5-HT1B Receptors and aggression / impulsivity


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(Updated 4th quarter 2002)

Clark MS, Neumaier JF.
The 5-HT1B receptor: behavioral implications.
Psychopharmacol Bull. 2001 Autumn;35(4):170-85.
"5-HT1B receptors are expressed throughout the mammalian central nervous system. These receptors are located in the axon terminals of both serotonergic and nonserotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. 5-HT1B receptors inhibit the release of a range of neurotransmitters, including serotonin, GABA, acetylcholine, and glutamate. These receptors have been difficult to study because of the diversity of their cellular localization and the absence of highly selective agonists and antagonists. There has been accumulating evidence, however, that 5-HT1B receptors modulate drug reinforcement, stress sensitivity, mood, anxiety, and aggression. The general results of a number of studies suggest that reduced 5-HT1B heteroreceptor activity may increase impulsive behaviors, whereas reduced 5-HT1B autoreceptor activity may have an antidepressant-like effect. This review focuses on the evidence from animal studies and human genetics that suggest that 5-HT1B receptors may be involved in the mechanism of action of antidepressants and may become important targets of drug therapy in the future." [Abstract]

Scearce-Levie K, Chen JP, Gardner E, Hen R.
5-HT receptor knockout mice: pharmacological tools or models of psychiatric disorders.
Ann N Y Acad Sci. 1999 Apr 30;868:701-15.
"The molecular diversity of cloned serotonin receptor subtypes in the brain makes it difficult to understand the specific modulatory roles played by different receptors. In order to understand the role of the 5-HT1B receptor subtype in behavior and neuropsychiatric disorders, we have been studying genetic knockout mice lacking the 5-HT1B receptor. The 5-HT1B knockout mice show evidence of increased aggression and impulsivity, behavioral patterns that are also associated with reduced 5-HT function. They also show reduced or absent locomotor stimulation to some serotoninergic drugs, indicating that the locomotor effects of these drugs require the 5-HT1B receptor. However, in some cases, data obtained with knockout mice conflicts with the pharmacological data. The 5-HT1B receptor knockout mice show a phenotype of increased vulnerability to drugs of abuse such as cocaine. However, pharmacological studies suggest that 5-HT1B stimulation enhances the effects of cocaine, while 5-HT1B blockade can attenuate some of the effects of cocaine. Compensations that enhance dopamine function appear to be responsible for the drug-vulnerable phenotype of 5-HT1B receptor knockout mice. By studying these compensations and changes in neural function, we can learn more about the fundamental mechanisms underlying addiction. The 5-HT1B knockout mice should be considered a model for the disease state of vulnerability to drugs of abuse, rather than a direct pharmacological model of 5-HT1B receptor function." [Abstract]

Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM, Khait V, Mann JJ.
Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.
Neuropsychopharmacology. 2003 Jan;28(1):163-9.
"The 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies." [Abstract]

Lappalainen J, Long JC, Eggert M, Ozaki N, Robin RW, Brown GL, Naukkarinen H, Virkkunen M, Linnoila M, Goldman D.
Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations.
Arch Gen Psychiatry. 1998 Nov;55(11):989-94.
"BACKGROUND: In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism. METHODS: Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects. RESULTS: In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-861C allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01). CONCLUSION: These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15." [Abstract]

Rujescu D, Giegling I, Sato T, Moller HJ.
Lack of association between serotonin 5-HT1B receptor gene polymorphism and suicidal behavior.
Am J Med Genet. 2003 Jan 1;116B(1):69-71.
"A genetic susceptibility to suicide attempts has been repeatedly suggested by family-, twin-, and adoption-studies. Because elevated impulsive aggression is one of the most prominent characteristics of suicide attempters and aggressive behavior has been reported in 5-HT1B receptor gene knockout mice, the serotonin receptor 1B gene (5-HT1B) is an attractive candidate. The distribution of a polymorphism (G861C) in the 5-HT1B gene was examined in 148 consecutively hospitalized German suicide attempters, and 327 German healthy volunteers randomly recruited from the general population. The controls and their first degree relatives had no history of mental disorders or suicidal behavior. We found no significant difference in allele or genotype frequency between patients and controls. The results did not differ when the patients were divided into several subgroups (gender, suicide attempters with a violent method or suicide attempters with unipolar-, bipolar-, borderline personality-, and schizophrenia spectrum disorders). These findings suggest that the 5-HT1B polymorphism is unlikely to play a major role in the genetic susceptibility to suicide attempts." [Abstract]

