5-HT1B receptors and aggression: a review.

The serotonergic (5-HT) system in the brain is involved in the modulation of offensive aggressive behavior. The dogma that activity of the 5-HT system is inversely related to aggression is obsolete now. Research on the status of the 5-HT system before, during and after the execution of aggression is ongoing but has not yet led to a clear picture about the actual functional role of the 5-HT system, the more because state versus trait aggression seems to play a pivotal role in the outcome. Pharmacological challenges pinpoint 5-HT(1A) and 5-HT(1B) receptors as key players in the modulation of offensive aggression. This review emphasizes in particular the role of postsynaptic 5-HT(1B) (hetero) receptors as a premier site to modulate offensive aggression. Modulation of the firing and 5-HT release of the serotonergic neuron, via presynaptic 5-HT(1A) (auto) receptors, presynaptic 5-HT(1B) (auto) receptors and serotonergic transporters, may also have striking influences on aggression under certain conditions. Therefore, it is hypothesized that postsynaptic 5-HT(1B) (hetero) receptors directly influence the executive, consummatory phases of agonistic behavior, whereas presynaptic serotonergic feedback systems are particularly useful in the introductory (appetitive) phases of the agonistic behavioral complex.

[1]  C. Benkelfat,et al.  A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior , 2003, Molecular Psychiatry.

[2]  Frederick K. Goodwin,et al.  Aggression in humans correlates with cerebrospinal fluid amine metabolites , 1979, Psychiatry Research.

[3]  J. Rapoport,et al.  Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behavior disorders of children and adolescents. , 1990, Archives of general psychiatry.

[4]  K. Miczek,et al.  Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline , 2001, Psychopharmacology.

[5]  K. Miczek,et al.  Aggressive Behavior, Increased Accumbal Dopamine, and Decreased Cortical Serotonin in Rats , 2000, The Journal of Neuroscience.

[6]  M. Millan,et al.  Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists. , 1994, The Journal of pharmacology and experimental therapeutics.

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

[8]  B. Olivier,et al.  The effects of intraventricular administration of eltoprazine, 1-(3-trifluoromethylphenyl)piperazine hydrochloride and 8-hydroxy-2-(di-n-propylamino)tetralin on resident intruder aggression in the rat. , 1992, European journal of pharmacology.

[9]  S. D. de Boer,et al.  Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635. , 1999, The Journal of pharmacology and experimental therapeutics.

[10]  K. Miczek,et al.  Zolmitriptan – a 5-HT1B/D agonist, alcohol, and aggression in mice , 2001, Psychopharmacology.

[11]  M. Hamon,et al.  Cellular and subcellular localization of 5-hydroxytryptamine1B receptors in the rat central nervous system: immunocytochemical, autoradiographic and lesion studies , 1999, Neuroscience.

[12]  M. Tansella,et al.  Brain serotonin metabolism in isolated aggressive mice. , 1968, Biochemical pharmacology.

[13]  C. Broeckhoven,et al.  Genetics of personality: are we making progress? , 2003, Molecular Psychiatry.

[14]  B. Olivier,et al.  The effects of dorsal raphe administration of eltoprazine, TFMPP and 8-OH-DPAT on resident intruder aggression in the rat. , 1993, European journal of pharmacology.

[15]  T. Gregg,et al.  Neuropharmacology of brain-stimulation-evoked aggression , 1999, Neuroscience & Biobehavioral Reviews.

[16]  D. Adams,et al.  Offense produced by chemical stimulation of the anterior hypothalamus of the rat , 1993, Physiology & Behavior.

[17]  B. Bondy,et al.  Serotonin 1B (5HT‐1B) receptor polymorphism (G861C) in suicide victims: Association studies in German and Slavic population , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

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

[19]  S. Snyder,et al.  Selective labeling of serotonin uptake sites in rat brain by [3H]citalopram contrasted to labeling of multiple sites by [3H]imipramine. , 1987, The Journal of pharmacology and experimental therapeutics.

[20]  P. Bonaventure,et al.  Detailed mapping of serotonin 5-HT1B and 5-HT1D receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function , 1997, Neuroscience.

[21]  D. Rujescu,et al.  Lack of association between serotonin 5‐HT1B receptor gene polymorphism and suicidal behavior , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[22]  J. Koolhaas,et al.  Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression , 2001, Physiology & Behavior.

