TY - JOUR
T1 - Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques
AU - Bethea, Cynthia L.
AU - Phu, Kenny
AU - Belikova, Yelena
AU - Bethea, Sarah C.
N1 - Funding Information:
We are very grateful to Kevin Muller for training the animals, administering drugs and monitoring the health and wellbeing of the animals. We greatly appreciate Dr. Kris Coleman and Nicola Robertson for earlier behavioral observations and analysis. We thank the Primate Genetics Program at the Oregon National Primate Research Center for calculations of the relatedness of our animals. We are also grateful to Dr. Jay Welch and the technicians of the Division of Comparative Medicine (DCM), for the management and care of our animals. We thank the Surgery and Pathology Sections of DCM for their expertise and handling of our needed surgeries and necropsies. This work was funded by an NIH grant MH 86542 to CLB and P51 OD11092 for support of the Oregon National Primate Research Center .
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - We previously showed that tryptophan hydroxylase 2 (TPH2) and serotonin reuptake transporter (SERT) mRNAs are increased by the androgens, testosterone (T) and dihydrotestosterone (DHT) in serotonin neurons of male macaques. In addition, we observed that serotonin in axons of a terminal region were markedly decreased by aromatase inhibition and lack of estradiol (E) from metabolism of T. These observations implicated androgen receptors (AR) and estrogen receptors (ER) in the transduction of steroid hormone actions in serotonin neurons. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. We used single and double immunohistochemistry to quantitate and phenotypically localize AR, ERα and ERβ in the dorsal raphe of male macaques. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with [1] placebo, [2] T, [3] DHT (non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) plus ATD (n= 5/group). After single labeling of each receptor, quantitative image analysis was applied and receptor positive neurons were counted. Double-label of raphe neurons for each receptor plus TPH2 determined whether the receptors were localized in serotonin neurons. There were significantly more AR-positive neurons in T- and DHT. +. ATD-treated groups (p= 0.0014) compared to placebo or FLUT. +. ATD-treated groups. There was no difference in the number of positive-neurons stained for ERα or ERβ{dot operator} Double-immunohistochemistry revealed that serotonin neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, approximately 40% of dorsal raphe serotonin neurons contained ERα or ERβ{dot operator} In conclusion, the stimulatory effect of androgens on TPH2 and SERT mRNA expression is mediated indirectly by neighboring neurons contain AR. The stimulatory effect of E, derived from T metabolism, on serotonin transport is partially mediated directly via nuclear ERs.
AB - We previously showed that tryptophan hydroxylase 2 (TPH2) and serotonin reuptake transporter (SERT) mRNAs are increased by the androgens, testosterone (T) and dihydrotestosterone (DHT) in serotonin neurons of male macaques. In addition, we observed that serotonin in axons of a terminal region were markedly decreased by aromatase inhibition and lack of estradiol (E) from metabolism of T. These observations implicated androgen receptors (AR) and estrogen receptors (ER) in the transduction of steroid hormone actions in serotonin neurons. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. We used single and double immunohistochemistry to quantitate and phenotypically localize AR, ERα and ERβ in the dorsal raphe of male macaques. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with [1] placebo, [2] T, [3] DHT (non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) plus ATD (n= 5/group). After single labeling of each receptor, quantitative image analysis was applied and receptor positive neurons were counted. Double-label of raphe neurons for each receptor plus TPH2 determined whether the receptors were localized in serotonin neurons. There were significantly more AR-positive neurons in T- and DHT. +. ATD-treated groups (p= 0.0014) compared to placebo or FLUT. +. ATD-treated groups. There was no difference in the number of positive-neurons stained for ERα or ERβ{dot operator} Double-immunohistochemistry revealed that serotonin neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, approximately 40% of dorsal raphe serotonin neurons contained ERα or ERβ{dot operator} In conclusion, the stimulatory effect of androgens on TPH2 and SERT mRNA expression is mediated indirectly by neighboring neurons contain AR. The stimulatory effect of E, derived from T metabolism, on serotonin transport is partially mediated directly via nuclear ERs.
KW - Androgen receptors
KW - Estrogen receptors
KW - Macaque
KW - Male
KW - Serotonin
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UR - http://www.scopus.com/inward/citedby.url?scp=84936863197&partnerID=8YFLogxK
U2 - 10.1016/j.jchemneu.2015.04.001
DO - 10.1016/j.jchemneu.2015.04.001
M3 - Article
C2 - 25908331
AN - SCOPUS:84936863197
SN - 0891-0618
VL - 66-67
SP - 19
EP - 27
JO - Journal of Chemical Neuroanatomy
JF - Journal of Chemical Neuroanatomy
ER -