Huang YY, Grailhe R, Arango V, Hen R, Mann JJ.
Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue.
Neuropsychopharmacology. 1999 Aug;21(2):238-46.
"Knockout of the 5-HT1B gene in mice results in increased aggression, as well as alcohol and cocaine consumption. Given the clinical association of aggression, suicide, alcoholism, and substance abuse, we studied relationship of psychopathology to the human 5-HT1B receptor gene (N = 178) and postmortem human 5-HT1B receptor binding (N = 96) in the brain. The sample comprised: 71 suicide victims, 107 nonsuicides, 45 with a history of major depression and 79 without, 64 with a history of a alcoholism or substance abuse and 60 without, as well as 36 with a history of pathological aggression and 42 without. Single-strand conformational polymorphism (SSCP) analysis and DNA sequencing techniques were used to screen the coding region of the human 5-HT1B receptor gene in genomic DNA isolated from postmortem human brain tissue. Two common polymorphisms were identified in the 5-HT1B receptor gene, involving a silent C to T substitution at nucleotide 129 and a silent G to C substitution at nucleotide 861 of the coding region. These polymorphisms were found with the same frequency in the suicide and the nonsuicide groups and in those with and without a history of major depression, alcoholism, or pathological aggression. The binding indices (Bmax and KD of the 5-HT1B receptor in prefrontal cortex also did not differ in suicides and controls, major depression, alcoholism, and cases with a history of pathological aggression. The C129 or G861 allele had 20% fewer 5-HT1B receptor compared to the 129T or 861C allele. We did not identify a relationship between suicide, major depression, alcoholism, or pathological aggression with 5-HT1B receptor binding indices or genotype." [Abstract]

de Almeida RM, Miczek KA.
Aggression escalated by social instigation or by discontinuation of reinforcement ("frustration") in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist.
Neuropsychopharmacology. 2002 Aug;27(2):171-81.
"Experiments with social instigation or the omission of scheduled reinforcement show that serotonergic mechanisms may be involved in escalated aggression in animals. 5-HT1B receptor agonists have anti-aggressive effects in individuals who show moderate as well as high levels of aggression. The present study compared the effects of the 5-HT1B agonist anpirtoline (0.125-1.5 mg/kg) on (1) species-typical aggressive behavior in male mice, (2) aggression "instigated" or primed by prior exposure to the opponent, and (3) aggression heightened by "frustration" caused by omission of scheduled reinforcement. The effects of anpirtoline on species-typical behavior were also assessed after pretreatment with the 5-HT1B/1D receptor antagonist GR127935 (10 mg/kg). Anpirtoline, like other 5-HT1B agonists (CP-94,253, zolmitriptan), decreased both instigated and frustration-heightened aggression, while motor behavior was unaffected. The aggression-inhibiting effects of anpirtoline were blocked by pretreatment with GR127935. The current results indicate that the 5-HT(1B) receptor is critically involved in the modulation of escalated aggression." [Abstract]

Miczek KA, de Almeida RM.
Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline.
Psychopharmacology (Berl). 2001 Oct;157(4):421-9.
"RATIONALE: In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. OBJECTIVES: To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. METHODS: Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. RESULTS: After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. CONCLUSIONS: Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression." [Abstract]

Ferris CF, Melloni RH Jr, Koppel G, Perry KW, Fuller RW, Delville Y.
Vasopressin/serotonin interactions in the anterior hypothalamus control aggressive behavior in golden hamsters.
J Neurosci. 1997 Jun 1;17(11):4331-40.
"Studies in several species of rodents show that arginine vasopressin (AVP) acting through a V1A receptor facilitates offensive aggression, i.e., the initiation of attacks and bites, whereas serotonin (5-HT) acting through a 5-HT1B receptor inhibits aggressive responding. One area of the CNS that seems critical for the organization of aggressive behavior is the basolateral hypothalamus, particularly the anterior hypothalamic region. The present studies examine the neuroanatomical and neurochemical interaction between AVP and 5-HT at the level of the anterior hypothalamus (AH) in the control of offensive aggression in Syrian golden hamsters. First, specific V1A and 5-HT1B binding sites in the AH are shown by in vitro receptor autoradiography. The binding for each neurotransmitter colocalizes with a dense field of immunoreactive AVP and 5-HT fibers and putative terminals. Putative 5-HT synapses on AVP neurons in the area of the AH are identified by double-staining immunocytochemistry and laser scanning confocal microscopy. These morphological data predispose a functional interaction between AVP and 5-HT at the level of the AH. When tested for offensive aggression in a resident/intruder paradigm, resident hamsters treated with fluoxetine, a selective 5-HT reuptake inhibitor, have significantly longer latencies to bite and bite fewer times than vehicle-treated controls. Conversely, AVP microinjections into the AH significantly shorten the latency to bite and increase biting attacks. The action of microinjected AVP to increase offensive aggression is blocked by the pretreatment of hamsters with fluoxetine. These data suggest that 5-HT inhibits fighting, in part, by antagonizing the aggression-promoting action of the AVP system." [Abstract]

