title: Progesterone protects normative anxiety-like responding among ovariectomized female mice that conditionally express the HIV-1 regulatory protein, Tat, in the CNS.
abstract: Increased anxiety is co-morbid with human immunodeficiency virus (HIV) infection. Actions of the neurotoxic HIV-1 regulatory protein, Tat, may contribute to affective dysfunction. We hypothesized that Tat expression would increase anxiety-like behavior of female GT-tg bigenic mice that express HIV-1 Tat protein in the brain in a doxycycline-dependent manner. Furthermore, given reports that HIV-induced anxiety may occur at lower rates among women, and that the neurotoxic effects of Tat are ameliorated by sex steroids in vitro, we hypothesized that 17β-estradiol and/or progesterone would ameliorate Tat-induced anxiety-like effects. Among naturally-cycling proestrous and diestrous mice, Tat-induction via 7days of doxycycline treatment significantly increased anxiety-like responding in an open field, elevated plus maze and a marble-burying task, compared to treatment with saline. Proestrous mice demonstrated less anxiety-like behavior than diestrous mice in the open field and elevated plus maze, but these effects did not significantly interact with Tat-induction. Among ovariectomized mice, doxycycline-induced Tat protein significantly increased anxiety-like behavior in an elevated plus maze and a marble burying task compared to saline-treated mice, but not an open field (where anxiety-like responding was already maximal). Co-administration of progesterone (4mg/kg), but not 17β-estradiol (0.09mg/kg), with doxycycline significantly ameliorated anxiety-like responding in the elevated plus maze and marble burying tasks. When administered together, 17β-estradiol partially antagonized the protective effects of progesterone on Tat-induced anxiety-like behavior. These findings support evidence of steroid-protection over HIV-1 proteins, and extend them by demonstrating the protective capacity of progesterone on Tat-induced anxiety-like behavior of ovariectomized female mice.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA. Electronic address: jparis@tpims.org.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Paris
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA. Electronic address: jfenwick@tpims.org.
authors.forename: Jason
authors.initials: J
authors.lastname: Fenwick
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA. Electronic address: jmclaughlin@tpims.org.
authors.forename: Jay P
authors.initials: JP
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004967:Estrogens; D011372:Progestins; D054322:tat Gene Products, Human Immunodeficiency Virus; D011374:Progesterone; D004958:Estradiol; D004318:Doxycycline
keywords: 17β-estradiol; Elevated plus maze; Estrous cycle; GT-tg bigenic mice; Marble burying; Neuroaids; Open field; Ovariectomy; Tat(1–86); Transactivating transcriptor
references.citation: J Clin Endocrinol Metab. 2013 Apr;98(4):E610-8
references.pmid: 23418313
references.citation: N Engl J Med. 2011 Aug 11;365(6):493-505
references.pmid: 21767103
references.citation: Eur J Pharmacol. 1986 Jul 31;126(3):223-9
references.pmid: 2875886
references.citation: J Immunol. 1999 Jun 15;162(12):7510-8
references.pmid: 10358206
references.citation: Physiol Behav. 2010 Mar 3;99(3):301-16
references.pmid: 19931548
references.citation: Neuropsychopharmacology. 2014 Jan;39(2):380-8
references.pmid: 23945478
references.citation: Psychopharmacology (Berl). 1987;92(2):180-5
references.pmid: 3110839
references.citation: Endocrinology. 1979 May;104(5):1247-55
references.pmid: 571329
references.citation: J Biol Chem. 1998 Jul 10;273(28):17852-8
references.pmid: 9651389
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19182-7
references.pmid: 17148615
