Androgens and Estrogens Modulate 5-HT1A and 5-HT1B Agonist Effects on Aggression

Cologer-Clifford, Athena; Simon, Neal G.; Richter, Martin L.; Smoluk, S. A.; Lu, Shi-fang

doi:10.1016/s0031-9384(98)00240-6

Cited by 56 publications

(29 citation statements)

References 44 publications

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“…Male aggressive behaviors (3, 4) were also severely impaired in AR LϪ/Y mice [ 2 (1) ϭ 10.8, P Ͻ 0.01] as measured by decreased numbers of aggressive bouts (F 7,79 ϭ 6.71, P Ͻ 0.01) with longer latency periods (F 7,79 ϭ 6.55, P Ͻ 0.01). Unexpectedly, treatment with either DHT or a nonaromatizable synthetic AR ligand (R1881) (15) enhanced, to at least some extent, the impaired male aggressive behaviors of AR LϪ/Y mice [DHT, 2(1) ϭ 4.0, P Ͻ 0.05, and R1881, 2(1) ϭ 5.5, P Ͻ 0.05; Fig. 2 b-d].…”

Section: Generation Of Ar-deficientmentioning

confidence: 99%

Brain masculinization requires androgen receptor function

Satō

Μatsumoto

Kawano

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

269

207

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Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (AR L؊/Y ) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (AR L؊/L؊ ) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5␣-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in AR L؊/Y mice. Impaired maletypical behaviors in ER␣ ؊/؊ mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in AR L؊/L؊ mice. Perinatal DHT treatment of females led to adult females sensitive to both 17␤-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling.

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Section: Generation Of Ar-deficientmentioning

confidence: 99%

Brain masculinization requires androgen receptor function

Satō

Μatsumoto

Kawano

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

269

207

View full text Add to dashboard Cite

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“…While testosterone undoubtedly plays an important role in aggressive behaviour, castration-replacement studies in mice have shown that oestrogen-sensitive regulatory pathways, which are distinct from androgen-sensitive pathways, also participate in the promotion of intermale aggression (Cologer-Clifford et al 1999). The importance of the oestrogens/oestrogen receptor (ER) signalling pathway in intermale aggression was also reported in a study on mice lacking one of the ERs, ER (ER knockout mice, ERKO), in which males rarely displayed aggression against olfactory bulbectomised wild-type males (Ogawa et al 1997(Ogawa et al , 1998.…”

Section: Introductionmentioning

confidence: 99%

A loss of aggressive behaviour and its reinstatement by oestrogen in mice lacking the aromatase gene (Cyp19)

Toda¹,

Saibara²,

Okada³

et al. 2001

Journal of Endocrinology

108

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Aromatase P450 (CYP19) is an enzyme responsible for conversion of androgens to oestrogens. We generated CYP19 knockout (ArKO) mice by targeting disruption of the CYP19 gene and observed that the ArKO males exhibited a complete loss of aggressive behaviour against intruder mice when examined using a resident-intruder paradigm. The defect in the behaviour of ArKO males was reinstated when the mice received supplements of 17 -oestradiol soon after birth. Nevertheless, the cumulative duration of the behaviour displayed by the treated mice during the test period of 15 min was 19 10 s, which was much shorter than that displayed by wild-type males, 90 17 s. When the supplementation was started at 7 days after birth, the defect was not restored. These findings illustrate an absolute requirement for oestrogen during the neonatal stage of a male's life for the development of the potential for aggression observed in adulthood. Furthermore, the present study demonstrates that ArKO males are a useful model in which to investigate the neural mechanisms by which aggressive behaviour is controlled.

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“…Both testosterone and estradiol increase the levels of 5-HT 2A receptor mRNA and binding site densities in the brains of male rats (Sumner and Fink, 1998). Importantly, both androgens and estrogens modulate 5-HT 1A and 5-HT 1B receptor agonist effects on murine aggression (Cologer-Clifford et al, 1999). Indeed, estrogens appear to directly interfere with 5-HT binding (Frankfurt et al, 1994).…”

Section: -Ht and Female Aggressionmentioning

confidence: 98%

Interaction of nitric oxide and serotonin in aggressive behavior

Chiavegatto

Nelson

2003

Hormones and Behavior

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Nitric oxide (NO) modulates many behavioral and neuroendocrine responses. Genetic or pharmacological inhibition of the synthetic enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Recently, the excessive aggressive and impulsive traits of neuronal NO synthase knockout (nNOS Ϫ/Ϫ ) mice were shown to be caused by reductions in serotonin (5-HT) turnover and deficient 5-HT 1A and 5-HT 1B receptor function in brain regions regulating emotion. The consistently high levels of aggression observed in nNOS Ϫ/Ϫ mice could be reversed by 5-HT precursors and by treatment with specific 5-HT 1A and 5-HT 1B receptor agonists. The expression of the aggressive phenotype of nNOS Ϫ/Ϫ knockout mice requires isolated housing prior to testing. The effects of social factors such as housing condition and maternal care can affect 5-HT and aggression, but the interaction among extrinsic factors, 5-HT, NO, and aggression remains unspecified. Taken together, NO appears to play an important role in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressive and impulsive behaviors.

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Androgens and Estrogens Modulate 5-HT1A and 5-HT1B Agonist Effects on Aggression

Cited by 56 publications

References 44 publications

Brain masculinization requires androgen receptor function

Brain masculinization requires androgen receptor function

A loss of aggressive behaviour and its reinstatement by oestrogen in mice lacking the aromatase gene (Cyp19)

Interaction of nitric oxide and serotonin in aggressive behavior

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