Rilke O, Will K, Jahkel M, Oehler J.
Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice.
Prog Neuropsychopharmacol Biol Psychiatry. 2001 Jul;25(5):1125-44.
"Acute effects of serotonergic drugs acting via different mechanisms were investigated by a social interaction test and subsequent determination of serotonin and dopamine metabolisms in mice housed in groups or isolated for 6 weeks. A resident/intruder test was performed with anpirtoline (5-HT1B receptor agonist in rodents; 1 mg/kg), citalopram (SSRI; 0.5 mg/kg) and saline treatment before animals were decapitated and different brain regions were frozen for subsequent HPLC-analyses. Behavioral investigations indicated a strong increase of aggressive behavior after 6 weeks of isolation housing. Acute citalopram treatment did not influence behavioral parameters of isolated and group housed mice. In contrast, anpirtoline antagonized isolation induced aggressive behavioral components in a specific manner. Analysis of dopamine and serotonin metabolism revealed that citalopram treatment did not affect dopamine metabolism, but reduced serotonin metabolism in the striatum, hippocampus, cortex and midbrain independent of housing conditions. In contrast, anpirtoline treatment increased dopamine metabolism in cortex, striatum and midbrain as well as influenced serotonin metabolism in a structure- and state-specific manner. Whereas anpirtoline decreased serotonin metabolism in the cortex, the midbrain and the hippocampus independent of housing conditions, in the striatum anpirtoline abolished the isolation induced decrease of serotonin metabolism. These results indicate that anpirtoline might induce antiaggressive effects via postsynaptic receptor- and structure-specific activation of serotonergic but also dopaminergic processes, whereas structure independent increase of synaptic serotonin via citalopram was ineffective to reverse aggressivity in isolated mice." [Abstract]






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Recent 5-HT1B and Aggression/Impulsivity Research

1) Yohe LR, Suzuki H, Lucas LR
Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT(1B)/ striatal dopamine D (2) receptor density.
Cogn Affect Behav Neurosci. 2012 Sep;12(3):446-59.
Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed. [PubMed Citation] [Order full text from Infotrieve]

2) Dennis RL, Cheng HW
Effects of selective serotonin antagonism on central neurotransmission.
Poult Sci. 2012 Apr;91(4):817-22.
Aggression and cannibalism in laying hens can differ in intensity and degree due to many factors, including genetics. Previous behavioral analysis of 2 strains of White Leghorns, DeKalb XL (DXL) and HGPS (a group-selected line for high group productivity and survivability), revealed high and low aggressive phenotypes, respectively. However, the exact genetic mechanisms mediating aggressiveness are currently unknown. Analysis of serotonin (5-HT) mediation of aggression in subordinate hens of these strains revealed increases in aggression in DXL hens following antagonism of the 5-HT1A receptor and in HGPS hens following antagonism of the 5-HT1B receptor. Here, we investigate the different neurotransmitter response in the hypothalamus and raphe nucleus mediating these aggressive responses to receptor antagonism. Elevated aggressive response to 5-HT1B antagonism by HGPS hens was also accompanied by a decrease in raphe nucleus dopamine (DA) and an increase in DA turnover. Increased aggressiveness in DXL hens did not coincide with a reduction in raphe nucleus 5-HT or turnover (as indicated by 5-hydroxyindoleacetic acid levels) following 5-HT1A antagonism. A reduction in 5-hydroxyindoleacetic acid (but not 5-HT) was seen in HGPS hens treated with 5-HT1A antagonist; however, these hens exhibited no change in aggressive behaviors. Our data show evidence of different heritable mechanisms of neurotransmitter regulation of aggressive response, specifically heritable differences in the interaction between 5-HT and catecholamines in regulating aggression. [PubMed Citation] [Order full text from Infotrieve]