references.citation: J Neurochem. 2002 Nov;83(4):955-63
references.pmid: 12421368
references.citation: Pharmacol Biochem Behav. 2008 Dec;91(2):261-70
references.pmid: 18786558
references.citation: Prog Brain Res. 2009;175:219-37
references.pmid: 19660659
references.citation: Ann Neurol. 1995 Mar;37(3):373-80
references.pmid: 7695237
references.citation: Behav Brain Res. 2012 Jan 15;226(2):376-80
references.pmid: 21946309
references.citation: Neuroendocrinology. 2006;83(5-6):336-47
references.pmid: 17028418
references.citation: Neurol Clin. 2008 Aug;26(3):799-819, x
references.pmid: 18657727
references.citation: Ann Emerg Med. 2006 Apr;47(4):381-9
references.pmid: 16546625
references.citation: BMC Neurosci. 2005 Jun 08;6:40
references.pmid: 15943860
references.citation: Psychoneuroendocrinology. 2009 Jul;34(6):909-16
references.pmid: 19216030
references.citation: Horm Behav. 1997 Jun;31(3):197-211
references.pmid: 9213134
references.citation: Menopause Int. 2008 Dec;14(4):163-8
references.pmid: 19037065
references.citation: J Natl Cancer Inst Monogr. 2004;(32):57-71
references.pmid: 15263042
references.citation: Int J Methods Psychiatr Res. 2002;11(2):75-82
references.pmid: 12459797
references.citation: Neurobiol Dis. 2010 Mar;37(3):542-8
references.pmid: 20044002
references.citation: Biol Psychiatry. 2005 Aug 1;58(3):175-89
references.pmid: 16084838
references.citation: Neuroscience. 1991;42(2):309-20
references.pmid: 1654533
references.citation: Immunol Lett. 2009 Aug 15;125(2):151-5
references.pmid: 19607861
references.citation: Behav Brain Res. 2012 Apr 1;229(1):48-56
references.pmid: 22197678
references.citation: J Clin Psychiatry. 2012 Mar;73(3):384-91
references.pmid: 22053858
references.citation: Menopause. 2012 Jul;19(7):820-4
references.pmid: 22549170
references.citation: J Acquir Immune Defic Syndr. 2007 Feb 1;44(2):159-66
references.pmid: 17146374
references.citation: J Exp Anal Behav. 1981 Jan;35(1):31-44
references.pmid: 16812198
references.citation: Am J Pathol. 2003 May;162(5):1693-707
references.pmid: 12707054
references.citation: Mol Cancer Ther. 2005 Jul;4(7):1065-75
references.pmid: 16020664
references.citation: J Steroid Biochem Mol Biol. 1998 Apr;65(1-6):295-9
references.pmid: 9699883
references.citation: Behav Brain Res. 2002 Apr 15;132(1):85-93
references.pmid: 11853861
references.citation: PLoS One. 2012;7(5):e37540
references.pmid: 22629415
references.citation: Am J Obstet Gynecol. 2007 Aug;197(2):144.e1-8
references.pmid: 17689627
references.citation: Psychopharmacology (Berl). 2011 Jan;213(1):93-103
references.pmid: 20878318
references.citation: Menopause. 2014 Feb;21(2):198-206
references.pmid: 24448106
references.citation: Toxicol Appl Pharmacol. 2009 Oct 15;240(2):286-91
references.pmid: 19576918
references.citation: Glia. 2005 Apr 15;50(2):91-106
references.pmid: 15630704
references.citation: AIDS. 1991;5 Suppl 2:S3-14
references.pmid: 1845057
references.citation: Mini Rev Med Chem. 2012 Oct;12(11):1049-54
references.pmid: 22827217
references.citation: J Steroid Biochem Mol Biol. 2005 Feb;94(1-3):263-6
references.pmid: 15862974
references.citation: J Virol. 1996 Mar;70(3):1475-80
references.pmid: 8627665
references.citation: Obstet Gynecol Int. 2013;2013:340309
references.pmid: 24454386
references.citation: Pharmacol Biochem Behav. 2006 Aug;84(4):581-97
references.pmid: 16945406
references.citation: AIDS Care. 2010 Feb;22(2):159-65
references.pmid: 20390494
references.citation: Lancet. 1997 Sep 27;350(9082):922-7
references.pmid: 9314871
references.citation: Brain Behav Immun. 2011 Nov;25(8):1569-75
references.pmid: 21620953
references.citation: J Neurosci. 2008 Nov 26;28(48):12604-13
references.pmid: 19036954
references.citation: EMBO J. 1999 Jul 1;18(13):3688-701
references.pmid: 10393184
