Aggressiveness by Isolation and Brain Serotonin Turnover Changes in Different Strains of Mice

Valzelli, L.; Bernasconi, Sergio

doi:10.1159/000117674

Cited by 103 publications

(26 citation statements)

References 24 publications

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“…Socially isolated (SI) male mice also show a marked decrease of Allo brain content (5, 7) and a down-regulation of serotonergic neurotransmission (8)(9)(10).…”

mentioning

confidence: 99%

In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

Pinna¹,

Dong²,

Matsumoto³

et al. 2003

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

209

236

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Social isolation (SI) of male mice lasting >4 weeks is associated with aggression toward intruders and a down-regulation of brain allopregnanolone (Allo) content. SI of female mice fails to downregulate brain Allo content or to induce aggressiveness. Fluoxetine (Prozac in clinical use) is an S-and R-fluoxetine (FLX) mixture, which in mammals is metabolized into S-and R-norfluoxetine (NFLX). The S isomers of FLX and NFLX are more active than their respective R isomers in normalizing brain Allo down-regulation and in reducing the aggressiveness induced by SI. Thus, FLX stereospecifically reduces brain Allo down-regulation and the aggressiveness induced by SI, whereas serotonin (5-HT) uptake inhibition lacks stereospecificity. The doses of S-FLX and S-NFLX that reduce aggressiveness and Allo brain content down-regulation induced by SI are at least one order of magnitude lower than the doses that block 5-HT reuptake. Doses of imipramine that inhibit 5-HT uptake neither reduce aggressiveness nor normalize brain Allo downregulation. We conclude that Allo brain content normalization is a better candidate than 5-HT reuptake inhibition to explain the reduction of aggressiveness elicited by S-FLX and S-NFLX.A ggressive behavior and violence are included in the phenotypic expression of several central nervous system disorders (i.e., schizophrenia, premenstrual dysphoria, major manicdepressive illness, posttraumatic stress disorder, and epilepsy).Human and animal studies suggest that often a genetic component contributes to aggressive behavior. For example, the altered transcription of genes encoding for various serotonin (5-HT) receptor subtypes or for the 5-HT transporter has been implicated in the pathophysiology of violence and aggression in humans and other mammals (1-3). However, a Mendelian inheritance of these 5-HT neurotransmission dysregulations could not be demonstrated (4). Probably, epigenetic factors contribute to aggressive behavior.Social isolation (SI) of male mice for Ͼ4 weeks causes a syndrome characterized by anxiety, decreased susceptibility to barbiturates and other ␥-aminobutyric acid (GABA)mimetic drugs, and frequent severe attacks against an intruder mouse (5, 6). Socially isolated (SI) male mice also show a marked decrease of Allo brain content (5, 7) and a down-regulation of serotonergic neurotransmission (8-10).Valzelli and his coinvestigators (11) pioneered studies of SI-induced aggression in mice and concluded that this aggressiveness involves an impairment of 5-HT neurotransmission (11,12). This conclusion was supported by mouse knockout studies of the 5-HT transporter (3), and by other studies in which mice received selective 5-HT reuptake inhibitors (SSRIs), which mitigate aggression in psychiatric patients (13,14) and reduce SI-induced aggression in mice (5, 6).In patients with major depression, the allopregnanolone (Allo) content of cerebrospinal fluid (CSF) is reduced, and this reduction is reversed by appropriate treatment with fluoxetine (FLX) or fluvoxamine (15). Interestingly, in depr...