3) Clinton SM, Kerman IA, Orr HR, Bedrosian TA, Abraham AD, Simpson DN, Watson SJ, Akil H
Pattern of forebrain activation in high novelty-seeking rats following aggressive encounter.
Brain Res. 2011 Nov 8;1422:20-31.
We have previously demonstrated that selectively-bred High (bHR) and Low (bLR) novelty-seeking rats exhibit agonistic differences, with bHRs acting in a highly aggressive manner when facing homecage intrusion. In order to discover the specific neuronal pathways responsible for bHRs' high levels of aggression, the present study compared c-fos mRNA expression in several forebrain regions of bHR/bLR males following this experience. bHR/bLR males were housed with female rats for 2 weeks, and then the females were replaced with a male intruder for 10 min. bHR/bLR residents were subsequently sacrificed by rapid decapitation, and their brains were removed and processed for c-fos in situ hybridization. Intrusion elicited robust c-fos mRNA expression in both phenotypes throughout the forebrain, including the septum, amygdala, hippocampus, cingulate cortex, and the hypothalamus. However, bHRs and bLRs exhibited distinct activation patterns in select areas. Compared to bHR rats, bLRs expressed greater c-fos in the lateral septum and within multiple hypothalamic nuclei, while bHRs showed greater activation in the arcuate hypothalamic nucleus and in the hippocampus. No bHR/bLR differences in c-fos expression were detected in the amygdala, cortical regions, and striatum. We also found divergent 5-HT1A receptor mRNA expression within some of these same areas, with bLRs having greater 5-HT1A, but not 5-HT1B, receptor mRNA levels in the septum, hippocampus and cingulate cortex. These findings, together with our earlier work, suggest that bHRs exhibit altered serotonergic functioning within select circuits during an aggressive encounter. [PubMed Citation] [Order full text from Infotrieve]

4) da Veiga CP, Miczek KA, Lucion AB, de Almeida RM
Social instigation and aggression in postpartum female rats: role of 5-Ht1A and 5-Ht1B receptors in the dorsal raphé nucleus and prefrontal cortex.
Psychopharmacology (Berl). 2011 Feb;213(2-3):475-87.
[PubMed Citation] [Order full text from Infotrieve]

5) Suzuki H, Han SD, Lucas LR
Increased 5-HT1B receptor density in the basolateral amygdala of passive observer rats exposed to aggression.
Brain Res Bull. 2010 Aug 30;83(1-2):38-43.
Previous studies have shown that repeated observations of aggressive incidents (i.e., chronic passive exposure to aggression) increase aggressiveness of a passive observer and downregulate the densities of serotonin 5-HT(1B) receptors in some tegmental regions. However, other brain areas (e.g., medial- and basolateral amygdala, hypothalamus, and hippocampus) have been implicated in different types of aggressive behavior including fear-induced defensive rage, steroid-induced aggression, and other types of aggression (e.g., learned aggression). The present study analyzed 5-HT(1B) receptor densities in those brain regions of aggressive observers to compare them with neurochemical markers of the different types of aggression. It was hypothesized that passive exposure to aggression for 23 consecutive days would result in altered 5-HT(1B) receptor densities in the ventromedial hypothalamus, medial amygdaloid nucleus, CA1 of the hippocampus, globus pallidus, dentate gyrus, and/or basolateral amygdala. Here we report that observer rats exposed to aggression exhibited higher densities of 5-HT(1B) receptors in only the basolateral amygdala, compared with those exposed to the non-aggressive condition. These results suggest that chronic passive exposure to aggression may elicit a form of learned aggression rather than fear- or steroid-induced aggression among passive observers. In addition, our study implies that 5-HT(1B) receptors play brain-region specific roles in expressing aggression. [PubMed Citation] [Order full text from Infotrieve]

