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N G Simon

Publications and source records attributed to N G Simon.

At least 19 recordsLinked to original sources
PubMed1999

Neural androgen receptor regulation: effects of androgen and antiandrogen.

Androgens exert profound effects on the organization and function of the central nervous system. These effects are mediated by the androgen receptor (AR), a ligand-dependent transcription factor. The mechanisms of AR regulation in neural tissue, however, remain to be fully elucidated. Characterizing this process can provide important information regarding receptor function and AR gene regulation in the brain. Previously, it was shown that testosterone (T) up-regulated neural AR in a dose-dependent manner in both male and female mice. In the present study, whether AR was differentially regulated by the natural agonists T and dihydrotestosterone (DHT) or the nonsteroidal antagonist flutamide (FLU) was assessed. Males were gonadectomized and AR levels were allowed to decline to baseline 3 days after surgery. Changes in AR protein content produced by the various treatments were measured by semiquantitative Western blot of limbic system extracts. Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR. The antiandrogen FLU failed to up-regulate AR at doses up to 100 times higher than T or DHT. When administered concomitantly with T or DHT, it effectively inhibited the augmentation of AR normally seen 3 h after androgen treatment. While immunohistochemical studies showed that FLU was able to promote nuclear translocation of AR, Western analysis revealed that FLU, in contrast to T and DHT, failed to maintain the integrity of AR. The results demonstrate that (a) the endogenous androgens T and DHT regulate AR differently, suggesting a potential cellular mechanism that may contribute to the difference in neural target gene sensitivity to these androgens; (b) up-regulation of AR occurs only in the presence of agonists; (c) the mechanism of action of FLU in the brain involves inhibition of AR protein up-regulation normally seen in response to androgen; and (d) FLU promotes AR nuclear translocation but not augmentation of cellular AR populations. These findings demonstrate that in vivo AR regulation in the brain basically parallels mechanisms proposed from results obtained with transfected cells and cell lines.

Androgen Antagonists↗
PubMed1998

Testosterone and its metabolites modulate 5HT1A and 5HT1B agonist effects on intermale aggression.

Our understanding of the neurochemical and neuroendocrine systems' regulating the display of offensive intermale aggression has progressed substantially over the past twenty years. Pharmacological studies have shown that serotonin, via its action at 5HT1A and/or 5HT1B receptor sites, modulates the display of intermale aggressive behavior and that its effects serve to decrease behavioral expression. Neuroendocrine investigations, in turn, have demonstrated that male-typical aggression is testosterone-dependent and studies of genetic effects, metabolic function and steroid receptor binding have shown that facilitation of behavioral displays can occur via independent androgen-sensitive or estrogen-sensitive pathways. Remarkably, there have been virtually no studies that examined the interrelationship between these facilitative and inhibitory systems. As an initial step toward characterizing the interaction between the systems, studies were conducted that assessed hormonal modulation of serotonin function at 5HT1A and 5HT1B receptor sites. They demonstrated: (1) that the androgenic and estrogenic metabolites of testosterone differentially modulate the ability of systemically administered 8-OH-DPAT (a 5HT1A agonist) and CGS12066B (a 5HT1B agonist) to decrease offensive aggression; and (2) when microinjected into the lateral septum (LS) or medial preoptic area (MPO), the aggression-attenuating effects of 1A and 1B agonists differ regionally and vary with the steroidal milieu. In general, the results suggest that estrogens establish a restrictive environment for attenuation of T-dependent aggression by 8-OH-DPAT and CGS 12066B, while androgens either do not inhibit, or perhaps even facilitate, the ability of 5HT1A and 5HT1B agonists to reduce aggression. Potential mechanisms involved in the production of these steroidal effects are discussed and emerging issues that may impact on efforts to develop an integrative neurobiological model of offensive, intermale aggression are considered.

Aggression↗
PubMed1998

Androgen receptor in mouse brain: sex differences and similarities in autoregulation.

