Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse.
Gonadotropin-releasing hormone (GnRH) neurons are the central regulators of reproduction. GABAergic transmission plays a critical role in pubertal activation of pulsatile GnRH secretion. Self-administration of excessive doses of anabolic androgenic steroids (AAS) disrupts reproductive function and may have critical repercussions for pubertal onset in adolescent users. Here, we demonstrate that chronic treatment of adolescent male mice with the AAS 17alpha-methyltestosterone significantly decreased action potential frequency in GnRH neurons, reduced the serum gonadotropin levels, and decreased testes mass. AAS treatment did not induce significant changes in GABAA receptor subunit mRNA levels or alter the amplitude or decay kinetics of GABAA receptor-mediated spontaneous postsynaptic currents (sPSCs) or tonic currents in GnRH neurons. However, AAS treatment significantly increased action potential frequency in neighboring medial preoptic area (mPOA) neurons and GABAA receptor-mediated sPSC frequency in GnRH neurons. In addition, physical isolation of the more lateral aspects of the mPOA from the medially localized GnRH neurons abrogated the AAS-induced increase in GABAA receptor-mediated sPSC frequency and the decrease in action potential firing in the GnRH cells. Our results indicate that AAS act predominantly on steroid-sensitive presynaptic neurons within the mPOA to impart significant increases in GABAA receptor-mediated inhibitory tone onto downstream GnRH neurons, resulting in diminished activity of these pivotal mediators of reproductive function. These AAS-induced changes in central GABAergic circuits of the forebrain may significantly contribute to the disruptive actions of these drugs on pubertal maturation and the development of reproductive competence in male steroid abusers.
Penatti
Carlos A A
CA
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Davis
Matthew C
MC
Porter
Donna M
DM
Henderson
Leslie P
LP
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D045930:Anabolic Agents / Q000633:toxicity*; D000728:Androgens / Q000633:toxicity; D000818:Animals; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006062:Gonadotropins / Q000097:blood; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008777:Methyltestosterone / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011301:Preoptic Area / Q000187:drug effects / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013737:Testis / Q000187:drug effects / Q000473:pathology
D045930:Anabolic Agents; D000728:Androgens; D006062:Gonadotropins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D008777:Methyltestosterone
Endocrinology. 2003 May;144(5):2055-67
12697714
Neuropharmacology. 2002 Sep;43(4):634-45
12367608
Endocrinology. 2001 Jul;142(7):3261-4
11416051
Eur J Neurosci. 2000 Mar;12(3):810-8
10762310
Steroids. 2003 Mar;68(3):235-43
12628686
Biol Reprod. 2009 Aug;81(2):327-32
19357366
J Physiol. 2006 Jun 15;573(Pt 3):571-93
16543268
J Androl. 2002 Sep-Oct;23(5):661-8
12185100
Endocrinology. 2003 Aug;144(8):3351-8
12865313
Pharmacol Biochem Behav. 2006 Mar;83(3):410-9
16603236
Endocrinology. 2008 Nov;149(11):5335-44
18703628
Endocrinology. 1977 Jan;100(1):122-7
11987
Mol Cell Endocrinol. 2006 Jul 25;254-255:32-8
16781054
Nucleic Acids Res. 2002 May 1;30(9):e36
11972351
Brain Res Rev. 2008 Mar;57(2):277-87
17604108
Horm Behav. 2008 Feb;53(2):378-85
18201704
Trends Endocrinol Metab. 2002 Dec;13(10):409-10
12431832
J Neurosci. 2009 Oct 7;29(40):12484-96
19812324
J Neurosci. 2009 Apr 29;29(17):5616-27
19403828
Horm Behav. 2007 Jun;52(1):45-55
17499249
J Comp Neurol. 1997 Aug 11;384(4):569-79
9259490
J Neuroendocrinol. 2000 Dec;12(12):1200-4