6) Conner TS, Jensen KP, Tennen H, Furneaux HM, Kranzler HR, Covault J
Functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):67-78.
We examined associations between haplotypes of the serotonin 1B receptor gene and individual differences in anger and hostility. Data were analyzed from a study of 361 university students (47% male). Participants were genotyped at five polymorphisms in the HTR1B gene (rs11568817, rs130058, rs6296, rs6297, rs13212041), including promoter and 3'UTR polymorphisms with opposite functional effects on gene expression. Participants reported their emotional states across 30 consecutive days for up to 4 years. Haplotype pairs were constructed statistically and assigned to a level of HTR1B expression based on the presence of the functional polymorphisms. Six haplotypes accounted for >97% of chromosomes. Three low expression haplotypes contained the 3'UTR variant (rs13212041 A-allele) that enables a microRNA-mediated reduction in expression. One intermediate expression haplotype contained the 3'UTR A-allele paired with the high-activity promoter. Two high expression haplotypes contained the 3'UTR variant (rs13212041 G-allele) that attenuates microRNA-mediated reduction in expression. Men with low expression haplotypes reported greater anger and hostility than men with one or two high expression haplotypes. Diplotype classification accounted for 8.4% of the variance in men's anger and hostility, primarily due to the 3'UTR polymorphism (rs13212041), but with some contribution of the functional promoter combination (rs11568817, rs130058). Associations with anger and hostility were not found in women. These findings extend our understanding of the genetic basis of anger and hostility by showing that newly characterized HTR1B haplotypes, particularly those with rs13212041, which modulates microRNA-mediated regulation of HTR1B expression, may have important implications for aggression-related phenotypes among young men. [PubMed Citation] [Order full text from Infotrieve]

7) Centenaro LA, Vieira K, Zimmermann N, Miczek KA, Lucion AB, de Almeida RM
Social instigation and aggressive behavior in mice: role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex.
Psychopharmacology (Berl). 2008 Dec;201(2):237-48.
[PubMed Citation] [Order full text from Infotrieve]

8) Dennis RL, Chen ZQ, Cheng HW
Serotonergic mediation of aggression in high and low aggressive chicken strains.
Poult Sci. 2008 Apr;87(4):612-20.
Serotonin (5-HT) regulates aggressive behavior via binding to its receptors, such as 5-HT1A and 1B, in humans and rodents. Here we investigate the heritable components of 5-HT regulation of aggressiveness in chickens, utilizing 3 distinct genetic strains. In this study, we used 2 divergently selected strains (high and low group productivity and survivability, respectively; HGPS and LGPS) and a third strain, Dekalb XL (DXL), an aggressive out-group. Hens were paired within the same strain. At 24 wk of age, the subordinate of each pair received a daily i.p. injection of NAN-190 (0.5 mg/kg, a 5-HT1A antagonist), GR-127935 (0.5 mg/kg, a 5-HT1B antagonist), or saline (control) for 5 consecutive days. Frequency of aggressive behaviors was increased in the hens of DXL and LGPS treated with 5-HT1A antagonist and in the HGPS hens treated with 5-HT1B antagonist. The 5-HT1B antagonist-treated HGPS hens and 5-HT1A antagonist-treated LGPS hens also displayed increased feather pecking, but neither antagonist had an effect on feather pecking of DXL hens. This may suggest that multiple mediating factors alter feather pecking behaviors. Among the controls, LGPS hens have higher epinephrine levels than HGPS or DXL hens, indicative of the inferior stress-coping ability of LGPS hens. Treatment with 5-HT1B antagonist reduced epinephrine in LGPS hens but not in DXL or HGPS hens, suggesting a role of 5-HT1B in stress regulation in LGPS hens. The results provide evidence for different heritable serotonergic mediation of aggressive behaviors and stress coping in chickens. [PubMed Citation] [Order full text from Infotrieve]

9) Faccidomo S, Bannai M, Miczek KA
Escalated aggression after alcohol drinking in male mice: dorsal raphé and prefrontal cortex serotonin and 5-HT(1B) receptors.
Neuropsychopharmacology. 2008 Nov;33(12):2888-99.
A significant minority of individuals engages in escalated levels of aggression after consuming moderate doses of alcohol (Alc). Neural modulation of escalated aggression involves altered levels of serotonin (5-HT) and the activity of 5-HT(1B) receptors. The aim of these studies was to determine whether 5-HT(1B) receptors in the dorsal raphé (DRN), orbitofrontal (OFC), and medial prefrontal (mPFC) cortex attenuate heightened aggression and regulate extracellular levels of 5-HT. Male mice were trained to self-administer Alc by performing an operant response that was reinforced with a delivery of 6% Alc. To identify Alc-heightened aggressors, each mouse was repeatedly tested for aggression after consuming either 1.0 g/kg Alc or H2O. Next, a cannula was implanted into either the DRN, OFC, or mPFC, and subsets of mice were tested for aggression after drinking either Alc or H(2)O prior to a microinjection of the 5-HT(1B) agonist, CP-94,253. Additional mice were implanted with a microdialysis probe into the mPFC, through which CP-94,253 was perfused and samples were collected for 5-HT measurement. Approximately 60% of the mice were more aggressive after drinking Alc, confirming the aggression-heightening effects of 1.0 g/kg Alc. Infusion of 1 microg CP-94,253 into the DRN reduced both aggressive and motor behaviors. However, infusion of 1 microg CP-94,253 into the mPFC, but not the OFC, after Alc drinking, increased aggressive behavior. In the mPFC, reverse microdialysis of CP-94,253 increased extracellular levels of 5-HT; levels decreased immediately after the perfusion. This 5-HT increase was attenuated in self-administering mice. These results suggest that 5-HT(1B) receptors in the mPFC may serve to selectively disinhibit aggressive behavior in mice with a history of Alc self-administration. [PubMed Citation] [Order full text from Infotrieve]