The androgen receptor (AR) is generally considered an autoregulated protein. However, studies in brain have produced mixed results regarding sex differences, which should be present given the higher endogenous levels of androgens in males, and the effects of gonadectomy, which presumably should lead to a loss of AR. Resolving these issues is a necessary step in developing a model of AR regulation in the central nervous system and, more broadly, in determining how regulation of this receptor may mediate neural target tissue responsiveness to androgen. To further investigate these issues, the distribution, density, and regulation of neural AR were compared among male and female mice that were intact, gonadectomized, or gonadectomized and given testosterone propionate (TP) through immunocytochemical and Western blot analyses. Four brain areas that have been linked to the regulation of male-typical behavior were evaluated: bed nucleus of the stria terminalis, posterior aspect, medial preoptic area, and dorsal and ventral aspects of the lateral septum. In the immunocytochemical study, integrated particle density, which reflects the average intensity of AR staining, was assessed among the six groups 24 h after surgery using PG-21, a peptide-based AR antiserum. Major findings included regional differences in the intensity of immunostaining; a robust sexual dimorphism in each region, with males exhibiting more intense staining than females; a loss of AR in both sexes after gonadectomy, with more dramatic changes evident in males; and significant up-regulation of AR in response to TP that was equivalent in both sexes. The Western blot analyses of AR in limbic system extracts prepared from the six groups showed a pattern of differences that mirrored the immunocytochemical results, indicating that PG-21 recognized both liganded and unliganded AR. In addition, a dose-response study, in which gonadectomized males and females were administered from 25-1000 microg TP, demonstrated a significant linear trend in up-regulation of AR in both males and females, with no sexual dimorphism in the response to hormone treatment. These results demonstrate that the regulation of AR in both male and female neural tissue is comparable and that the critical determinant of AR expression is the presence or absence of androgen.

Animals↗
PubMed1997

Serotonin agonist-induced decreases in intermale aggression are dependent on brain region and receptor subtype.

Testosterone (T) and its androgenic and estrogenic metabolites modulate the ability of serotonin (5-HT)1A and 5-HT1B agonists to inhibit intermale aggressive behavior. This study tested whether the lateral septum (LS) and medial preoptic area (MPO), which are part of the neuroanatomical substrate for aggression and contain androgen, estrogen, 5-HT1A and 5-HT1B receptors, represent sites where these modulatory effects occur. Gonadectomized CF-1 male mice were given silastic implants containing diethylstilbestrol (DES, a synthetic estrogen) or dihydrotestosterone (DHT, a nonaromatizable androgen) and implanted bilaterally with guide cannula directed at the LS or MPO. They were microinjected with either CGS12066B, a 5-HT1B agonist (400 microM LS, 200 microM MPO); 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A agonist (10 microM LS, 5 microM MPO); or combined CGS + 8-OH-DPAT treatment and tested for aggression 15 min later. When microinjections were given in the LS, androgen-treated males exhibited significantly reduced attack behavior in response to CGS or to CGS + 8-OH-D PAT. The attack behavior of DES-treated males was not reduced by any of the treatments. In contrast, all agonist treatments decreased aggression when injected into the MPO in both hormone conditions. The findings demonstrate regional variation in the ability of androgens and estrogens to modulate 5-HT1A- and 5-HT1B-agonist mediated reductions in aggression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1996

Development and expression of hormonal systems regulating aggression.

There are multiple pathways involved in the regulation of male typical aggression by T, and the functional pathway is determined by genotype. Target-tissue sensitivity to the aggression-promoting properties of T and its estrogenic and androgenic metabolites is determined by a complex sequence of events in which steroid receptors play a critical role. To date, it appears that the relative density of AR may be an important factor in the biobehavioral effects of androgens. Regarding sensitivity to estrogens, characterization of ER-NM interactions, and understanding of the contribution of the two activating functions within ER, appears to be necessary to comprehensively describe the cellular basis for responsiveness to the aggression-promoting effect of this T metabolite. In broader terms, these observations indicate that understanding the relationship between T and the expression of aggression in humans will require models that incorporate cellular aspects of steroid hormone action, including metabolism, receptor function, and gene regulation.

Aggression↗
PubMed1993

Genetic differences in progestin sensitivity in CD-1 and SW female mice.

The lordotic behavior of ovariectomized CD1 and SW female mice was tested in response to estradiol benzoate(EB)+progesterone (P) or EB + 5 alpha-dihydroprogesterone (DHP) to determine (i) the role of progestin metabolism in the regulation of sexually receptive behavior, and (ii) strain differences in sensitivity to these progestins. A greater proportion of SW females resisted mounting attempts than CD-1 females, regardless of the progestin administered. However, the differences in mounting were not correlated with the expression of lordotic behavior. A greater proportion of SW females exhibited sexually receptive behavior when given EB+P in comparison to the CD-1 females. There were no genotypic differences in lordotic behavior in response to EB+DHP. The potential mechanisms mediating genotype-based differences in responsiveness are discussed, and the relationship of this report to previously described strain differences in progestin sensitivity are considered.

20-alpha-Dihydroprogesterone↗
PubMed1992

An assessment of agonist/antagonist effects of tamoxifen in the female mouse brain.

