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  1. Article: BNST GluN2D-containing NMDARs contribute to ethanol intake but not negative affective behaviors in female mice.

    Doyle, Marie A / Salimando, Gregory J / Altemus, Megan E / Badt, Justin K / Bedenbaugh, Michelle N / Vardy, Alexander S / Adank, Danielle N / Park, Anika S / Winder, Danny G

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), ... ...

    Abstract Alcohol use disorder (AUD) is a chronic, relapsing disease, highly comorbid with anxiety and depression. The bed nucleus of the stria terminalis (BNST), and
    Language English
    Publishing date 2024-04-21
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.19.590258
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism.

    Bedenbaugh, Michelle N / Brener, Samantha C / Maldonado, Jose / Lippert, Rachel N / Sweeney, Patrick / Cone, Roger D / Simerly, Richard B

    The Journal of comparative neurology

    2022  Volume 530, Issue 16, Page(s) 2835–2851

    Abstract: The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well- ... ...

    Abstract The central melanocortin system is fundamentally important for controlling food intake and energy homeostasis. Melanocortin-3 receptor (MC3R) is one of two major receptors of the melanocortin system found in the brain. In contrast to the well-characterized melanocortin-4 receptor (MC4R), little is known regarding the organization of MC3R-expressing neural circuits. To increase our understanding of the intrinsic organization of MC3R neural circuits, identify specific differences between males and females, and gain a neural systems level perspective of this circuitry, we conducted a brain-wide mapping of neurons labeled for MC3R and characterized the distribution of their projections. Analysis revealed MC3R neuronal and terminal labeling in multiple brain regions that control a diverse range of physiological functions and behavioral processes. Notably, dense labeling was observed in the hypothalamus, as well as areas that share considerable connections with the hypothalamus, including the cortex, amygdala, thalamus, and brainstem. Additionally, MC3R neuronal labeling was sexually dimorphic in several areas, including the anteroventral periventricular area, arcuate nucleus, principal nucleus of the bed nucleus of the stria terminalis, and ventral premammillary region. Altogether, anatomical evidence reported here suggests that MC3R has the potential to influence several different classes of motivated behavior that are essential for survival, including ingestive, reproductive, defensive, and arousal behaviors, and is likely to modulate these behaviors differently in males and females.
    MeSH term(s) Animals ; Brain/metabolism ; Female ; Hypothalamus/metabolism ; Male ; Melanocortins ; Mice ; Receptor, Melanocortin, Type 3/genetics ; Receptor, Melanocortin, Type 3/metabolism ; Sex Characteristics
    Chemical Substances Mc3r protein, mouse ; Melanocortins ; Receptor, Melanocortin, Type 3
    Language English
    Publishing date 2022-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3086-7
    ISSN 1096-9861 ; 0021-9967 ; 0092-7317
    ISSN (online) 1096-9861
    ISSN 0021-9967 ; 0092-7317
    DOI 10.1002/cne.25379
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: BNST PKCδ neurons are activated by specific aversive conditions to promote anxiety-like behavior.

    Williford, Kellie M / Taylor, Anne / Melchior, James R / Yoon, Hye Jean / Sale, Eryn / Negasi, Milen D / Adank, Danielle N / Brown, Jordan A / Bedenbaugh, Michelle N / Luchsinger, Joseph R / Centanni, Samuel W / Patel, Sachin / Calipari, Erin S / Simerly, Richard B / Winder, Danny G

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2023  Volume 48, Issue 7, Page(s) 1031–1041

    Abstract: The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta ( ... ...

    Abstract The bed nucleus of the stria terminalis (BNST) is a critical mediator of stress responses and anxiety-like behaviors. Neurons expressing protein kinase C delta (BNST
    MeSH term(s) Septal Nuclei/metabolism ; Anxiety ; Central Amygdaloid Nucleus/metabolism ; Neurons/physiology ; Affect
    Language English
    Publishing date 2023-03-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-023-01569-5
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  4. Article ; Online: An ensemble recruited by α

    Brown, Jordan A / Petersen, Nicholas / Centanni, Samuel W / Jin, Allie Y / Yoon, Hye Jean / Cajigas, Stephanie A / Bedenbaugh, Michelle N / Luchsinger, Joseph R / Patel, Sachin / Calipari, Erin S / Simerly, Richard B / Winder, Danny G

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2022  Volume 48, Issue 8, Page(s) 1133–1143

    Abstract: ... ...