references.citation: Horm Behav. 2013 Feb;63(2):291-300
references.pmid: 22626570
references.citation: Prog Neurobiol. 2014 Feb;113:6-39
references.pmid: 24172649
references.citation: J Neuroimmune Pharmacol. 2009 Dec;4(4):430-47
references.pmid: 19768553
references.citation: Proc Soc Exp Biol Med. 1976 Nov;153(2):254-7
references.pmid: 1033549
references.citation: Front Biosci (Schol Ed). 2011 Jan 01;3:474-86
references.pmid: 21196391
references.citation: Psychopharmacology (Berl). 2014 Jun;231(11):2349-60
references.pmid: 24352568
references.citation: Ann N Y Acad Sci. 2006 Nov;1089:218-27
references.pmid: 17261769
references.citation: Br J Pharmacol. 2002 Feb;135(4):901-9
references.pmid: 11861317
references.citation: AIDS Rev. 2010 Apr-Jun;12(2):113-20
references.pmid: 20571605
references.citation: Brain Res. 1999 Jun 5;830(2):285-91
references.pmid: 10366685
references.citation: Med Hypotheses. 2012 May;78(5):672-4
references.pmid: 22386322
references.citation: J Acquir Immune Defic Syndr. 2005 Mar;38 Suppl 1:S18-21
references.pmid: 15867603
references.citation: JAMA. 1993 Jun 9;269(22):2860-4
references.pmid: 8497089
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3774-8
references.pmid: 7731982
references.citation: BMC Neurosci. 2001;2:3
references.pmid: 11252157
references.citation: J Neuroimmunol. 2004 Dec;157(1-2):3-10
references.pmid: 15579274
references.citation: Exp Neurol. 1998 Dec;154(2):276-88
references.pmid: 9878167
references.citation: Trends Neurosci. 2001 Jul;24(7):411-6
references.pmid: 11410272
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2014 Jan 3;48:64-78
references.pmid: 24044974
references.citation: Biochem Biophys Res Commun. 2004 Jan 2;313(1):148-55
references.pmid: 14672711
references.citation: J Pharmacol Exp Ther. 2009 Jun;329(3):1071-83
references.pmid: 19325033
references.citation: AIDS Care. 2006 Jul;18(5):441-5
references.pmid: 16777635
references.citation: Menopause. 2014 Sep;21(9):997-1006
references.pmid: 24496085
references.citation: Physiol Behav. 2001 Aug;73(5):705-17
references.pmid: 11566205
references.citation: Menopause. 2013 Sep;20(9):983-90
references.pmid: 23531684
references.citation: J Neurochem. 1999 Oct;73(4):1363-74
references.pmid: 10501179
references.citation: J Affect Disord. 1993 Oct-Nov;29(2-3):85-96
references.pmid: 8300981
references.citation: J Steroid Biochem Mol Biol. 2013 Nov;138:63-71
references.pmid: 23542659
references.citation: Epilepsia. 2006 Sep;47(9):1423-40
references.pmid: 16981857
references.citation: Synapse. 2011 Nov;65(11):1251-4
references.pmid: 21538554
references.citation: Synapse. 2010 Nov;64(11):829-38
references.pmid: 20340172
references.citation: Front Endocrinol (Lausanne). 2011 Dec 02;2:90
references.pmid: 22654832
references.citation: Synapse. 2006 Jan;59(1):51-60
references.pmid: 16237680
references.citation: Neurobiol Learn Mem. 2006 Jul;86(1):35-46
references.pmid: 16529958
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2013 Jun 3;43:49-54
references.pmid: 23269344
references.citation: PLoS One. 2013 Apr 17;8(4):e62069
references.pmid: 23614015
references.citation: Brain Res. 2011 Mar 16;1379:149-63
references.pmid: 21044614
references.citation: AIDS. 2004 Jan 23;18(2):205-9
references.pmid: 15075537
references.citation: J Steroid Biochem Mol Biol. 2012 Oct;132(1-2):66-72
references.pmid: 22342838
references.citation: Psychosom Med. 1998 Jan-Feb;60(1):11-6
references.pmid: 9492233
references.citation: J Neuroimmunol. 2012 Jun 15;247(1-2):16-24
references.pmid: 22503372
references.citation: Horm Behav. 2001 Dec;40(4):472-82
references.pmid: 11716576
references.citation: AIDS. 2009 Jul 17;23(11):1377-82
references.pmid: 19448528
references.citation: Arch Gen Psychiatry. 2001 Aug;58(8):721-8
references.pmid: 11483137