Ovariectomized CFW mice were treated with tamoxifen (TAM) alone or in combination with estradiol benzoate (EB) to determine its ability to promote/block lordotic behavior and the induction of hypothalamic progestin receptors (PR). Across a range of doses, TAM plus progesterone treatment did not activate female sexual behavior. When given with EB, TAM suppressed lordotic behavior in a dose-dependent fashion. TAM did not induce PR when given alone and it completely blocked the ability of EB to induce PR. It therefore appears that for these responses TAM functioned as a pure antagonist in the female mouse brain, although the degree of its antiestrogenicity varied with the response under consideration. A potential mechanism mediating this differential effectiveness is discussed.

Animals↗
PubMed1992

Genotype, uterine position, and testosterone sensitivity in older female mice.

CF-1 and CK (C57BL/6J x AKr) female mice that developed in utero between two males (2M), adjacent to one male (1M), or between two females (0M) were tested for their sensitivity to the aggression-promoting property of testosterone (T) beginning at 9 months of age. Comparisons between the strains showed that a higher proportion of CF-1 females fought in response to T and that the period of hormone exposure required to induce aggression also was shorter in this strain. Within each of the genotypes, there were no systematic differences in responsiveness to T related to contiguity to males during fetal development. While the results provide further evidence for genotype as a major influence on neural sensitivity to androgen, they do not support uterine position of females relative to males as a source of phenotypic variation in responsiveness.

Aggression↗
PubMed1991

In utero contiguity to males does not influence morphology, behavioral sensitivity to testosterone, or hypothalamic androgen binding in CF-1 female mice.

Physiological and behavioral systems presumably influenced by prenatal exposure to testosterone (T) were compared in CF-1 female mice from known uterine positions. Anogenital distance did not differ among females that developed in utero between two females (0M), adjacent to one male (1M), or between two males (2M) at birth, at weaning on Day 21, or on Day 60 postpartum. The age of vaginal opening and mean estrous cycle length also were similar among the groups. When ovariectomized and implanted with a T-containing silastic capsule, the mean number of days of treatment required to activate male-like aggressive behavior also did not differ among the three positional classifications. Finally, androgen binding in combined hypothalamic-preoptic-septal cytosol was assessed after 8 days of T treatment, and no systematic variation in [3H]DHT binding related to uterine position was found. These results indicate that contiguity to male fetuses did not induce variation among CF-1 females in morphological, behavioral, or biochemical systems thought to be influenced by prenatal exposure to T.

Aggression↗
PubMed1991

Timing of neonatal testosterone exposure in the differentiation of estrogenic regulatory systems for aggression.

Neonatal female CF-1 mice were exposed to testosterone (T) or oil vehicle on Days 1-3, 4-6, or 7-9 postpartum and were tested for the display of male-like aggressive behavior in response to diethylstilbestrol (DES) after ovariectomy during adulthood. The results showed that only the Day 1-3 T treatment established the capacity to exhibit fighting behavior following estrogen administration. These data suggest that sexual differentiation of an estrogen-responsive regulatory system for aggressive behavior occurs during a highly restricted period early in life.

Aggression↗
PubMed1990

Genetic variation in hypothalamic methyltrienolone (R1881) binding in male mice.

Methyltrienolone (R1881) binding to androgen receptors (AR) from combined hypothalamic-preoptic-septal cytosol was examined in CF-1, CFW, and CD-1 male mice, strains that differ in their sensitivity to the aggression-promoting property of this hormone. Both the affinity of R1881-AR binding and the number of binding sites (Bmax) significantly differed among the genotypes. The dissociation constant (Kd) was lower in CF-1 males (6.7 nM), a behaviorally responsive strain, in comparison to the insensitive CFW and CD-1 males (3.0 nM and 2.0 nM, respectively). The number of binding sites was higher in CF-1 and CFW males (9.07 and 8.81 fmol/mg protein, respectively) than in CD-1 males (5.11 fmol). The results were basically consistent with studies of neural dihydrotestosterone (DHT) binding in these genotypes, and the implications and limits of these data for understanding the androgenic regulation of intermale aggression are discussed.

Animals↗
PubMed1988

Medroxyprogesterone acetate and tamoxifen do not decrease aggressive behavior in CF-1 male mice.

Intact CF-1 male mice were given daily injections of either medroxyprogesterone acetate (MPA, an antiandrogen), tamoxifen (TAM, an antiestrogen), or the two drugs in combination and tested for aggressive behavior toward bulbectomized stimulus males. None of the treatments decreased fighting behavior over a 20-day test period and the presence of TAM led to increased aggression even in the presence of MPA. Testis weight was reduced by MPA while both compounds decreased seminal vesicle weight. The mechanisms involved in the observed effects are considered as well as the implications of the results for the clinical use of these compounds as modulators of testosterone-facilitated behaviors.

