Androgens and estrogens modulate 5-HT1A and 5-HT1B agonist effects on aggression.

Intermale offensive aggressive behavior is facilitated by gonadal steroids and inhibited by serotonin (5-HT), presumably through its effects at 5-HT1A and 5-HT1B receptor sites. To examine the interaction between these neuroendocrine and neurochemical regulatory systems, CF-1 male mice were gonadectomized and implanted with silastic capsules containing either diethylstilbestrol (DES, a synthetic estrogen), the nonaromatizable androgens methyltrienolone (R1881) or dihydrotestosterone (DHT), or testosterone (T). Two weeks later, they were given 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A agonist; 0.1 or 1.0 mg/kg), CGS12066B (a 5-HT1B agonist; 4.0 or 8.0 mg/kg), 0.1 or 1.0 mg/kg 8-OH-DPAT + 4.0 mg/kg CGS12066B, or vehicle, and tested for aggression. In the presence of DES, the higher 8-OH-DPAT dose given in combination with CGS attenuated aggression in comparison to vehicle controls. When given nonaromatizable androgen (R1881 or DHT), all drug treatments except 0.1 mg/kg 8-OH-DPAT significantly reduced offensive attack behavior. In the presence of T, which provides estrogenic and androgenic stimulation, aggression scores were significantly reduced when males were given the high dose of 8-OH-DPAT or CGS12066B, as well as in the 1.0 mg/kg 8-OH-DPAT + CGS12066B condition. Assessments of changes in motor behavior showed significant impairment when 8.0 mg/kg CGS12066B was administered across all hormonal conditions, indicating that reductions in offensive aggression in these treatment groups were nonspecific. The results demonstrate differential effects of the steroidal environment on the ability of 5-HT1A and 5-HT1B agonists to modulate aggression, with estrogens producing a more restrictive environment than androgens for serotonergic inhibition of male-typical aggressive behavior.

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.