title: Altered GABAA receptor-mediated synaptic transmission disrupts the firing of gonadotropin-releasing hormone neurons in male mice under conditions that mimic steroid abuse.
abstract: 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.
authors.affiliation: Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Carlos A A
authors.initials: CA
authors.lastname: Penatti
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Davis
authors.forename: Donna M
authors.initials: DM
authors.lastname: Porter
authors.forename: Leslie P
authors.initials: LP
authors.lastname: Henderson
mesh_terms: 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
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D006062:Gonadotropins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D008777:Methyltestosterone
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