10) Jensen KP, Covault J, Conner TS, Tennen H, Kranzler HR, Furneaux HM
A common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors.
Mol Psychiatry. 2009 Apr;14(4):381-9.
Non-coding regulatory elements can transduce the human genome's response to environmental stimuli. Thus, there is a possibility that variation in non-coding regulatory elements may underlie some of the diversity in human behavior. However, this idea has remained largely untested due to the difficulty in accurately identifying regulatory elements in the 98% of the human genome that does not encode protein. The recent recognition that small trans-acting RNAs anneal to mRNA and regulate gene expression provides a means to identify and test such variants. Here, we show that microRNA-directed silencing of mRNA can be attenuated by a common human polymorphism. We have identified an element (A-element) within serotonin receptor 1B (HTR1B) mRNA that confers repression by miR-96. The repressive activity of this element is attenuated by a common human variant (G-element) that disrupts a nucleotide critical for its interaction with miR-96. Because deletion of the HTR1B gene leads to an aggressive phenotype in mice, we hypothesized an association between the A/G polymorphism and aggressive phenotypes in a sample of 359 college students. As predicted, individuals homozygous for the ancestral A-element reported more conduct-disorder behaviors than individuals with the G-element. Our studies suggest that such functional variants may be common and may help to refine the search for genes involved in complex behavioral disorders. [PubMed Citation] [Order full text from Infotrieve]

11) Zhang CL, Chen H, Wang YH, Zhang RF, Lan XY, Lei CZ, Zhang L, Zhang AL, Hu SR
Serotonin receptor 1B (HTR1B) genotype associated with milk production traits in cattle.
Res Vet Sci. 2008 Oct;85(2):265-8.
Serotonin receptor 1B (HTR1B) is one of the 14 different identified serotonin receptors which are involved in the regulation of behaviors such as sleep, fear, aggression, mood, and feeding. The aims of this study were to characterize polymorphisms in the 5' coding and the 3' flanking regions of the bovine HTR1B gene among Chinese Holsteins and to identify the association of HTR1B polymorphisms with milk production performance. SSCP was used to examine the polymorphisms at four loci and the fragments with different SSCP patterns were sequenced. A total of three single nucleotide polymorphisms (SNPs) were detected, among which the 205G>T mutation was found to cause a predicted amino acid change: from Ala to Ser at position 69. The polymorphism of G205T was identified to be associated with milk yield trait. Furthermore, the H1-C genotype was found to be associated with a significant increase in milk yield of 489kg vs. the H1-A genotype (P<0.05). [PubMed Citation] [Order full text from Infotrieve]

12) Fish EW, McKenzie-Quirk SD, Bannai M, Miczek KA
5-HT(1B) receptor inhibition of alcohol-heightened aggression in mice: comparison to drinking and running.
Psychopharmacology (Berl). 2008 Mar;197(1):145-56.
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13) van den Berg L, Vos-Loohuis M, Schilder MB, van Oost BA, Hazewinkel HA, Wade CM, Karlsson EK, Lindblad-Toh K, Liinamo AE, Leegwater PA
Evaluation of the serotonergic genes htr1A, htr1B, htr2A, and slc6A4 in aggressive behavior of golden retriever dogs.
Behav Genet. 2008 Jan;38(1):55-66.
Aggressive behavior displays a high heritability in our study group of Golden Retriever dogs. Alterations in brain serotonin metabolism have been described in aggressive dogs before. Here, we evaluate whether four genes of the canine serotonergic system, coding for the serotonin receptors 1A, 1B, and 2A, and the serotonin transporter, could play a major role in aggression in Golden Retrievers. We performed mutation screens, linkage analysis, an association study, and a quantitative genetic analysis. There was no systematic difference between the coding DNA sequence of the candidate genes in aggressive and non-aggressive Golden Retrievers. An affecteds-only parametric linkage analysis revealed no strong major locus effect on human-directed aggression related to the candidate genes. An analysis of 41 single nucleotide polymorphisms (SNPs) in the 1 Mb regions flanking the genes in 49 unrelated human-directed aggressive and 49 unrelated non-aggressive dogs did not show association of SNP alleles, genotypes, or haplotypes with aggression at the candidate loci. We completed our analyses with a study of the effect of variation in the candidate genes on a collection of aggression-related phenotypic measures. The effects of the candidate gene haplotypes were estimated using the Restricted Maximum Likelihood method, with the haplotypes included as fixed effects in a linear animal model. We observed no effect of the candidate gene haplotypes on a range of aggression-related phenotypes, thus extending our conclusions to several types of aggressive behavior. We conclude that it is unlikely that these genes play a major role in the variation in aggression in the Golden Retrievers that we studied. Smaller phenotypic effects of these loci could not be ruled out with our sample size. [PubMed Citation] [Order full text from Infotrieve]

