Autoradiographic Demonstration of Increased Serotonin 5-HT2 and β-Adrenergic Receptor Binding Sites in the Brain of Suicide Victims

Arango, Victoria; Ernsberger, Paul; Marzuk, Peter M.; Chen, Jaw Sy; Tierney, Helen; Stanley, Michael; Reis, Donald J.; Mann, J. John

doi:10.1001/archpsyc.1990.01810230054009

Cited by 404 publications

(178 citation statements)

References 82 publications

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“…To take into account the potential confounding effects of age and PMI on these significant results, an analysis of covariance was performed and any significant differences in both the amygdala and BA9 were observed (p ¼ 0.036 and 0.046, respectively). Considering the involvement of the 5-HT2AR in suicide, the BA9 is an extremely intriguing area because increased level of the 5-HT2AR density in the BA9 of suicide subjects has been repeatedly reported Arango et al, 1990;Arora and Meltzer, 1989;Mann et al, 1986). To examine possible co-regulation of RGS2 and the 5-HT2AR, we examined the correlation between RGS2 immunoreactivity and 3 H-ketanserin binding reflecting 5-HT2AR density in BA9 of normal control subjects (n ¼ 12).…”

Section: Resultsmentioning

confidence: 99%

“…RGS2 mainly attenuates Gaqmediated GPCR signaling (Heximer et al, 1997;Heximer, 2004). It is noteworthy that 5-HT2AR is also coupled with Gaq (Adlersberg et al, 2000), and its levels have been shown to be significantly higher in the prefrontal cortex (BA 8 and/ or 9) of the postmortem brains of suicide victims Mann et al, 1986;Arora and Meltzer, 1989;Arango et al, 1990). The activity of phosphoinositide- Association between RGS2 gene and suicide H Cui et al specific phospholipase C and the level of phospholipase Cb, both of which are enzymes that are important 5-HT2AR intracellular signal molecules, have been shown to be significantly reduced in the prefrontal cortex (BA8/9) of the postmortem brains of suicide subjects (Pandey et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…We also examined RGS2 immunoreactivity in the amygdala and prefrontal cortex (Brodmann area 9 (BA9)) of postmortem brains of suicide victims and controls. The amygdala is thought to play an important role in emotional control (LeDoux, 2000;Davidson, 2002), and BA9 is one of the most informative areas for the biological susceptibility to suicide because some proteins were altered in this area in the postmortem brains of suicide victims Pandey et al, 2002;Arango et al, 1990;Arora and Meltzer, 1989;Mann et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

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Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

Cui

Nishiguchi

Ivleva

et al. 2007

Neuropsychopharmacol

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Regulators of G-protein signaling are a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors, such as the serotonin receptor. Recent studies have suggested that one of these proteins, the regulator of G-protein signaling 2 (RGS2), plays an important part in anxiety and/or aggressive behavior. To explore the involvement of the RGS2 gene in the vulnerability to suicide, we screened Japanese suicide victims for sequence variations in the RGS2 gene and carried out an association study of RGS2 gene polymorphisms with suicide victims. In the eight identified polymorphisms that were identified by mutation screening, we genotyped four common single-nucleotide polymorphisms (SNPs) in the RGS2 gene, and found significant differences in the distribution of the SNP3 (C + 2971G, rs4606) genotypes and alleles of the SNP2 (C-395G, rs2746072) and the SNP3 between completed suicides and the controls. The distribution of the haplotype was also significantly different between the two groups (global po0.0001). Furthermore, RGS2 immunoreactivity significantly increased in the amygdala and the prefrontal cortex (Brodmann area 9 (BA9)) of the postmortem brain of the suicide subjects. These findings suggest that RGS2 is genetically involved in the biological susceptibility to suicide in the Japanese population.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

