title: Decreased allopregnanolone induced by hormonal contraceptives is associated with a reduction in social behavior and sexual motivation in female rats.
abstract: BACKGROUND
  Allopregnanolone is a neurosteroid involved in depression, memory, social, and sexual behavior. We have previously demonstrated that treatment with a combination of ethinylestradiol (EE) and levonorgestrel (LNG), two compounds frequently used in hormonal contraception, decreased brain allopregnanolone concentrations. These changes may contribute to some of the emotional and sexual disorders observed in hormonal contraceptive users.
  
  
  OBJECTIVE
  We thus examined whether the reduction in allopregnanolone concentrations induced by long-term EE/LNG administration was associated with altered emotional, learning, social, and sexual behaviors.
  
  
  METHODS
  Rats were orally treated with a combination of EE (0.030 mg) and LNG (0.125 mg) once a day for 4 weeks and were subjected to behavioral tests 24 h after the last administration.
  
  
  RESULTS
  EE/LNG treatment reduced immobility behavior in the forced swim test, without affecting sucrose preference and spatial learning and memory. In the resident-intruder test, EE/LNG-treated rats displayed a decrease in dominant behaviors associated with a reduction in social investigation. In the paced mating test, EE/LNG treated rats showed a reduction in proceptive behaviors, while the lordosis quotient was not affected. Progesterone, but not estradiol, administration to EE/LNG-treated rats increased sexual activity and cerebrocortical allopregnanolone concentrations. Prior administration of finasteride decreased allopregnanolone concentrations and abolished the increase in proceptivity induced by progesterone administration.
  