14) Nakamura K, Kikusui T, Takeuchi Y, Mori Y
Changes in social instigation- and food restriction-induced aggressive behaviors and hippocampal 5HT1B mRNA receptor expression in male mice from early weaning.
Behav Brain Res. 2008 Mar 5;187(2):442-8.
The time of weaning has numerous effects on neurobehavioral development. Previous findings suggest that the early weaning influences development of aggressive behaviors. Behavioral and neuroendocrine responsiveness to stressors in the adulthood are also influenced by maternal care received early in life, and early-weaned male mice and rats show higher responsiveness to acute stresses than do normally weaned males. Therefore, it is conceivable that early weaning influences stress-related aggressive behaviors. We investigated the effects of early weaning on aggressive behaviors under two stress conditions: social stress (social instigation) and ecological stress (food restriction), both of which augment aggression. Male ICR mice were divided into two groups based on weaning period. Normally weaned mice (weaned PD21) showed twice the baseline level of attack bites after 5 min of social instigation, whereas early-weaned animals (weaned PD14) were not more aggressive following social instigation. However, the early-weaned mice were more aggressive after food restriction stress than were the normally weaned mice, suggesting lower threshold for aggressive behavior after food shortage. We also measured 5HT1A and 5HT1B receptor mRNA expression in the hippocampus which involved in aggression using real-time PCR. Early-weaned mice had lower 5HT1B expression levels than did normally weaned mice; no effect was found for 5HT1A expression. These results suggest that manipulation of weaning time modulates adult aggressive behavior depending on the stressors imposed and that this change may involve the 5HT1B receptor system in the hippocampus. [PubMed Citation] [Order full text from Infotrieve]

15) Veiga CP, Miczek KA, Lucion AB, Almeida RM
Effect of 5-HT1B receptor agonists injected into the prefrontal cortex on maternal aggression in rats.
Braz J Med Biol Res. 2007 Jun;40(6):825-30.
Serotonin (5-HT1B) receptors play an essential role in the inhibition of aggressive behavior in rodents. CP-94,253, a 5-HT1B receptor agonist, can reduce aggression in male mice when administered directly into the ventro-orbitofrontal (VO) prefrontal cortex (PFC). The objective of the current study was to assess the effects of two selective 5-HT1B receptor agonists (CP-94,253 and CP-93,129), microinjected into the VO PFC, on maternal aggressive behavior after social instigation in rats. CP-94,253 (0.56 microg/0.2 microL, N = 8, and 1.0 microg/0.2 microL, N = 8) or CP-93,129 (1.0 microg/0.2 microL, N = 9) was microinjected into the VO PFC of Wistar rats on the 9th day postpartum and 15 min thereafter the aggressive behavior by the resident female against a male intruder was recorded for 10 min. The frequency and duration of aggressive and non-aggressive behaviors were analyzed using ANOVA and post hoc tests. CP-93,129 significantly decreased maternal aggression. The frequency of lateral attacks, bites and pinnings was reduced compared to control, while the non-aggressive behaviors and maternal care were largely unaffected by this treatment. CP-94,253 had no significant effects on aggressive or non-aggressive behaviors when microinjected into the same area of female rats. CP-93,129, a specific 5-HT1B receptor agonist, administered into the VO PFC reduced maternal aggressive behavior, while the CP-94,253 agonist did not significantly affect this behavior after social instigation in female rats. We conclude that only the 5-HT1B receptor agonist CP-93,129 administered into the VO PFC decreased aggression in female rats postpartum after social instigation. [PubMed Citation] [Order full text from Infotrieve]

