Reduced aggression in mice lacking the serotonin transporter

Abstract.Rationale: Dysregulation of the brain serotonergic system has been implicated in the pathophysiology of violence and aggression. As a key regulator of central serotonergic activity, dysfunction of the serotonin transporter (5-HTT) represents a potential mechanism mediating pathological aggression. Objectives: To assess aggressive behavior in 5-HTT knockout (KO) mice. To examine home cage activity and 5-HT1A/1B receptor function in 5-HTT KO mice as factors contributing to an aggressive phenotype. Methods: Isolated male 5-HTT KO mice were compared to +/+ control mice using the resident-intruder test for aggression over two encounters. Locomotor activity was measured in the home cage over a 24-h period. 5-HT1A/1B receptor function was assessed via the pharmacological effects of the 5-HT1A/1B receptor agonist, RU24969, on locomotion. Results: 5-HTT –/– mice were slower to attack the intruder and attacked with less frequency than +/+ littermates, but showed equivalent social investigation. 5-HTT +/– mice were as quick to attack, but made fewer overall attacks, as compared to +/+ controls. Aggression increased with repeated exposure to an intruder in 5-HTT +/– and +/+ mice, but not in 5-HTT –/– mice. 5-HTT –/– mice showed a normal circadian pattern of home cage activity, but less activity overall, as compared to 5-HTT +/– and +/+ mice. RU24969 (5 mg/kg) produced hyperlocomotor effects in 5-HT +/– and +/+, but not 5-HTT –/– mice. Conclusions: Deletion of the 5-HTT gene produces a reduction in aggressive behavior and home cage activity. Desensitization of 5-HT1A/1B receptor function may contribute to reduced aggression in 5-HTT KO mice.

[1]  R. Hen,et al.  Serotonin receptors and animal models of aggressive behavior. , 1995, Pharmacopsychiatry.

[2]  S. Tonegawa,et al.  Abnormal fear response and aggressive behavior in mutant mice deficient for alpha-calcium-calmodulin kinase II. , 1994, Science.

[3]  K. Lesch,et al.  Altered expression and functions of serotonin 5‐HT1A and 5‐HT1B receptors in knock‐out mice lacking the 5‐HT transporter , 2000, The European journal of neuroscience.

[4]  D. Murphy,et al.  Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. , 2001, The Journal of pharmacology and experimental therapeutics.

[5]  E H Cook,et al.  Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. , 1998, The American journal of psychiatry.

[6]  J. Schipper,et al.  Postsynaptic 5-HT1 receptors and offensive aggression in rats: A combined behavioural and autoradiographic study with eltoprazine , 1991, Pharmacology Biochemistry and Behavior.

[7]  R. Blanchard,et al.  Specific anti-aggressive effects of fluprazine hydrochloride , 2004, Psychopharmacology.

[8]  P. Guillot,et al.  Intermale aggression and dark/light preference in ten inbred mouse strains , 1996, Behavioural Brain Research.

[9]  J. Winslow,et al.  Habituation of aggressive behavior in mice: A parametric study , 1984 .

[10]  M. Virkkunen,et al.  Aggression, suicidality, and serotonin. , 1992, The Journal of clinical psychiatry.

[11]  Qian Li,et al.  Genetic perspectives on the serotonin transporter , 2001, Brain Research Bulletin.

[12]  P. Bonaventure,et al.  Humanization of mouse 5-hydroxytryptamine1B receptor gene by homologous recombination: in vitro and in vivo characterization. , 1999, Molecular pharmacology.

[13]  A. Roy.  Suicidal Behavior in Depression: Relationship to Platelet Serotonin Transporter , 1999, Neuropsychobiology.

[14]  R Hen,et al.  Enhanced aggressive behavior in mice lacking 5-HT1B receptor. , 1994, Science.

[15]  G. Barr,et al.  Manipulations of dietary tryptophan: Effects on mouse killing and brain serotonin in the rat , 1979, Brain Research.

[16]  S. R. Snodgrass,et al.  Effects of 5-HT receptor subtype-selective drugs on locomotor activity and motor habituation in the DHT adult rat model , 1987, Pharmacology Biochemistry and Behavior.

[17]  R. Nelson,et al.  Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  W. Soudijn,et al.  The concept of selectivity in 5-HT receptor research. , 1990, European journal of pharmacology.

[19]  D. Murphy,et al.  Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine ("Ecstasy") in serotonin transporter-deficient mice. , 1998, Molecular pharmacology.

[20]  E. Coccaro,et al.  Impulsive aggression and central serotonergic system function in humans: an example of a dimensional brain‐behavior relationship , 1992, International clinical psychopharmacology.

[21]  D. Ely,et al.  A comparative study of aggression related changes in brain serotonin in CBA, C57BL, and DBA mice , 1984, Behavioural Brain Research.

[22]  D. Murphy,et al.  Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice. , 1999, The Journal of pharmacology and experimental therapeutics.

[23]  K. Miczek,et al.  Aggressive behavioral phenotypes in mice , 2001, Behavioural Brain Research.

[24]  K. Miczek,et al.  Drug Effects on Agonistic Behavior , 1979 .

[25]  R. Nelson,et al.  Molecular basis of aggression , 2001, Trends in Neurosciences.