  
  CONCLUSIONS
  The decrease in brain allopregnanolone concentrations induced by EE/LNG treatment is associated with a reduction in social behavior and sexual motivation in female rats. These results might be relevant to the side effects sometimes exhibited by women taking hormonal contraceptives.
authors.affiliation: Department of Life and Environment Sciences, University of Cagliari, SS 554 (Km. 4,500), 09042, Monserrato, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santoru
authors.forename: Roberta
authors.initials: R
authors.lastname: Berretti
authors.forename: Andrea
authors.initials: A
authors.lastname: Locci
authors.forename: Patrizia
authors.initials: P
authors.lastname: Porcu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Concas
mesh_terms: D000378:Agonistic Behavior / Q000187:drug effects; D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003278:Contraceptives, Oral, Hormonal / Q000494:pharmacology*; D003863:Depression / Q000139:chemically induced / Q000523:psychology; D004338:Drug Combinations; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D016912:Levonorgestrel / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D009042:Motivation / Q000187:drug effects*; D011280:Pregnanolone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D012919:Social Behavior; D013550:Swimming / Q000523:psychology
chemical_list: D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D011280:Pregnanolone
references.citation: Horm Behav. 2003 Nov;44(4):319-26
references.pmid: 14613726
references.citation: Neurosci Biobehav Rev. 1990 Summer;14(2):217-32
references.pmid: 2190121
references.citation: Int J Neurosci. 1988 Aug;41(3-4):271-86
references.pmid: 3263344
references.citation: Eur Neuropsychopharmacol. 2007 Jan;17(1):1-11
references.pmid: 16626946
references.citation: Contraception. 2010 Aug;82(2):147-54
references.pmid: 20654755
references.citation: Psychoneuroendocrinology. 2004 Jan;29(1):21-34
references.pmid: 14575727
references.citation: J Sex Med. 2010 Nov;7(11):3598-609
references.pmid: 20646182
references.citation: Psychopharmacology (Berl). 2002 Oct;163(3-4):459-66
references.pmid: 12373446
references.citation: J Med Chem. 1990 Jun;33(6):1572-81
references.pmid: 2160534
references.citation: Psychopharmacology (Berl). 1997 Dec;134(4):319-29
references.pmid: 9452163
references.citation: J Sex Med. 2008 Oct;5(10):2282-90
references.pmid: 19007404
references.citation: J Clin Endocrinol Metab. 2001 Dec;86(12):5981-7
references.pmid: 11739473
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44
references.pmid: 9501247
references.citation: Brain Res Brain Res Rev. 2001 Nov;37(1-3):201-22
references.pmid: 11744087
references.citation: Fertil Steril. 2004 Mar;81(3):645-51
references.pmid: 15037415
references.citation: Neurosci Biobehav Rev. 2006;30(3):319-45
references.pmid: 16483890
references.citation: Anim Reprod Sci. 2008 Nov;108(3-4):412-24
references.pmid: 17980521
references.citation: Horm Behav. 2000 Dec;38(4):234-42
references.pmid: 11104641
references.citation: Behav Processes. 2011 Jan;86(1):46-51
references.pmid: 20804831
references.citation: Contraception. 2001 Jul;64(1):51-8
references.pmid: 11535214
references.citation: Brain Res. 1993 Apr 2;607(1-2):324-8
references.pmid: 8386975
references.citation: J Neuroendocrinol. 2001 Dec;13(12):1076-86
references.pmid: 11722704
references.citation: Neuropharmacology. 2007 Jun;52(7):1439-53
references.pmid: 17433821
references.citation: Physiol Behav. 1997 Nov;62(5):1053-7
references.pmid: 9333199
references.citation: Front Neuroendocrinol. 2008 Oct;29(4):476-89
references.pmid: 18280561
references.citation: Behav Biol. 1978 Sep;24(1):77-87
references.pmid: 736867
references.citation: Am J Obstet Gynecol. 1994 May;170(5 Pt 2):1499-507
references.pmid: 8178898
references.citation: J Clin Endocrinol Metab. 1998 Jun;83(6):2099-103
references.pmid: 9626145
references.citation: Arch Womens Ment Health. 2006 Jan;9(1):1-14
references.pmid: 16206030
references.citation: Pharmacol Biochem Behav. 2000 Sep;67(1):137-43
references.pmid: 11113493
references.citation: Pharmacol Biochem Behav. 2006 Aug;84(4):628-34
references.pmid: 16854457
references.citation: Psychoneuroendocrinology. 2011 Aug;36(7):935-44
references.pmid: 21367531
references.citation: Brain Res. 1998 Oct 12;808(1):72-83
references.pmid: 9795145
references.citation: Horm Behav. 2003 Sep;44(3):242-57
references.pmid: 14609546
references.citation: Endocrinology. 1990 Apr;126(4):1854-9
references.pmid: 2156667
references.citation: Expert Opin Drug Saf. 2007 Jul;6(4):371-4
references.pmid: 17688380
references.citation: Psychoneuroendocrinology. 2010 Aug;35(7):1008-22
references.pmid: 20129736
references.citation: Climacteric. 2008 Jun;11(3):212-20
references.pmid: 18568786
references.citation: Contraception. 2009 Jan;79(1):50-5
references.pmid: 19041441
references.citation: Arch Gynecol Obstet. 2012 Jul;286(1):231-6
references.pmid: 22467147
references.citation: Obstet Gynecol. 1997 Nov;90(5):709-14
references.pmid: 9351749
references.citation: J Affect Disord. 2002 Aug;70(3):229-40
references.pmid: 12128235
references.citation: J Clin Endocrinol Metab. 1996 Mar;81(3):1076-82
references.pmid: 8772579
references.citation: J Neuroendocrinol. 2006 Dec;18(12):960-75
references.pmid: 17076771
references.citation: J Sex Med. 2012 Feb;9(2):550-7
references.pmid: 22188640
references.citation: Neuropharmacology. 2002 Mar;42(3):325-36
references.pmid: 11897111
references.citation: Brain Res. 2002 May 3;934(2):125-31
references.pmid: 11955475
references.citation: Brain Res. 2007 Sep 12;1169:1-8
references.pmid: 17698049
references.citation: Contraception. 1995 Dec;52(6):363-9
references.pmid: 8749600
references.citation: Fertil Steril. 2006 May;85(5):1371-8
references.pmid: 16580672
references.citation: J Sex Med. 2013 Jul;10(7):1692-706
references.pmid: 23634744
references.citation: Pharmacol Biochem Behav. 2012 Aug;102(2):366-72
references.pmid: 22634062
references.citation: J Sex Med. 2004 Nov;1(3):237-53
references.pmid: 16422954
references.citation: Life Sci. 2004 May 14;74(26):3181-97
references.pmid: 15094320
references.citation: Arch Int Pharmacodyn Ther. 1977 Oct;229(2):327-36
references.pmid: 596982
references.citation: Contraception. 2012 Nov;86(5):470-80
references.pmid: 22465115
references.citation: Psychopharmacology (Berl). 2013 Nov;230(2):151-88
references.pmid: 24071826
references.citation: Proc Soc Exp Biol Med. 1992 Oct;201(1):73-9
references.pmid: 1528911
references.citation: Contraception. 2010 Aug;82(2):155-9
references.pmid: 20654756
references.citation: Physiol Behav. 1985 Jun;34(6):871-7
references.pmid: 4059375
references.citation: Hum Reprod. 2005 Apr;20(4):1100-6
references.pmid: 15608030
references.citation: Biol Psychiatry. 2010 Nov 15;68(10):956-63
references.pmid: 20471631
references.citation: Pharmacol Ther. 2007 Oct;116(1):125-39
references.pmid: 17597217
references.citation: Biol Psychiatry. 2001 May 1;49(9):788-97
references.pmid: 11331087
references.citation: Psychopharmacology (Berl). 2008 Aug;199(2):161-8
references.pmid: 18551282
references.citation: Evol Psychol. 2013 Jul 18;11(3):718-42
references.pmid: 23864301
references.citation: Neuropsychopharmacology. 2001 May;24(5):502-10
references.pmid: 11282250
references.citation: Horm Behav. 1980 Mar;14(1):65-75
references.pmid: 7399422
references.citation: Psychopharmacology (Berl). 2001 Feb;153(4):473-83
references.pmid: 11243495
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13284-9
references.pmid: 9789080
references.citation: Psychoneuroendocrinology. 2007 Apr;32(3):246-55
references.pmid: 17314012
references.citation: Am J Psychiatry. 1998 Jul;155(7):910-3
references.pmid: 9659856
references.citation: Gynecol Endocrinol. 2005 Nov;21(5):268-79
references.pmid: 16373246
references.citation: Contraception. 2012 Nov;86(5):518-25
references.pmid: 22673038
references.citation: Contraception. 2004 Mar;69(3):237-40
references.pmid: 14969672
references.citation: Front Endocrinol (Lausanne). 2011 Oct 04;2:44
references.pmid: 22654809