16) Zouk H, McGirr A, Lebel V, Benkelfat C, Rouleau G, Turecki G
The effect of genetic variation of the serotonin 1B receptor gene on impulsive aggressive behavior and suicide.
Am J Med Genet B Neuropsychiatr Genet. 2007 Dec 5;144B(8):996-1002.
Impulsive-aggressive behaviors (IABs) are regarded as possible suicide intermediate phenotypes, mediating the relationship between genes and suicide outcome. In this study, we aimed to investigate the putative relationship between genetic variation at the 5-HT1B receptor gene, which in animal models is involved in impulse-aggression control, IABs, and suicide risk. We investigated the relationship of variation at five 5-HT1B loci and IAB measures in a sample of 696 subjects, including 338 individuals who died by suicide and 358 normal epidemiological controls. We found that variation at the 5-HT1B promoter A-161T locus had a significant effect on levels of IABs, as measured by the Buss-Durkee Hostility Inventory (BDHI). Suicides also differed from controls in distribution of variants at this locus. The A-161T locus, which seems to impact 5-HT1B transcription, could play a role in suicide predisposition by means of mediating impulsive-aggressive behaviors. [PubMed Citation] [Order full text from Infotrieve]

17) Bannai M, Fish EW, Faccidomo S, Miczek KA
Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice.
Psychopharmacology (Berl). 2007 Aug;193(2):295-304.
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18) Jacobs C, Van Den Broeck W, Simoens P
Neurons expressing serotonin-1B receptor in the basolateral nuclear group of the amygdala in normally behaving and aggressive dogs.
Brain Res. 2007 Mar 9;1136(1):102-9.
The present study aimed to quantify neurons expressing the serotonin-1B receptor and evaluate numerical differences in normally behaving and pathologically aggressive dogs in order to assess whether the serotonin-1B receptor is involved in pathological canine aggression. Because previous studies have reported structural alterations in the basolateral nuclear group (BNG) of the amygdaloid body of aggressive dogs, this structure was selected as region of interest in the present study. Indirect immunohistochemistry was applied to visualise the serotonin-1B-receptor-positive neurons. Immunoreactivity was located predominantly within the neuronal cell bodies and adjacent neuronal processes. In the aggressive dogs the BNGs contained a significantly higher number of serotonin-1B-receptor-positive neurons compared to the normally behaving dogs. This number was strongly correlated with the total number of neurons per BNG, which was also significantly increased in aggressive dogs compared to normal dogs. The percentage of neurons expressing the serotonin-1B receptor did not differ significantly between both groups. No significant asymmetries were observed for the number and percentage of serotonin-1B-receptor-positive neurons. Potential relationships between the present findings and the etiology of aggressive behaviour, the neuroprotective role of the serotonin-1B receptor and receptor dysfunction are discussed. [PubMed Citation] [Order full text from Infotrieve]

19) Grimes JM, Melloni RH
Prolonged alterations in the serotonin neural system following the cessation of adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).
Behav Neurosci. 2006 Dec;120(6):1242-51.
In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is modulated, in part, by serotonin (5-HT) signaling and development and by signaling and expression of 5-HT1B receptors. To examine whether these effects are persistent or reversible, the authors administered AAS to hamsters, then examined them for aggression at 1, 4, 11, 18, or 25 days following cessation of AAS treatment. Then, 1 day later, hamsters were killed by transcardial perfusion and examined for 5-HT afferents to and 5-HT1B receptor-containing neuronal puncta and somata in areas of the brain altered by AAS, namely, the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Although aggression resulting from AAS exposure returned to control, nonaggressive levels by 18 days following cessation of AAS treatment, alterations in 5-HT afferent innervation and 5-HT1B receptor localization were observed throughout the extended time period examined. These data suggest that adolescent AAS exposure may have long-term, irreversible effects on 5-HT neural systems and that return to nonaggressive behavioral phenotypes following adolescent AAS exposure may not be a function of plasticity in central 5-HT systems. [PubMed Citation] [Order full text from Infotrieve]

20) Heiser P, Dempfle A, Friedel S, Konrad K, Hinney A, Kiefl H, Walitza S, Bettecken T, Saar K, Linder M, Warnke A, Herpertz-Dahlmann B, Schäfer H, Remschmidt H, Hebebrand J
Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample.
J Neural Transm. 2007;114(4):513-21.
Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD. [PubMed Citation] [Order full text from Infotrieve]