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“…Socially isolated (SI) male mice also show a marked decrease of Allo brain content (5, 7) and a down-regulation of serotonergic neurotransmission (8)(9)(10).…”

mentioning

confidence: 99%

In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

Pinna¹,

Dong²,

Matsumoto³

et al. 2003

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

209

236

View full text Add to dashboard Cite

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“…For instance, a negative correlation exists between serotonin (5-hydroxytryptamine; 5-HT) metabolites and impulsive aggressiveness in humans (10-12) and rodents (13,14). Pharmacological manipulations that increase 5-HT neurotransmission decrease the severity of aggressiveness in humans (15) and reduce aggression in animal models (16,17).…”

mentioning

confidence: 99%

Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase

Chiavegatto

Dawson

Mamounas

et al. 2001

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

152

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Genetically engineered mice with targeted disruption of the neuronal nitric oxide synthase (nNOS) gene established the inhibitory role of nitric oxide (NO) in male impulsive aggressive behavior. This was later confirmed by using selective nNOS inhibitors in male wild-type mice. The molecular mechanisms accounting for the aggressive behavior caused by the lack of neuronally derived NO is not known. Recent studies suggest that central serotonergic neuronal circuits and particularly 5-HT1A and 5-HT1B receptors play a prominent role in the regulation of aggression. Accordingly, we investigated whether the aggressiveness caused by the lack of nNOS might be because of alterations in serotonergic function. We now demonstrate that the excessive aggressiveness and impulsiveness of nNOS knockout mice is caused by selective decrements in serotonin (5-HT) turnover and deficient 5-HT1A and 5-HT1B receptor function in brain regions regulating emotion. These results indicate an important role for NO in normal brain 5-HT function and may have significant implications for the treatment of psychiatric disorders characterized by aggressiveness and impulsivity.T he gene encoding neuronal nitric oxide synthase (nNOS) was disrupted and inactivated by homologous recombination to clarify the functional role of nitric oxide (NO) as a messenger molecule in the nervous system (1). Mice lacking the gene for nNOS (nNOS Ϫ/Ϫ ) exhibit a variety of abnormalities including enlargement of the stomach (1), hypertrophied urinary bladders (2), reduced parasympathetic tone (3), and nocturnal motor deficits (4). In addition, male nNOS Ϫ/Ϫ mice display dramatic increases in aggressive and sexual behavior (5). Pharmacological treatment of male wild-type (WT) mice with selective nNOS inhibitor also evokes an increase in impulsive aggressive behavior to the levels displayed by nNOS Ϫ/Ϫ mice (6), indicating that the aggressive behavior is caused by loss of neuronally derived NO and not developmental abnormalities. nNOS is enriched throughout the limbic system (7, 8), an area important in emotional and agonistic behaviors and thus nNOS-derived NO is appropriately positioned to play a prominent role in regulating impulsive and aggressive behavior. Despite the evidence which implicates neuron-derived NO in the modulation of aggressive behavior, the molecular mechanisms by which NO regulate aggression are not known. Plasma androgen concentrations can affect the display of aggressive behavior in male mice, but testosterone concentrations in nNOS Ϫ/Ϫ and WT mice are similar (9).Previous studies of the brain mechanisms underlying aggression reveal that central serotonergic neuronal circuits are prominent in the regulation of aggression. For instance, a negative correlation exists between serotonin (5-hydroxytryptamine; 5-HT) metabolites and impulsive aggressiveness in humans (10-12) and rodents (13,14). Pharmacological manipulations that increase 5-HT neurotransmission decrease the severity of aggressiveness in humans (15) and reduce aggression in animal models ...

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“…Aggression increases after 3-6 weeks of individual housing (Garattini et al, 1967;Oehler et al, 1985). Coincident with this transient increase in isolationevoked aggression in mice is a decrease of 5-HT metabolism in diverse brain areas (Valzelli and Bernasconi, 1979;Kempf et al, 1984;Rilke et al, 1998Rilke et al, , 2001.…”

Section: -Ht and Extrinsic Factors That Affect Aggressionmentioning

confidence: 99%

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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Aggressiveness by Isolation and Brain Serotonin Turnover Changes in Different Strains of Mice

Cited by 103 publications

References 24 publications

In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase

Interaction of nitric oxide and serotonin in aggressive behavior

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