[26]  K. Lesch,et al.  Functional Consequences of 5-HT Transporter Gene Disruption on 5-HT1A Receptor-Mediated Regulation of Dorsal Raphe and Hippocampal Cell Activity , 2001, The Journal of Neuroscience.

[27]  K. Lesch,et al.  Impulsivity, aggression, and serotonin: a molecular psychobiological perspective. , 2000, Behavioral sciences & the law.

[28]  M. Kung,et al.  Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A , 1999, Brain Research.

[29]  R. Hen,et al.  5‐HT Receptor Knockout Mice: Pharmacological Tools or Models of Psychiatric Disorders , 1999, Annals of the New York Academy of Sciences.

[30]  M. Linnoila,et al.  CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. , 1990, The Journal of clinical psychiatry.

[31]  M. Geyer,et al.  Tolerance and cross-tolerance to the activating effects of 3,4-methylenedioxymethamphetamine and a 5-hydroxytryptamine1B agonist. , 1992, The Journal of pharmacology and experimental therapeutics.

[32]  K. Lesch,et al.  Reduction in the Density and Expression, But Not G-Protein Coupling, of Serotonin Receptors (5-HT1A) in 5-HT Transporter Knock-Out Mice: Gender and Brain Region Differences , 2000, The Journal of Neuroscience.

[33]  Dennis L. Murphy,et al.  Excessive Activation of Serotonin (5-HT) 1B Receptors Disrupts the Formation of Sensory Maps in Monoamine Oxidase A and 5-HT Transporter Knock-Out Mice , 2001, The Journal of Neuroscience.

[34]  E. Coccaro.  Central Serotonin and Impulsive Aggression , 1989, British Journal of Psychiatry.

[35]  P. Mandel,et al.  Inhibition of mouse killing behavior by serotonin-mimetic drugs: Effects of partial alterations of serotonin neurotransmission , 1987, Pharmacology Biochemistry and Behavior.

[36]  G. Barr,et al.  Effects of para-chlorophenylalanine and 5-hydroxytryptophan on mouse killing behavior in killer rats , 1978, Pharmacology Biochemistry and Behavior.

[37]  L. Valzelli,et al.  p-Chlorophenylalanine-induced muricidal aggression in male and female laboratory rats. , 1981, Neuropsychobiology.

[38]  Antoine Depaulis,et al.  Parachlorophenylalanine-induced serotonin depletion increases offensive but not defensive aggression in male rats , 1986, Physiology & Behavior.

[39]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[40]  D. Hoyer,et al.  Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice. , 1999, Journal of neurobiology.

[41]  C. Oberlander,et al.  Tolerance to the serotonin 5-HT1 agonist RU 24969 and effects on dopaminergic behaviour. , 1987, European journal of pharmacology.

[42]  K. Miczek,et al.  Brain 5-HT and inhibition of aggressive behavior in animals: 5-HIAA and receptor subtypes. , 1989, Psychopharmacology bulletin.

[43]  D. Murphy,et al.  Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Gaspar,et al.  Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. , 1995, Science.

[45]  S. Tyano,et al.  Family-based association study of serotonin transporter promoter in suicidal adolescents: no association with suicidality but possible role in violence traits. , 2001, American journal of medical genetics.

[46]  R. Hen,et al.  Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice. , 2001, Biological psychiatry.

[47]  J. Neill,et al.  Pharmacological analysis of the behavioural and thermoregulatory effects of the putative 5-HT1 receptor agonist, RU 24969, in the rat , 1986, Neuropharmacology.

[48]  R. Saunders,et al.  In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. , 1998, The American journal of psychiatry.

[49]  B. Olivier,et al.  Serotonergic modulation of social interactions in isolated male mice , 2004, Psychopharmacology.

[50]  K. Matthews,et al.  Aggression, Impulsivity, and Central Nervous System Serotonergic Responsivity in a Nonpatient Sample , 1998, Neuropsychopharmacology.

[51]  S. Snyder,et al.  Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase , 1995, Nature.

[52]  G. Kennett,et al.  5-HT1B agonists induce anorexia at a postsynaptic site. , 1987, European journal of pharmacology.

[53]  K. Miczek,et al.  Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists , 1998, Psychopharmacology.

[54]  B. Bondy,et al.  Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide , 2000, Molecular Psychiatry.

[55]  L. Valzelli,et al.  Aggressiveness by isolation and brain serotonin turnover changes in different strains of mice. , 1979, Neuropsychobiology.

[56]  M. Geyer,et al.  Serotonin1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release , 1993, Neuropsychopharmacology.

[57]  S. Peroutka,et al.  Pharmacological Differentiation and Characterization of 5‐HT1A, 5‐HT1B, and 5‐HT1C Binding Sites in Rat Frontal Cortex , 1986, Journal of neurochemistry.

[58]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[59]  Jeremy Veenstra-Vander Weele,et al.  Serotonin Transporter and Seasonal Variation in Blood Serotonin in Families with Obsessive-Compulsive Disorder , 1998, Neuropsychopharmacology.

[60]  M. Scheinin,et al.  Adrenergic α2C-Receptors Modulate the Acoustic Startle Reflex, Prepulse Inhibition, and Aggression in Mice , 1998, The Journal of Neuroscience.

[61]  D. Murphy,et al.  Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. , 1999, American journal of medical genetics.