Aggression↗
PubMed1987

Sexual differentiation of androgen-sensitive and estrogen-sensitive regulatory systems for aggressive behavior.

CF-1 female mice were treated with either testosterone (T), diethylstilbestrol (DES), or methyltrienolone (R1881) on the day of birth and were subsequently tested for their responsiveness to the aggression-promoting property of androgen or estrogen during adulthood. The results showed that neonatal exposure to androgen enhanced subsequent sensitivity to androgenic stimulation but did not alter responsiveness to estrogens. Neonatal estrogen treatment established the capacity to exhibit aggression in response to estrogenic stimulation in adulthood but had little effect on responsiveness to androgens. These data indicate that the androgenic and estrogenic metabolites of T have distinct roles in masculinization of the neural substrate for aggressive behavior.

Aggression↗
PubMed1987

Nonaromatizable androgens may stimulate a male mouse reproductive behavior by binding estrogen receptors.

Castrated DBA/2J male mice emitted 70 kHz vocalizations to female stimuli in response to 10 days of treatment with either testosterone (T, 300 micrograms/day), diethylstilbestrol (DES, 1 or 3 micrograms/day) or methyltrienolone (R1881, 900 micrograms/day). Lower dosages of R1881 (300 and 600 micrograms/day) and the oil vehicle were relatively ineffective in restoring vocalizations. The effects of these hormones on restoring seminal vesicle weight did not always parallel their effects upon behavior. In general T and R1881 (600 and 900 micrograms/day) were effective in restoring seminal vesicles while DES, the lowest dose of R1881 (300 micrograms/day), and the oil vehicle were ineffective. In receptor competition studies, R1881 pretreatment significantly reduced estrogen binding in hypothalamic-preoptic cytosol. In fact the most effective dose for restoring vocalizations (900 micrograms/day) reduced available estrogen binding sites by 91%. We propose that the male-typical vocalizations of mice may normally be stimulated through the activation of estrogen receptors following androgen aromatization and that the ability of a pharmacological dosage of R1881 (900 micrograms/day) to restore behavior may be due to interaction with estrogen receptors in the brain.

Androgens↗
PubMed1987

Activation of male-typical aggression by testosterone but not its metabolites in C57BL/6J female mice.

Ovariectomized adult C57BL/6J mice were exposed to androgens, estrogens, or combined androgen-estrogen treatments and tested for the display of male-typical aggressive behavior toward olfactory bulbectomized stimulus males. Among the androgenic treatments (testosterone, dihydrotestosterone, or methyltrienolone) only testosterone, which, in contrast to the other androgens, can be aromatized, activated fighting behavior. In the second experiment, estradiol benzoate (EB) was totally ineffective as an aggression-promoting compound. Lastly, combined EB+dihydrotestosterone also did not induce male-like aggression. These data suggest that T itself may be capable of promoting aggression without undergoing aromatization or 5 alpha-reduction.

Aggression↗
PubMed1986

On the expression of H-Y antigen in transsexuals.

Histocompatibility-Y (H-Y) antigen, the presumptive inducer of the mammalian testis, is present in the cells of normal males and not in the cells of normal females. Recent reports have implied that patients with transsexualism exhibit H-Y antigen phenotypes at variance with those of normal males and females and, thus, that H-Y serology might provide a tool for the diagnosis and study of the transsexual condition. We therefore evaluated blood and testicular cells from 21 male-to-female transsexuals using conventional and monoclonal H-Y antibodies. We found no evidence of abnormal H-Y phenotype. Five of the patients were interviewed postoperatively by two examiners and rated for the diagnosis of transsexualism. Three of the five were rated primary transsexual by one or both examiners, and two were rated secondary transsexual.

Adult↗
PubMed1985

Induction of male-typical aggression by androgens but not by estrogens in adult female mice.

Ovariectomized adult CF-1 female mice were implanted with silastic capsules containing either testosterone (T), dihydrotestosterone (DHT), methyltrienolone (R1881), estradiol (E2), diethylstilbestrol (DES), or oil vehicle and were tested for aggressive behavior. The androgenic treatments (T, DHT, R1881) were highly effective in promoting male-like aggression while the estrogens (DES, E2) were completely ineffective. Subsequent receptor-binding studies confirmed assumptions about the specificity of DES, DHT, and R1881 binding to estrogen and androgen receptors in mouse hypothalamus.

Aggression↗