title: Motivated behaviors and levels of 3α,5α-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats.
abstract: BACKGROUND
  Progesterone (P4 ) and its product, 5α-pregnan-3α-ol-20-one (3α,5α-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3α,5α-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats.
  
  
  OBJECTIVE
  The role of PXR in the midbrain for 3α,5α-THP formation, which precedes modulation of motivated behaviors, was investigated.
  
  
  METHODS
  Rats had estrous cycle phase determined and were assessed when they were in diestrus or proestrus. Diestrous and proestrous rats were infused with control or antisense oligodeoxyribonucleotides (AS-ODNs) targeted against PXR to the VTA.
  
  
  METHODS
  In pilot studies, PXR gene and protein expression in the midbrain were determined with quantitative reverse transcriptase polymerase chain reaction and Western blotting, respectively. Diestrous and proestrous rats infused with control or AS-ODNs to the VTA were tested for anxiety (open field and plus maze), social (social interaction), and sexual (paced mating) behavior. Expression of PXR in the midbrain was verified with Western blotting. Plasma estradiol, P4 , dihydroprogesterone (DHP), and 3α,5α-THP levels, and brain P4 , DHP, and 3α,5α-THP levels were measured. We predicted that proestrous rats infused with PXR AS-ODNs would have decreased anti-anxiety, social, and sexual behavior, lower midbrain expression of PXR, and lower midbrain levels of 3α,5α-THP compared with controls.
  
  
  RESULTS
  Results supported the hypothesis that formation of 3α,5α-THP requires PXR and may be important for motivated behaviors. PXR AS-ODN, compared with control, infusions to the VTA reduced PXR expression and 3α,5α-THP levels in the midbrain and attenuated sexual receptivity of proestrous rats.
  