Cui

Nishiguchi

Ivleva

et al. 2007

Neuropsychopharmacol

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“…Clinical and demographic characteristics and cause of death in the suicides and nonsuicides are shown in Table 1. Prefrontal cortical tissue (Brodmann area 9) was dissected for the membrane binding studies because we have previously reported changes in levels of binding to the serotonin transporter and other serotonin receptors in suicide victims in this brain area (Arango et al 1990;Stanley and Mann 1983;Stanley et al 1982). The cerebellum was used for genomic DNA extraction.…”

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confidence: 99%

Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue

Huang¹,

Grailhe

Arango

et al. 1999

Neuropsychopharmacology

134

102

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Knockout of the 5-HT 1B 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-HT 1B receptor gene (N ϭ 178) and postmortem human 5-HT 1B receptor binding (N ϭ96Several neuropsychiatric disorders such as mood disorders, substance abuse, or alcoholism have been associated with dysfunctions of the central serotonergic system (Coppen 1972;Goodwin and Post 1983;Ballenger et al. 1979;Virkkunen et al. 1994). The risk for suicidal behavior and aggressive acts has been suggested to be related to a common underlying predisposition to impulsive behavior that is modulated by serotonergic activity (Mann 1998). In rodents and primates, aggressiveness is increased after inhibition of serotonin synthesis or in association with lower serotonergic activity (Vergnes et al. 1986;Molina et al. 1987;Higley et al. 1992). Both suicidal acts and aggression have a genetic contribution in terms of cause or diathesis that is independent of the heritability of major psychiatric disorders (Brent et al. Received October 15, 1998; revised February 15, 1999; accepted February 25, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 2 Psychopathology and Human 5-HT 1B Binding and Genotype 239 1996;Roy 1986;Roy et al. 1991;Schulsinger et al. 1979). The mechanism whereby genetics can affect aggressive and suicidal behavior is not known. The serotonergic system is one possibility because serotonergic activity is under substantial genetic control (Ishikawa et al. 1989;Higley et al. 1992;van Harten 1993). Patients at risk for suicidal acts not only have an increased level of lifetime aggression (Mann and Arango 1998), but also an increased rate of alcoholism and substance abuse. Alcoholism and substance abuse may facilitate suicidal acts, or may share a common predisposing factor with suicide and aggression, such as lower serotonergic activity. Genetic factors play a role in alcoholism (Schuckit et al. 1985) and major depression (Gershon et al. 1989) but their precise nature is unknown. Again, the serotonergic system may play a role.Recently, aggressive behavior as well as increased alcohol and cocaine intake have been reported in 5-HT 1B receptor gene knockout mice (Saudou et al. 1994;Ramboz et al. 1996;Crabbe et al. 1996;Rocha et al. 1998). This set of observations raises the possibility that abnormalities in the 5-HT 1B receptor gene may contribute to human psychopathologies such as suicide, aggression, major depression, alcoholism, or substance abuse.Molecular cloning techniques have revealed the existence of two humans 5-HT 1D receptor subtypes: 5-HT 1D ␣ and 5-HT 1D ␤ (Hamblin and Metcalf 1991;Demchyshyn et al. 1992;Weinshank et al. 1992;Levy et al. 1992). The mouse 5-HT 1B receptor is the homologue of the human 5-HT 1D ␤ . We have adopted the recommendation that the human 5-HT 1D ␤ receptor be renamed human 5-HT 1B (h5-HT 1B ) receptor (for a review see H...

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“…Neuroadaptive effects have also been observed in other serotonergic systems (5-HT 1A or 5-HT 2 receptor systems) in response to chronic antidepressant treatment (Cooper et al 1996;Hyman and Nestler 1996;Nair and Sharma 1989;Schwaninger et al 1997). In the postmortem brains of depressed subjects and suicides most investigators report an increase in 5-HT 2 receptor binding (Arango et al 1990;Arora and Meltzer 1989) as compared to nondepressed patients matched for age, sex, and time to autopsy. Furthermore, winter reductions in serotonin levels have been reported in postmortem hypothalamic tissues of patients diagnosed with seasonal affective disorder (Oren and Rosenthal 1992;Carlsson et al 1980).…”

