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Estrogen, Serotonin, and Aggression

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Intestinal Serotonin and Bone Loss

“Estrogen is often said to achieve some of its “wonderful” effects by increasing the effects of serotonin…Many experiments have shown that estrogen is very important for aggressive behavior in animals, and estrogen promotes serotonin’s actions. Some research shows that increased serotonin is associated with certain types of increased aggressiveness, and antiserotonin agents decrease aggresiveness (Ieni, et al., 1985; McMillen, et al., 1987)…” -Ray Peat, PhD

“…there is clear evidence from both animal and human studies that serotonin, like estrogen, is associated with aggression, but the dominating stereotype is that serotonin is the agent of serenity and peace.” -Ray Peat, PhD

Horm Behav. 2006 Aug;50(2):338-45. Epub 2006 Jun 6.
Individual differences in estrogen receptor alpha in select brain nuclei are associated with individual differences in aggression.
Trainor BC, Greiwe KM, Nelson RJ.
“When males were treated with fadrozole (an aromatase inhibitor), aggressive behavior was reduced, although castration did not reduce aggression. These results suggest that estrogens modulate aggressive behavior by acting on a circuit that includes the LS, vBNST, and AHA and that the source of estrogens is non-gonadal. Fadrozole also decreased c-fos expression in the lateral septum following aggressive encounters. Although the effects of estrogen on aggression appear to involve regulation of neuronal activity in the LS, additional processes are likely involved. These results suggest that estrogen acts in a specific subset of a complex network of nuclei to affect aggressive behavior.”

Front Neuroendocrinol. 2006 Jul;27(2):170-9. Epub 2006 Jan 10.
Estrogenic encounters: how interactions between aromatase and the environment modulate aggression.
Trainor BC, Kyomen HH, Marler CA.
“Thus, differences in aromatase enzyme activity, estrogen receptor expression, and related cofactors may have important effects on how steroids affect aggressive behavior. Hormone manipulation studies conducted in a wide variety of species indicate that estrogens modulate aggression. There is also growing evidence that social experience has important effects on the production of estrogen within the brain, and some cases can not be explained by androgenic regulation of aromatase. Such changes in central aromatase activity may play an important role in determining how social experiences affect the probability of whether an individual engages in aggressive behavior. Although studies have been conducted in many taxa, there has been relatively little integration between literatures examining aggression in different species. In this review, we compare and contrast studies examining aggression in birds, mammals, and humans. By taking an integrative approach to our review, we consider mechanisms that could explain species differences in how estrogen modulates aggression.”

Hormones and Behavior 53 (2008) 192–199
Rapid effects of estradiol on male aggression depend on photo period in
reproductively non-responsive mice

BrianC. Trainor M. Sima Finy, Randy J. Nelson
“However, males housed in short days were significantly more aggressive than males housed in long days. Similar to previous work in beach mice (Peromyscus polionotus), estradiol rapidly increased aggression when male California mice were housed in short days but not when housed in long days. These data suggest that the effects of photoperiod on aggression and estrogen signaling are independent of reproductive responses. The rapid action of estradiol on aggression in short-day mice also suggests that nongenomic mechanisms mediate the effects of estrogens in short days.”

Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9840-5. Epub 2007 May 24.
Photoperiod reverses the effects of estrogens on male aggression via genomic and nongenomic pathways.
Trainor BC, Lin S, Finy MS, Rowland MR, Nelson RJ.
We demonstrate that the behavioral effects of estrogens on aggression are completely reversed by a discrete environmental signal, day length. Selective activation of either estrogen receptor alpha or beta decreases aggression in long days and increases aggression in short days. In the bed nucleus of the stria terminalis, one of several nuclei in a neural circuit that controls aggression, estrogen-dependent gene expression is increased in long days but not in short days, suggesting that estrogens decrease aggression by driving estrogen-dependent gene expression. Estradiol injections increased aggression within 15 min in short days but not in long days, suggesting that estrogens increase aggression in short days primarily via nongenomic pathways. These data demonstrate that the environment can dictate how hormones affect a complex behavior by altering the molecular pathways targeted by steroid receptors.

The Ohio State University. Department of Psychology Honors Theses; 2006
Effects of Estrogen on Aggressive Behavior
Nelson, Randy
Estrogens are known modulators of aggression however, the specific action of estrogens on brain function has not been determined. In a correlational study, the number of estrogen receptors in regions of the hypothalamus and limbic system was correlated with aggressive behavior in a domestic strain of mice (CD-1). To determine whether these correlations reflect the effect of estrogen on aggression, the production of estrogen was manipulated by an aromatase inhibitor (fadrozole) to observe the subsequent effects on aggressive behavior. Reduction of estrogen production resulted in a decrease in aggressive behavior, suggesting that estrogen acts to increase aggression.

Serotonin

Naunyn Schmiedebergs Arch Pharmacol. 1987 Apr;335(4):454-64.
Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission.
McMillen BA, Scott SM, Williams HL, Sanghera MK.
In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety.