  
  CONCLUSIONS
  Knockdown of PXR in the midbrain reduces 3α,5α-THP levels and sexual receptivity of proestrous rats. Thus, PXR in the midbrain may be required for the observed increase in 3α-5α-THP during proestrus, which has subsequent effects on motivated, reproductive behaviors.
authors: Department of Psychology, The University at Albany-SUNY, Albany, NY, USA. cafrye@alaska.edu
authors: Cheryl Anne
authors: CA
authors: Frye
authors: Carolyn J
authors: CJ
authors: Koonce
authors: Alicia A
authors: AA
authors: Walf
authors: Jamie C
authors: JC
authors: Rusconi
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D004958:Estradiol / Q000097:blood / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D007398:Interpersonal Relations; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D009042:Motivation; D000077297:Pregnane X Receptor; D011280:Pregnanolone / Q000097:blood / Q000378:metabolism*; D011359:Proestrus / Q000097:blood / Q000378:metabolism*; D011374:Progesterone / Q000097:blood / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012098:Reproduction; D012726:Sexual Behavior, Animal; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011374:Progesterone; D004958:Estradiol; D011280:Pregnanolone
keywords: Allopregnanolone; Lordosis; Mating; Neurosteroids; Progesterone; Receptivity
references: J Steroid Biochem. 1975 Sep;6(9):1307-10
references: 1181486
references: Horm Behav. 2009 Oct;56(4):410-5
references: 19646448
references: Behav Brain Res. 2008 Nov 21;193(2):269-76
references: 18590775
references: Horm Behav. 1997 Oct;32(2):114-24
references: 9367719
references: Horm Behav. 2010 Apr;57(4-5):474-80
references: 20171966
references: Drug Metab Pharmacokinet. 2008;23(1):14-21
references: 18305371
references: J Steroid Biochem. 1985 Jan;22(1):97-102
references: 3974231
references: Physiol Behav. 1981 Apr;26(4):631-5
references: 7196588
references: Reproduction. 2009 Jan;137(1):119-28
references: 18818272
references: Front Neurosci. 2012 Jan 19;5:136
references: 22294977
references: Horm Behav. 2004 Aug;46(2):151-7
references: 15256304
references: Mol Pharmacol. 2004 Sep;66(3):413-9
references: 15322232
references: Brain Res. 2011 Mar 16;1379:137-48
references: 21070751
references: Pharmacol Biochem Behav. 2002 Jul;72(4):923-9
references: 12062582
references: Neuroendocrinology. 1981 Sep;33(3):158-65
references: 6117024
references: Behav Brain Res. 2011 Sep 12;222(1):223-9
references: 21463656
references: Pharmacol Biochem Behav. 2008 Dec;91(2):261-70
references: 18786558
references: Neuroendocrinology. 2006;83(5-6):336-47
references: 17028418
references: Br J Pharmacol. 1976 Mar;56(3):382P-382P
references: 1260208
references: Reproduction. 2007 Mar;133(3):663-74
references: 17379660
references: Recent Prog Horm Res. 1999;54:345-67; discussion 367-8
references: 10548883
references: Neuroscience. 2003;120(2):523-33
references: 12890521
references: J Sex Med. 2012 Dec;9(12):3180-8
references: 23057791
references: Behav Neurosci. 1997 Feb;111(1):123-8
references: 9109630
references: J Sex Med. 2012 Mar;9(3):694-707
references: 22304661
references: Trends Pharmacol Sci. 2006 Aug;27(8):402-9
references: 16822554
references: Behav Brain Res. 2008 Feb 11;187(1):88-99
references: 17919744
references: Biol Reprod. 1986 Oct;35(3):516-23
references: 3790654
references: J Steroid Biochem Mol Biol. 1992 Jun;42(5):439-47
references: 1616873
references: Life Sci. 2007 Feb 13;80(10):910-7
references: 17161434
references: Mol Cell Endocrinol. 2001 Feb 14;172(1-2):47-56
references: 11165039
references: J Biol Chem. 2000 May 19;275(20):15122-7
references: 10748001
references: Endocrinology. 2005 Oct;146(10):4386-90
references: 16020475
references: Steroids. 2008 Oct;73(9-10):906-13
references: 18342351
references: Pharmacol Biochem Behav. 2000 Nov;67(3):587-96
references: 11164090
references: J Neuroendocrinol. 2005 Sep;17(9):545-52
references: 16101892
references: J Neurosci. 2002 Dec 15;22(24):10613-20
references: 12486153
references: Toxicol Appl Pharmacol. 2004 Sep 15;199(3):251-65
references: 15364541
references: J Endocrinol Invest. 2011 Jul-Aug;34(7):e188-99
references: 21060252
references: Brain Res. 1998 Oct 12;808(1):72-83
references: 9795145
references: J Sex Med. 2012 Mar;9(3):793-804
references: 22239862
references: Pharmacol Biochem Behav. 2007 Feb;86(2):209-19
references: 16979750
references: Brain Res. 1993 Dec 3;629(2):283-92
references: 8111631
references: Behav Brain Res. 2007 Dec 3;184(2):174-84
references: 17707520
references: J Neuroendocrinol. 2006 Dec;18(12):960-75
references: 17076771
references: J Sex Med. 2010 May;7(5):1757-67
references: 20163532
references: J Reprod Fertil. 1990 Nov;90(2):375-85
references: 2250236
references: J Sex Med. 2011 Jan;8(1):15-27
references: 20840530
references: J Sex Med. 2012 Apr;9(4):1074-85
references: 22248038
references: Endocrinology. 1973 Nov;93(5):1157-62
references: 4591653
references: Brain Res. 2004 Apr 9;1004(1-2):116-24
references: 15033426
references: J Sex Med. 2013 May;10(5):1231-9
references: 23421417
references: Pharmacol Biochem Behav. 1997 Feb;56(2):261-4
references: 9050083
references: Pharmacol Biochem Behav. 2008 May;89(3):292-7
references: 18255131