11106978
Neurosci Res. 2003 Aug;46(4):399-405
12871761
Endocrinology. 2007 Sep;148(9):4344-51
17569755
Neuropharmacology. 2007 Jun;52(7):1439-53
17433821
Endocrinology. 1996 Oct;137(10):4167-73
8828473
Endocrinology. 2005 Oct;146(10):4312-20
15976055
J Comp Neurol. 2006 Jan 1;494(1):190-214
16304687
Brain Res. 1999 Aug 21;839(1):209-12
10482817
Neuron. 1997 Sep;19(3):697-709
9331359
J Comp Neurol. 1988 Apr 8;270(2):209-42
3259955
Front Neuroendocrinol. 2003 Apr;24(2):79-93
12762999
Endocrinology. 2003 Nov;144(11):4967-74
12960087
Neuroscience. 2009 Jun 30;161(2):526-37
19324077
Neuroscience. 2005;135(2):533-43
16112473
BMC Biotechnol. 2008 Feb 06;8:10
18254955
Biol Reprod. 1995 Jul;53(1):103-9
7669840
J Neuroendocrinol. 1997 Sep;9(9):699-706
9355037
J Neurochem. 2005 Sep;94(6):1639-51
16011741
Drug Alcohol Depend. 2008 Nov 1;98(1-2):1-12
18599224
J Neurosci. 2009 Aug 5;29(31):9809-18
19657033
Endocrinology. 2002 Feb;143(2):544-50
11796509
J Comp Neurol. 1997 Jul 21;384(1):142-64
9214545
J Neuroendocrinol. 2009 Mar;21(4):305-11
19207812
Endocrinology. 2004 Feb;145(2):495-9
14617578
NIDA Res Monogr. 1990;102:113-30
2079969
Endocrinology. 2008 Jul;149(7):3598-604
18372332
Mol Cell Endocrinol. 2004 Feb 12;214(1-2):63-70
15062545
Ann N Y Acad Sci. 2003 Dec;1007:189-98
14993053
Endocrinology. 1973 Apr;92(4):1223-8
4686318
Brain Res. 2006 Dec 18;1126(1):122-38
17010954
Biol Reprod. 2006 May;74(5):931-7
16452459
Neuroendocrinology. 1992 Jan;55(1):28-34
1319004
Neuropharmacology. 2002 Sep;43(4):619-33
12367607
Endocrinology. 2002 Apr;143(4):1459-66
11897704
Endocrinology. 2005 Dec;146(12):5374-9
16123153
J Neurosci. 2007 Feb 21;27(8):1913-21
17314287
Horm Behav. 2008 May;53(5):647-58
18343381
Neuron. 2004 Aug 5;43(3):313-9
15294140
Fed Proc. 1970 Nov-Dec;29(6):1880-7
5529888
Endocrinology. 2000 Jan;141(1):412-9
10614664
Brain Res Mol Brain Res. 2003 Jan 31;110(1):7-14
12573528
Endocrinology. 2004 Jul;145(7):3055-61
14976146
Neuroendocrinology. 2001 Nov;74(5):300-8
11694762
Endocrinology. 1982 Dec;111(6):2055-61
6814897
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Anim Reprod Sci. 2000 Jul 2;60-61:313-26
10844203
Sports Med. 2000 Jun;29(6):397-405
10870866
J Neuroendocrinol. 2008 May;20(5):566-75
18363808
Brain Res. 2003 Mar 28;967(1-2):285-9
12650990
Brain Res. 2000 Oct 6;879(1-2):29-41
11011003
J Neurosci. 2009 Mar 25;29(12):3920-9
19321788
Neuroendocrinology. 2002 Nov;76(5):290-6
12457040
J Neurosci Methods. 2001 Jan 15;104(2):155-63
11164241
Brain Res. 1996 Dec 2;742(1-2):163-71
9117390
Methods. 2001 Dec;25(4):402-8
11846609
Neuroscience. 2005;131(4):945-51
15749347
Endocrinology. 2008 Mar;149(3):1155-62
18079199
Endocrinology. 1998 Apr;139(4):1594-601
9528939
Am J Physiol. 1999 Apr;276(4):E603-10
10198294
Endocrinology. 2008 Jul;149(7):3355-60
18403488
J Neuroendocrinol. 2002 May;14(5):375-83
12000543
Nucleic Acids Res. 2003 Jul 15;31(14):e73
12853650
Endocrinology. 2006 Mar;147(3):1166-74
16373420
Neuroscience. 2005;132(3):703-12
15837132
J Comput Neurosci. 2009 Feb;26(1):39-53
18461432
Brain Res Mol Brain Res. 1997 Jul;47(1-2):125-33
9221909
Neurosci Biobehav Rev. 2003 Aug;27(5):413-36
14505684
Neuroscience. 2004;127(1):243-50
15219686
Nat Rev Neurosci. 2005 Mar;6(3):215-29
15738957
J Neurosci. 1998 Apr 15;18(8):3003-13
9526017
Experientia. 1985 Nov 15;41(11):1414-6
4065295
Endocrinology. 2004 Oct;145(10):4500-6
15205372
J Pharmacol Exp Ther. 2001 Oct;299(1):21-30
11561059
Mol Endocrinol. 2002 Oct;16(10):2255-65
12351691
Mol Endocrinol. 2008 Oct;22(10):2250-9
18701637
J Comp Neurol. 1990 Apr 1;294(1):76-95
2324335
Anaesthesia. 2005 Jul;60(7):685-92
15960720
J Adolesc Health. 2002 Apr;30(4):243-52
11927236
Eur J Neurosci. 2000 Oct;12(10):3497-504
11029619