Pharmacological control of aggressive behavior in mice

Valzelli, L.; Giacalone, E.; Garattini, Silvio

doi:10.1016/0014-2999(67)90040-4

Cited by 97 publications

(24 citation statements)

References 4 publications

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“…55, 56 Low cerebrospinal 5-HIAA was correlated with elevated aggression in humans 26, 57, 58 and monkeys. 59 Furthermore, low-Trp diet resulted in increased aggressive behavior in humans, 60 whereas Trp-enriched diet initiated a reduction of physical aggression in subjects that had a history of elevated aggression.…”

Section: Discussionmentioning

confidence: 95%

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin

et al. 2012

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Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20–30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2−/−) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2−/− mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident–intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2+/− mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression.

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Section: Discussionmentioning

confidence: 95%

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin

et al. 2012

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“…(e.g. Ginsburg & Allee, 1942: Valzelli, Giacalone & Garattini, 1967Sofia, 1969). When the interaction of isolated versus group-housed mice was used, then in most cases only aggressive mice were selected (e.g.…”

Section: Discussionmentioning

confidence: 99%

Timid Singly‐housed Mice: Their Value in Prediction of Psychotropic Activity of Drugs

Kršiak

1975

British J Pharmacology

142

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I About 45% of singly-housed male mice showed timidity (alert postures, running away, defensive postures) instead of aggression on interactions in pairs with group-housed male mice, though their partners did not show any aggression. The isolation-induced timidity was stable in repeated interactions. Timid mice also showed locomotion (walking across cage and rearing) and a small amount of sociable activity (sniffing, following partners and climbing over them). 2 Diazepam (5 mg/kg), chlordiazepoxide (20 mg/kg), chlorpromazine (7.5 mg/kg) and barbitone (60 mg/kg) given orally inhibited the isolation-induced timidity without reducing other motor activities in the timid mice. Imipramine lessened timidity only in a dose (80 mg/kg) which also decreased other components of behaviour in the timid isolates. (+)-Amphetamine and lysergic acid diethylamide (LSD) increased the timid response. 3 Comparison of the inhibition of timid activities with changes in other behaviour occurring at the same time seems a better measure of selective timidity-reducing effects of drugs than the rota-rod test. 4 Diazepam (5 mg/kg) increased sociable and locomotor activities. Barbitone (20 and 60 mg/kg) increased sociable activities; however, the higher dose also evoked some aggression in timid mice. 5 Behaviour of timid singly-housed male mice seems to be a good measure for prediction of activity of drugs in relieving anxiety as well sociability-increasing effects of drugs.as for detection of aggression-evoking and

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“…Aggression against an intruder is a characteristic behavioral abnormality that can be elicited in male mice by social isolation (Valzelli 1969(Valzelli , 1981. Various strategies are available to quantify this territorially related aggressive behavior induced by social isolation.…”

Section: Pharmacological Strategies For the Treatment Of Neurosteroidmentioning

confidence: 99%

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake

2006

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It has recently become more clearly understood that in human brain pathophysiology, neurosteroids play a role in anxiety disorders, premenstrual syndrome, postpartum depression, posttraumatic stress disorder, and depression. In the treatment of major depression, recent clinical studies indicate that the pharmacological profiles of fluoxetine and fluvoxamine are correlated with the ability of these drugs to increase the brain and cerebrospinal fluid content of allopregnanolone (Allo), a potent positive allosteric modulator of gamma-aminobutyric acid (GABA) action at GABAA receptors. Thus, the neurosteroid-induced positive allosteric modulation of GABA action at GABAA receptors is facilitated by fluoxetine or its congeners (i.e., paroxetine, fluvoxamine, sertraline), which may not block 5-HT reuptake at the doses currently prescribed in the clinic. However, these doses are effective in the treatment of premenstrual dysphoria, anxiety, and depression. In socially isolated mice, we tested the hypothesis that fluoxetine, norfluoxetine, and other specific serotonin reuptake inhibitor (SSRI) congeners stereoselectively upregulate neurosteroid content at doses insufficient to inhibit 5-HT reuptake; although they potentiate pentobarbital-induced sedation and exert antiaggressive action. Very importantly, the inhibition of 5-HT reuptake lacks stereospecificity and requires fluoxetine and norfluoxetine doses that are 50-fold greater than those required to increase brain Allo content, potentiate the action of pentobarbital, or antagonize isolation-induced aggression. Based on these findings, it could be inferred that the increase of brain Allo content elicited by fluoxetine and norfluoxetine, rather than the inhibition selective of 5-HT reuptake, may be operative in the fluoxetine-induced remission of the behavioral abnormalities associated with mood disorders. Therefore, the term "SSRI" may be misleading in defining the pharmacological profile of fluoxetine and its congeners. To this extent, the term "selective brain steroidogenic stimulants" (SBSSs) could be proposed.

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Pharmacological control of aggressive behavior in mice

Cited by 97 publications

References 4 publications

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin

Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin

Timid Singly‐housed Mice: Their Value in Prediction of Psychotropic Activity of Drugs

Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake

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