D, Tunnicliff G: Submissive behavior in mice as a test for antidepressant drug activity. Pharmacol Biochem Behav 2005;82:306-313.
Strömberg J, Bäckström T, Lundgren P: Rapid non-genomic effect of glucocorticoid metabolites and neurosteroids on the γ-aminobutyric acid-A receptor. Eur J Neurosci 2005;21:2083-2088.
Smith SS, Ruderman Y, Frye C, Homanics G, Yuan M: Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder. Psychopharmacology (Berl) 2006;186:323-333.
Löfgren M, Johansson M, Strömberg J, Meyerson B, Bäckström T: The influence of social subordinate housing on the withdrawal effects from progesterone and estradiol in male rats. Gen Comp Endocrinol 2012;177:62-69.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.