    Abstract α
    MeSH term(s) Mice ; Animals ; Guanfacine/pharmacology ; Norepinephrine/pharmacology ; Neurons ; Substance-Related Disorders ; Signal Transduction ; Septal Nuclei
    Chemical Substances Guanfacine (30OMY4G3MK) ; Norepinephrine (X4W3ENH1CV)
    Language English
    Publishing date 2022-09-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-022-01442-x
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  5. Article ; Online: Neuroanatomical Relationship of Neuronal Nitric Oxide Synthase to Gonadotropin-Releasing Hormone and Kisspeptin Neurons in Adult Female Sheep and Primates.

    Bedenbaugh, Michelle N / McCosh, Richard B / Lopez, Justin A / Connors, John M / Goodman, Robert L / Hileman, Stanley M

    Neuroendocrinology

    2018  Volume 107, Issue 3, Page(s) 218–227

    Abstract: Background: Neuronal intermediates that communicate estrogen and progesterone feedback to gonadotropin-releasing hormone (GnRH) neurons are essential for modulating reproductive cyclicity. Individually, kisspeptin and nitric oxide (NO) influence GnRH ... ...

    Abstract Background: Neuronal intermediates that communicate estrogen and progesterone feedback to gonadotropin-releasing hormone (GnRH) neurons are essential for modulating reproductive cyclicity. Individually, kisspeptin and nitric oxide (NO) influence GnRH secretion. However, it is possible these 2 neuronal intermediates interact with one another to affect reproductive cyclicity.
    Methods: We investigated the neuroanatomical relationship of one isoform of the enzyme that synthesizes NO, neuronal NO synthase (nNOS), to kisspeptin and GnRH in adult female rhesus monkeys and sheep using dual-label immunofluorescence. Additionally, we evaluated if the phase of the reproductive cycle would affect these relationships.
    Results: Overall, no effect of the stage of cycle was observed for any variable in this study. In the arcuate nucleus (ARC) of sheep, 98.8 ± 3.5% of kisspeptin neurons colocalized with nNOS, and kisspeptin close-contacts were observed onto nNOS neurons. In contrast to ewes, no colocalization was observed between kisspeptin and nNOS in the infundibular ARC of primates, but kisspeptin fibers were apposed to nNOS neurons. In the preoptic area of ewes, 15.0 ± 4.2% of GnRH neurons colocalized with nNOS. In primates, 38.8 ± 10.1% of GnRH neurons in the mediobasal hypothalamus colocalized with nNOS, and GnRH close-contacts were observed onto nNOS neurons in both sheep and primates.
    Conclusion: Although species differences were observed, this work establishes a neuroanatomical framework between nNOS and kisspeptin and nNOS and GnRH in adult female nonhuman primates and sheep.
    MeSH term(s) Animals ; Female ; Gonadotropin-Releasing Hormone/metabolism ; Hypothalamus/metabolism ; Kisspeptins/metabolism ; Macaca mulatta ; Neurons/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Pituitary Gland/metabolism ; Preoptic Area/metabolism ; Protein Isoforms/metabolism ; Reproduction/physiology ; Sheep
    Chemical Substances Kisspeptins ; Protein Isoforms ; Gonadotropin-Releasing Hormone (33515-09-2) ; Nitric Oxide Synthase Type I (EC 1.14.13.39)
    Language English
    Publishing date 2018-06-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 123303-8
    ISSN 1423-0194 ; 0028-3835
    ISSN (online) 1423-0194
    ISSN 0028-3835
    DOI 10.1159/000491393
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  6. Article ; Online: Regulation of GnRH pulsatility in ewes.