Eur J Pharmacol. 1985 May 8;111(2):211-20.
Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor antagonists.
Ieni JR, Thurmond JB.
Drug treatments which influence brain serotonergic systems were administered to lactating female mice during the early postpartum period, and their effects on aggressive behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and 5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced frequencies of attack. In addition, postpartum mice treated with the serotonin receptor antagonists, mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed significantly less aggressive behavior than control mice, as measured by reduced number of attacks. Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral results are discussed in terms of drug-induced changes in brain chemistry and indicate a possible role for serotonin in the mediation of maternal aggressive behavior of mice.

Pharmacol Biochem Behav. 1976 Jul;5(1):55-61.
The role of serotonergic pathways in isolation-induced aggression in mice.
Malick JB, Barnett A.
Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed between potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration.

Pol J Pharmacol Pharm. 1979 Mar-Apr;31(2):97-106.
Determination of the role of serotonergic and cholinergic systems in apomorphine–induced aggressiveness in rats.
Roliński Z, Herbut M.
Aggressive behavior was produced in rats by administration of apomorphine (APO) 20 mg/kg ip. Serotonin (5-HT) agonists, L-tryptophan or 5-hydroxytryptophan and a MAO inhibitor, pargyline, suppressed the APO-induced aggressiveness. However, cyproheptadine was the only one of four 5-HT antagonists used which potentiated the aggressive behavior.

Animal studies show that darkness stimulates both aggression and eating (Russell and Singer, 1983), and that serotonin increases, while antiserotonin drugs decrease, aggression (Carlini and Lindsey, 1983). -Ray Peat, PhD

Physiol Behav. 1983 Jan;30(1):23-7.
Relations between muricide, circadian rhythm and consummatory behavior.
Russell JW, Singer G.
Three forms of behavior–muricide, eating, and drinking–have been studied at six photic periods during a 12/12 hr light/dark circadian cycle to which the subjects have been habituated. One hundred and eight rats served as subjects, 18 per photic period. The frequency of muricide was recorded for each period and subsequent food and water intakes were measured during a 1 hr test period. Results show a significantly higher frequency of muricide during the dark than during periods of light. Food intake covaried significantly with the incidence of muricide rs = 0.89, p less than 0.05), while no such relationship was found between muricide and water intake (rs = 0.17, p less than 0.05). The findings are consistent with reports of circadian changes in other rodent behaviors, including rhythmicity in home-cage and in shock-induced aggression. Covariation of muricide and eating does not establish a causal relation between the two. Three models of physiological mechanisms which might provide substrates for the covariance are discussed.

Braz J Med Biol Res. 1982 Oct;15(4-5):281-3.
Effect of serotonergic drugs on the aggressiveness induced by delta 9-tetrahydrocannabinol in rem-sleep-deprived rats.
Carlini EA, Lindsey CJ.
1. delta 9-Tetrahydrocannabinol (THC) induced aggressive behavior in rats previously deprived of REM sleep. This aggressiveness was significantly potentiated by tryptophan and fluoxetine, drugs which increase brain serotonin availability. 2. Conversely, drugs which decrease serotonergic function such as D,L-p-chlorophenylalanine, cinanserin and cyproheptadine strongly blocked the aggressive behavior. 3. On the basis of previous data indicating an involvement of dopaminergic mechanisms in this type of aggressiveness and the present results showing a role for serotonin, it is concluded that REM deprivation-THC aggression is under the control of at least these two neurotransmitters.

In an epidemiological study (Moffitt, et al., 1998), a record of violence was associated with above-average serotonin levels. -Ray Peat, PhD

Biol Psychiatry. 1998 Mar 15;43(6):446-57.
Whole blood serotonin relates to violence in an epidemiological study.
Moffitt TE, Brammer GL, Caspi A, Fawcett JP, Raleigh M, Yuwiler A, Silva P.
BACKGROUND:
Clinical and animal studies suggest that brain serotonergic systems may regulate aggressive behavior; however, the serotonin/violence hypothesis has not been assessed at the epidemiological level. For study of an epidemiological sample we examined blood serotonin, because certain physiological and behavioral findings suggested that it might serve as an analog marker for serotonergic function.
METHODS:
Whole blood serotonin was measured in a representative birth cohort of 781 21-year-old women (47%) and men (53%). Violence was measured using cumulative court conviction records and participants’ self-reports. Potential intervening factors addressed were: gender, age, diurnal variation, diet, psychiatric medications, illicit drug history, season of phlebotomy, plasma tryptophan, platelet count, body mass, suicide attempts, psychiatric diagnoses, alcohol, tobacco, socioeconomic status, IQ, and overall criminal offending.
RESULTS:
Whole blood serotonin related to violence among men but not women. Violent men’s mean blood serotonin level was 0.48 SD above the male population norm and 0.56 SD above the mean of nonviolent men. The finding was specific to violence, as opposed to general crime, and it was robust across two different methods of measuring violence. Together, the intervening variables accounted for 25% of the relation between blood serotonin and violence.
CONCLUSIONS:
To our knowledge, this is the first demonstration that an index of serotonergic function is related to violence in the general population

Article:
LARGE-SCALE STUDY LINKS SEROTONIN LEVELS, AGGRESSION

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