[23]  J. Quinn,et al.  A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[26]  B. Olivier.  Selective Anti-Aggressive Properties of DU 27725: Ethological Analyses of Intermale and Territorial Aggression in the Male Rat , 1981, Pharmacology Biochemistry and Behavior.

[27]  J. Koolhaas,et al.  Cerebrospinal fluid monoamine and metabolite concentrations and aggression in rats , 2003, Hormones and Behavior.

[28]  B. Olivier,et al.  Social behaviour in rats and mice: An ethologically based model for differentiating psychoactive drugs , 1982 .

[29]  J. Haller,et al.  Neurochemical characterization of hypothalamic neurons involved in attack behavior: Glutamatergic dominance and co-expression of thyrotropin-releasing hormone in a subset of glutamatergic neurons , 2005, Neuroscience.

[30]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[31]  M. Millan,et al.  S 15535: a highly selective benzodioxopiperazine 5-HT1A receptor ligand which acts as an agonist and an antagonist at presynaptic and postsynaptic sites respectively. , 1993, European journal of pharmacology.

[32]  Patrick Hardy,et al.  Possible association between serotonin transporter gene polymorphism and violent suicidal behavior in mood disorders , 2000, Biological Psychiatry.

[33]  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.

[34]  E. Morrel,et al.  [Quantitative autoradiography]. , 1982, Acta histochemica. Supplementband.

[35]  M. Kruk.  Ethology and pharmacology of hypothalamic aggression in the rat , 1991, Neuroscience & Biobehavioral Reviews.

[36]  Gerald L. Brown,et al.  Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations. , 1998, Archives of general psychiatry.

[37]  K. Miczek,et al.  Alcohol and heightened aggression in individual mice. , 1998, Alcoholism, clinical and experimental research.

[38]  B. Hoffman.  Molecular Biology of Serotonin Uptake Sites , 1993 .

[39]  R. Hen,et al.  Absence of 5-HT1B receptors is associated with impaired impulse control in male 5-HT1B knockout mice , 2001, Biological Psychiatry.

[40]  R. Hen,et al.  The mouse 5-hydroxytryptamine 1B receptor is localized predominantly on axon terminals , 1994, Neuroscience.

[41]  L. Kirby,et al.  Median and dorsal raphe neurons are not electrophysiologically identical. , 2004, Journal of neurophysiology.

[42]  R. Murray,et al.  A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. , 1996, Molecular psychiatry.

[43]  T. Branchek,et al.  The rat 5-hydroxytryptamine1B receptor is the species homologue of the human 5-hydroxytryptamine1D beta receptor. , 1992, Molecular pharmacology.

[44]  K. Miczek,et al.  ß Federation of European Neuroscience Societies Accumbal dopamine and serotonin in anticipation of the next aggressive episode in rats , 2022 .

[45]  S. D. de Boer,et al.  Individual Variation in Aggression of Feral Rodent Strains: A Standard for the Genetics of Aggression and Violence? , 2003, Behavior genetics.

[46]  E. Schlicker,et al.  Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[47]  R. Schreiber,et al.  S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT)1A receptors: II. Modulation of hippocampal serotonin release in relation to potential anxiolytic properties. , 1997, The Journal of pharmacology and experimental therapeutics.

[48]  P. Riederer,et al.  Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene , 2005, Journal of Neural Transmission / General Section JNT.

[49]  J. Duan,et al.  DNA variation and psychopharmacology of the human serotonin receptor 1B (HTR1B) gene. , 2002, Pharmacogenomics.

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

[51]  Subcellular localization of 5‐HT1B binding sites in the stratum griseum superficiale of the rat superior colliculus: An electron microscopic quantitative autoradiographic study , 1996, Synapse.

[52]  G Maura,et al.  Cholinergic terminals in rat hippocampus possess 5-HT1B receptors mediating inhibition of acetylcholine release. , 1986, European journal of pharmacology.

[53]  R. Summers,et al.  Antidepressant binding sites in brain: autoradiographic comparison of [3H]paroxetine and [3H]imipramine localization and relationship to serotonin transporter. , 1990, The Journal of pharmacology and experimental therapeutics.

[54]  D. Levinson,et al.  Polymorphisms in the 5′-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression , 2003, Molecular Psychiatry.

