Clark MS, Neumaier JF.
The 5-HT1B receptor: behavioral
Psychopharmacol Bull. 2001 Autumn;35(4):170-85.
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]
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)
Neuropsychopharmacology. 2003 Jan;28(1):163-9.
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
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.
"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.
of association between serotonin 5-HT1B receptor gene polymorphism and suicidal
Am J Med Genet. 2003 Jan 1;116B(1):69-71.
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.
of psychopathology to the human serotonin1B genotype and receptor binding kinetics
in postmortem brain tissue.
"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
de Almeida RM, Miczek KA.
escalated by social instigation or by discontinuation of reinforcement ("frustration")
in mice: inhibition by anpirtoline: a 5-HT1B receptor agonist.
"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.
self-administration in the home cage of mice: alcohol-heightened aggression and
inhibition by the 5-HT1B agonist anpirtoline.
(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]
CF, Melloni RH Jr, Koppel G, Perry KW, Fuller RW, Delville Y.
interactions in the anterior hypothalamus control aggressive behavior in golden
J Neurosci. 1997 Jun 1;17(11):4331-40.
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
Rilke O, Will K, Jahkel M, Oehler J.
and neurochemical effects of anpirtoline and citalopram in isolated and group
Prog Neuropsychopharmacol Biol Psychiatry.
"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]