    Nestor, Casey C / Bedenbaugh, Michelle N / Hileman, Stanley M / Coolen, Lique M / Lehman, Michael N / Goodman, Robert L

    Reproduction (Cambridge, England)

    2018  Volume 156, Issue 3, Page(s) R83–R99

    Abstract: Early work in ewes provided a wealth of information on the physiological regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by internal and external inputs. Identification of the neural systems involved, however, was limited by the ... ...

    Abstract Early work in ewes provided a wealth of information on the physiological regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by internal and external inputs. Identification of the neural systems involved, however, was limited by the lack of information on neural mechanisms underlying generation of GnRH pulses. Over the last decade, considerable evidence supported the hypothesis that a group of neurons in the arcuate nucleus that contain kisspeptin, neurokinin B and dynorphin (KNDy neurons) are responsible for synchronizing secretion of GnRH during each pulse in ewes. In this review, we describe our current understanding of the neural systems mediating the actions of ovarian steroids and three external inputs on GnRH pulsatility in light of the hypothesis that KNDy neurons play a key role in GnRH pulse generation. In breeding season adults, estradiol (E
    MeSH term(s) Animals ; Arcuate Nucleus of Hypothalamus/physiology ; Breeding ; Dynorphins/physiology ; Estradiol/pharmacology ; Estrous Cycle ; Feedback, Physiological ; Female ; Gonadotropin-Releasing Hormone/metabolism ; Homeostasis/physiology ; Kisspeptins/physiology ; Luteinizing Hormone/metabolism ; Neurokinin B/physiology ; Neurons/physiology ; Periodicity ; Progesterone/pharmacology ; Seasons ; Sexual Maturation/physiology ; Sheep/physiology
    Chemical Substances Kisspeptins ; Gonadotropin-Releasing Hormone (33515-09-2) ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E) ; Dynorphins (74913-18-1) ; Neurokinin B (86933-75-7) ; Luteinizing Hormone (9002-67-9)
    Language English
    Publishing date 2018-06-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 2034501-X
    ISSN 1741-7899 ; 1470-1626 ; 1476-3990
    ISSN (online) 1741-7899
    ISSN 1470-1626 ; 1476-3990
    DOI 10.1530/REP-18-0127
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  7. Article ; Online: Morphological and functional evidence for sexual dimorphism in neurokinin B signalling in the retrochiasmatic area of sheep.

    Lopez, Justin A / Bowdridge, Elizabeth C / McCosh, Richard B / Bedenbaugh, Michelle N / Lindo, Ashley N / Metzger, Makayla / Haller, Megan / Lehman, Michael N / Hileman, Stanley M / Goodman, Robert L

    Journal of neuroendocrinology

    2020  Volume 32, Issue 7, Page(s) e12877

    Abstract: Neurokinin B (NKB) is critical for fertility in humans and stimulates gonadotrophin-releasing hormone/luteinising hormone (LH) secretion in several species, including sheep. There is increasing evidence that the actions of NKB in the retrochiasmatic area ...

