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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.

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.

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.

CF-1 and CK (C57BL/6J × 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.

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 (OM), 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.