Section: Discussionmentioning

confidence: 99%

Effects of Antidepressants on 5-HT7 Receptor Regulation in the Rat Hypothalamus

Mullins

Gianutsos

1999

Neuropsychopharmacology

148

101

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Recent evidence suggests that a novel serotonin receptor 5-HT 7 localized in the hypothalamus downregulates in response to treatment with the antidepressant fluoxetine (Sleight et al. 1995). This receptor has also been implicated in the regulation of circadian rhythms (Lovenberg et al. 1993). Here Depression may involve many possible abnormalities corresponding to multiple biological correlates of dysfunction or dysregulation in either one or several brain neurotransmitter systems (Cooper et al. 1996;Nair and Sharma 1989), a property that may contribute to the apparent disparity in symptomology and response to antidepressant therapy. The strict classical notions of neurotransmitter dysregulation hypotheses that associate depression with a deficiency of a vailable neurotransmitter or subresponsivity of mainly noradrenergic and/ or serotonergic receptor systems are recently being expanded to include disturbances in biological rhythm regulation. Impairment of the efficiency of rhythm maintenance or rhythm desynchronization has been suggested by many to lead to mental fatigue and depression (Goodwin et al. 1982;Hallonquist et al. 1986;Healy 1987;Partonen 1994;Schwartz 1993;Wirz-Justice and Campbell 1982;Wirz-Justice et al. 1995). Clinically, it has been extensively documented that the timing and structure of rhythms in physiological, behavioral, and endocrinological functions seem to be abnormal in depression (Coiro et al. 1993;Duncan 1996;File 1990;Kupfer 1995;Nair and Sharma 1989;Wehr et al. 1979). Furthermore, studies investigating the patterns of circadian rhythms of patients diagnosed with depression have been undertaken with the premise of disturbed rhythmicity as a central theme underlying the etiology of some affective disorders (Duncan 1996;Goodwin et al. 1982;Healy 1987;Siever and Davis, 1985;Souetre et al. 1988).Although melatonin is generally thought to be a primary modulator of circadian function through the suprachiasmatic nucleus (SCN) of the hypothalamus (Armstrong and Redman 1993;Binkley 1993;Cassone et al. 1993;Dubocovich 1991;Ibata et al. 1997;Reiter 1993; From the Bristol-Myers Squibb Company (ULM, ASE), Neuroscience Drug Discovery, Wallingford, Connecticut; and University of Connecticut, Department of Pharmaceutical Sciences (GG), Storrs, Connecticut, USA.Address correspondence to: U. Lena Mullins, Ph.D., BristolMyers Squibb Company, Neuroscience Drug Discovery, Department 408, 5 Research Parkway, Wallingford, Connecticut 06492, USA.Received January 1, 1999; revised March 23, 1999; accepted March 26, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 3 Effects of Antidepressants 353 Stankov et al. 1993), the serotonergic system also plays a critical role in circadian modulation. The SCN receives dense projections from the raphe serotonergic neurons originating in the brainstem (Jacobs and Azmitia 1992;Meyer-Bornstein and Morin 1996;Van De Kar and Lorens 1979). Lesions of the median raphe serotonergic system using the neurotoxic agent 5,7-dihydroxytryptamine (5,7-DHT) produce a sever...

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Autoradiographic Demonstration of Increased Serotonin 5-HT2 and β-Adrenergic Receptor Binding Sites in the Brain of Suicide Victims

Cited by 404 publications

References 82 publications

Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

Association of RGS2 Gene Polymorphisms with Suicide and Increased RGS2 Immunoreactivity in the Postmortem Brain of Suicide Victims

Relationship of Psychopathology to the Human Serotonin1B Genotype and Receptor Binding Kinetics in Postmortem Brain Tissue

Effects of Antidepressants on 5-HT7 Receptor Regulation in the Rat Hypothalamus

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