    Abstract Neurokinin B (NKB) is critical for fertility in humans and stimulates gonadotrophin-releasing hormone/luteinising hormone (LH) secretion in several species, including sheep. There is increasing evidence that the actions of NKB in the retrochiasmatic area (RCh) contribute to the induction of the preovulatory LH surge in sheep. In the present study, we determined whether there are sex differences in the response to RCh administration of senktide, an agonist to the NKB receptor (neurokinin receptor-3 [NK3R]), and in NKB and NK3R expression in the RCh of sheep. To normalise endogenous hormone concentrations, animals were gonadectomised and given implants to mimic the pattern of ovarian steroids seen in the oestrous cycle. In females, senktide microimplants in the RCh produced an increase in LH concentrations that lasted for at least 8 hours after the start of treatment, whereas a much shorter increment (approximately 2 hours) was seen in males. We next collected tissue from gonadectomised lambs 18 hours after the insertion of oestradiol implants that produce an LH surge in female, but not male, sheep for immunohistochemical analysis of NKB and NK3R expression. As expected, there were more NKB-containing neurones in the arcuate nucleus of females than males. Interestingly, there was a similar sexual dimorphism in NK3R-containing neurones in the RCh, NKB-containing close contacts onto these RCh NK3R neurones, and overall NKB-positive fibres in this region. These data demonstrate that there are both functional and morphological sex differences in NKB-NK3R signalling in the RCh and raise the possibility that this dimorphism contributes to the sex-dependent ability of oestradiol to induce an LH surge in female sheep.
    MeSH term(s) Animals ; Arcuate Nucleus of Hypothalamus/metabolism ; Female ; Hypothalamus, Middle/metabolism ; Kisspeptins/metabolism ; Male ; Neurokinin B/metabolism ; Neurons/metabolism ; Receptors, Tachykinin/metabolism ; Sex Characteristics ; Sheep ; Signal Transduction/physiology
    Chemical Substances Kisspeptins ; Receptors, Tachykinin ; neurokinin receptor 4 ; Neurokinin B (86933-75-7)
    Language English
    Publishing date 2020-06-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1007517-3
    ISSN 1365-2826 ; 0953-8194
    ISSN (online) 1365-2826
    ISSN 0953-8194
    DOI 10.1111/jne.12877
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  8. Article ; Online: Evidence that Nitric Oxide Is Critical for LH Surge Generation in Female Sheep.

    McCosh, Richard B / Lopez, Justin A / Szeligo, Brett M / Bedenbaugh, Michelle N / Hileman, Stanley M / Coolen, Lique M / Lehman, Michael N / Goodman, Robert L

    Endocrinology

    2020  Volume 161, Issue 3

    Abstract: Elevated and sustained estradiol concentrations cause a gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) surge that is necessary for ovulation. In sheep, several different neural systems have been implicated in this stimulatory action ... ...

    Abstract Elevated and sustained estradiol concentrations cause a gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) surge that is necessary for ovulation. In sheep, several different neural systems have been implicated in this stimulatory action of estradiol and this study focused on somatostatin (SST) neurons in the ventral lateral region of the ventral medial nucleus (vlVMN) which express c-Fos during the surge. First, we determined if increased activity of SST neurons could be related to elevated GnRH secretion by assessing SST synapses onto GnRH neurons and neurons coexpressing kisspeptin, neurokinin B, dynorphin (KNDy). We found that the percentage of preoptic area GnRH neurons that receive SST input increased during the surge compared with other phases of the cycle. However, since SST is generally inhibitory, and pharmacological manipulation of SST signaling did not alter the LH surge in sheep, we hypothesized that nitric oxide (NO) was also produced by these neurons to account for their activation during the surge. In support of this hypothesis we found that (1) the majority of SST cells in the vlVMN (>80%) contained neuronal nitric oxide synthase (nNOS); (2) the expression of c-Fos in dual-labeled SST-nNOS cells, but not in single-labeled cells, increased during the surge compared with other phases of the cycle; and (3) intracerebroventricular (ICV) infusion of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, completely blocked the estrogen-induced LH surge. These data support the hypothesis that the population of SST-nNOS cells in the vlVMN are a source of NO that is critical for the LH surge, and we propose that they are an important site of estradiol positive feedback in sheep.
    MeSH term(s) Animals ; Female ; Luteinizing Hormone/blood ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Ovulation ; Sheep/blood ; Somatostatin/metabolism ; Ventromedial Hypothalamic Nucleus/enzymology
    Chemical Substances Nitric Oxide (31C4KY9ESH) ; Somatostatin (51110-01-1) ; Luteinizing Hormone (9002-67-9) ; Nitric Oxide Synthase Type I (EC 1.14.13.39)
    Language English
    Publishing date 2020-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqaa010
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  9. Article ; Online: The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.

    Sweeney, Patrick / Bedenbaugh, Michelle N / Maldonado, Jose / Pan, Pauline / Fowler, Katelyn / Williams, Savannah Y / Gimenez, Luis E / Ghamari-Langroudi, Masoud / Downing, Griffin / Gui, Yijun / Hadley, Colleen K / Joy, Stephen T / Mapp, Anna K / Simerly, Richard B / Cone, Roger D

    Science translational medicine

    2021  Volume 13, Issue 590

    Abstract: Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of ... ...