[55]  V. Arango,et al.  Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue , 1999, Neuropsychopharmacology.

[56]  K. Miczek,et al.  Aggression heightened by alcohol or social instigation in mice: reduction by the 5-HT1B receptor agonist CP-94,253 , 1999, Psychopharmacology.

[57]  E. Mundo,et al.  Is the 5-HT(1Dbeta) receptor gene implicated in the pathogenesis of obsessive-compulsive disorder? , 2000, The American journal of psychiatry.

[58]  R. Busch,et al.  A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety , 2004, Molecular Psychiatry.

[59]  G. Goodwin,et al.  Polymorphism in serotonin transporter gene associated with susceptibility to major depression , 1996, The Lancet.

[60]  E. Coccaro,et al.  Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. , 1997, Archives of general psychiatry.

[61]  R. McGuffin,et al.  Conversion of the human 5-HT1D beta serotonin receptor to the rat 5-HT1B ligand-binding phenotype by Thr355Asn site directed mutagenesis. , 1992, Biochemical pharmacology.

[62]  J. Palacios,et al.  Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors , 1985, Brain Research.

[63]  J. Gugten,et al.  Operant learning and differential-reinforcement-of-low-rate 36-s responding in 5-HT1A and 5-HT1B receptor knockout mice , 2003, Behavioural Brain Research.

[64]  B. O'dowd,et al.  A single amino-acid difference confers major pharmacological variation between human and rodent 5-HT1B receptors , 1992, Nature.

[65]  M. Göthert,et al.  Genetic Variation in Human 5‐HT Receptors: Potential Pathogenetic and Pharmacological Role a , 1998, Annals of the New York Academy of Sciences.

[66]  J. Palacios,et al.  Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in rat brain , 1993, Naunyn-Schmiedeberg's Archives of Pharmacology.

[67]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[68]  L. Siever,et al.  Suicide, impulsive aggression, and HTR1B genotype , 2001, Biological Psychiatry.

[69]  J. Veening,et al.  Behavioural responses of bicucculline methiodide injections into the ventral hypothalamus of freely moving, socially interacting rats , 1993, Brain Research.

[70]  K. Miczek,et al.  Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice: Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist , 2002, Neuropsychopharmacology.

[71]  E. Mundo,et al.  Is the 5-HT1Dβ Receptor Gene Implicated in the Pathogenesis of Obsessive-Compulsive Disorder? , 2000 .

[72]  D. Hyun,et al.  Possible association between serotonin transporter promoter region polymorphism and impulsivity in Koreans , 2003, Psychiatry Research.

[73]  P. Celada,et al.  Origin and functional role of the extracellular serotonin in the midbrain raphe nuclei , 2002, Brain Research Reviews.

[74]  H. Miyaoka,et al.  Association of a polymorphism of the serotonin 1B receptor gene and alcohol dependence with inactive aldehyde dehydrogenase-2 , 2002, Journal of Neural Transmission.

[75]  H. T. Chen,et al.  Quantitative autoradiography of 3H-paroxetine binding sites in rat brain. , 1992, Journal of pharmacological and toxicological methods.

[76]  H. Ono,et al.  No evidence of an association between 5HT1B receptor gene polymorphism and suicide victims in a Japanese population. , 2001, American journal of medical genetics.

[77]  J. Schipper,et al.  Serenics: the pharmacology of fluprazine and DU 28412. , 1984, Progress in clinical and biological research.

[78]  P. Blier,et al.  Autoregulation of serotonin neurons: role in antidepressant drug action. , 1999, Pharmacological reviews.

[79]  S. Lane,et al.  Effects of chronic paroxetine administration on measures of aggressive and impulsive responses of adult males with a history of conduct disorder , 2001, Psychopharmacology.

[80]  A. M. Poel,et al.  Anti-aggressive effect of a new phenylpiperazine compound (DU27716) on hypothalamically induced behavioural activities , 1982, Pharmacology Biochemistry and Behavior.

[81]  R. Hen,et al.  Insights into the Neurobiology of Impulsive Behavior from Serotonin Receptor Knockout Mice , 1997, Annals of the New York Academy of Sciences.