    Abstract Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
    MeSH term(s) Animals ; Anorexia/drug therapy ; Feeding Behavior ; Female ; Hypothalamus/metabolism ; Male ; Mice ; Neurons/metabolism ; Receptor, Melanocortin, Type 3/metabolism
    Chemical Substances Receptor, Melanocortin, Type 3
    Language English
    Publishing date 2021-04-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.abd6434
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  10. Article ; Online: Localization of kisspeptin, NKB, and NK3R in the hypothalamus of gilts treated with the progestin altrenogest.

    Lindo, Ashley N / Thorson, Jennifer F / Bedenbaugh, Michelle N / McCosh, Richard B / Lopez, Justin A / Young, Samantha A / Meadows, Lanny J / Bowdridge, Elizabeth C / Fergani, Chrysanthi / Freking, Bradley A / Lehman, Michael N / Hileman, Stanley M / Lents, Clay A

    Biology of reproduction

    2021  Volume 105, Issue 4, Page(s) 1056–1067

    Abstract: Mechanisms in the brain controlling secretion of gonadotropin hormones in pigs, particularly luteinizing hormone (LH), are poorly understood. Kisspeptin is a potent LH stimulant that is essential for fertility in many species, including pigs. Neurokinin ... ...

    Abstract Mechanisms in the brain controlling secretion of gonadotropin hormones in pigs, particularly luteinizing hormone (LH), are poorly understood. Kisspeptin is a potent LH stimulant that is essential for fertility in many species, including pigs. Neurokinin B (NKB) acting through neurokinin 3 receptor (NK3R) is involved in kisspeptin-stimulated LH release, but organization of NKB and NK3R within the porcine hypothalamus is unknown. Hypothalamic tissue from ovariectomized (OVX) gilts was used to determine the distribution of immunoreactive kisspeptin, NKB, and NK3R cells in the arcuate nucleus (ARC). Almost all kisspeptin neurons coexpressed NKB in the porcine ARC. Immunostaining for NK3R was distributed throughout the preoptic area (POA) and in several hypothalamic areas including the periventricular and retrochiasmatic areas but was not detected within the ARC. There was no colocalization of NK3R with gonadotropin-releasing hormone (GnRH), but NK3R-positive fibers in the POA were in close apposition to GnRH neurons. Treating OVX gilts with the progestin altrenogest decreased LH pulse frequency and reduced mean circulating concentrations of LH compared with OVX control gilts (P < 0.01), but the number of kisspeptin and NKB cells in the ARC did not differ between treatments. The neuroanatomical arrangement of kisspeptin, NKB, and NK3R within the porcine hypothalamus confirms they are positioned to stimulate GnRH and LH secretion in gilts, though differences with other species exist. Altrenogest suppression of LH secretion in the OVX gilt does not appear to involve decreased peptide expression of kisspeptin or NKB.
    MeSH term(s) Animals ; Female ; Gene Expression Profiling/veterinary ; Hypothalamus/drug effects ; Hypothalamus/metabolism ; Kisspeptins/genetics ; Kisspeptins/metabolism ; Neurokinin B/genetics ; Neurokinin B/metabolism ; Progestins/pharmacology ; Receptors, Neurokinin-3/genetics ; Receptors, Neurokinin-3/metabolism ; Sus scrofa/genetics ; Sus scrofa/metabolism ; Trenbolone Acetate/analogs & derivatives ; Trenbolone Acetate/pharmacology
    Chemical Substances Kisspeptins ; Progestins ; Receptors, Neurokinin-3 ; altrenogest (2U0X0JA2NB) ; Neurokinin B (86933-75-7) ; Trenbolone Acetate (RUD5Y4SV0S)
    Language English
    Publishing date 2021-05-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1118-6
    ISSN 1529-7268 ; 0006-3363
    ISSN (online) 1529-7268
    ISSN 0006-3363
    DOI 10.1093/biolre/ioab103
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