[82]  D. Copolov,et al.  Differential Role of Serotonergic Projections Arising from the Dorsal and Median Raphe Nuclei in Locomotor Hyperactivity and Prepulse Inhibition , 2003, Neuropsychopharmacology.

[83]  E. Zifa,et al.  5-Hydroxytryptamine receptors. , 1992, Pharmacological reviews.

[84]  J. Thome,et al.  Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology. , 2004, Behavioral sciences & the law.

[85]  V. Arango,et al.  Genetics of the serotonergic system in suicidal behavior. , 2003, Journal of psychiatric research.

[86]  R. McGuffin,et al.  Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity. , 1992, Biochemical and biophysical research communications.

[87]  B. Olivier,et al.  Impulsive-like behavior in differential-reinforcement-of-low-rate 36 s responding in mice depends on training history , 2004, Neuroscience Letters.

[88]  G. Juhász,et al.  Aggressive experience affects the sensitivity of neurons towards pharmacological treatment in the hypothalamic attack area , 1998, Behavioural pharmacology.

[89]  J. Kennedy,et al.  Association of the serotonin transporter and 5HT1D&bgr; receptor genes with extreme, persistent and pervasive aggressive behaviour in children , 2004, Psychiatric genetics.

[90]  L. Young,et al.  ANIMAL MODELS OF AGGRESSION , 2001 .

[91]  M. Buhot,et al.  5-HT1B receptor knock out — behavioral consequences , 1995, Behavioural Brain Research.

[92]  J. Koolhaas,et al.  Somatodendritic 5-HT1A Autoreceptors Mediate the Anti-Aggressive Actions of 5-HT1A Receptor Agonists in Rats: An Ethopharmacological Study with S-15535, Alnespirone, and WAY-100635 , 2000, Neuropsychopharmacology.

[93]  M Linnoila,et al.  Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior. , 1983, Life sciences.

[94]  M. Hamon,et al.  In situ hybridization evidence for the synthesis of 5‐HT1B receptor in serotoninergic neurons of anterior raphe nuclei in the rat brain , 1995, Synapse.

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

[96]  A. M. Poel,et al.  The induction of aggressive behaviour by electrical stimulation in the hypothalamus of male rats. , 1979, Behaviour.

[97]  B. Olivier,et al.  Chronic treatment with eltoprazine does not lead to tolerance in its anti-aggressive action, in contrast to haloperidol , 1996, European Neuropsychopharmacology.

[98]  J. Palacios,et al.  Localization of 5-HT1B, 5-HT1Dα, 5-HT1E and 5-HT1F receptor messenger RNA in rodent and primate brain , 1994, Neuropharmacology.

[99]  B. Olivier,et al.  BEHAVIOURAL PHARMACOLOGY OF THE SERENIC, ELTOPRAZINE , 1990, Drug metabolism and drug interactions.

[100]  R. Rozmahel,et al.  Characterization of the human 5-hydroxytryptamine1B receptor. , 1992, The Journal of biological chemistry.

[101]  M. Walsh,et al.  Selective serotonin reuptake inhibitors and violence: a review of the available evidence , 2001, Acta psychiatrica Scandinavica.

[102]  S. Tsai,et al.  Possible Association between Serotonin Transporter Promoter Region Polymorphism and Extremely Violent Crime in Chinese Males , 2004, Neuropsychobiology.

[103]  P. Seeburg,et al.  Molecular cloning and characterization of a rat brain cDNA encoding a 5‐hydroxytryptamine1B receptor. , 1991, The EMBO journal.

[104]  G. Martin,et al.  Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. , 1996, Trends in pharmacological sciences.

[105]  K. Miczek,et al.  Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and γ-aminobutyric acid systems , 2002, Psychopharmacology.

[106]  B. Olivier,et al.  Serenics and aggression , 1986 .

[107]  I. Törk.  Anatomy of the Serotonergic System a , 1990, Annals of the New York Academy of Sciences.

[108]  Y. Sari.  Serotonin1B receptors: from protein to physiological function and behavior , 2004, Neuroscience & Biobehavioral Reviews.

[109]  B. Bondy,et al.  Association of 5-HT1B receptor gene and antisocial behavior in alcoholism , 2004, Journal of Neural Transmission.

[110]  A. M. Poel,et al.  Hypothalamic substrates for brain stimulation-induced attack, teeth-chattering and social grooming in the rat , 1988, Brain Research.