Disturbances in brain serotonin (5-HT) metabolism have been implicated in the pathogenesis of affective disorders. The objectives of this proposal are to test the hypothesis that suicide victims have increased numbers of serotonin receptors in frontal cortex, and that previous psychiatric history of major depression, violence or impulsive behavior is correlated with receptor binding.
The specific aims of this research are: 1) to extend the finding of elevated serotonin 2 (5-HT[2]) receptor binding in homogenates of frontal cortex of violent suicides as compared with nonviolent suicides and matched controls by using in vitro quantitative autoradiography to anatomically localize and quantitate receptor binding. 2. To use in vitro quantitative autoradiography to extend the finding of elevated 5-HT 1A receptor binding in homogenates of frontal cortex of nonviolent suicides as compared with matched controls. 3. To compile a psychological history of the suicide completers used in the receptor binding experiments to determine if previous psychiatric diagnoses are correlated with altered receptor binding. 4. To determine with in vitro quantitative autoradiography whether the high-affinity binding of {3H}paroxetine to the 5-HT transporter complex in sections of frontal cortex of violent and nonviolent suicide completers is different from that in matched controls and if it correlates with 5-HT, and/or 5-HT 1A receptor binding. 5. To study the role of serotonin and dopamine in frontal cortex of suicide completers and matched controls by measuring concentrations of serotonin, dopamine, 5-hydroxyindoleacetic acid, and, homovanillic acid. The studies proposed here to combine psychiatric histories collected from structured interviews with next-of-kin using the SADS-L and SIDP assessment instruments together with quantitative in vitro receptor autoradiography should provide a significant improvement over previous attempts to test the hypothesis that serotonin receptor dysfunction is linked with violence, suicide and/or depression. These studies could provide important preliminary steps toward the eventual goal of imaging monoamine receptors in vivo in patients suffering from depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045488-02
Application #
3385246
Study Section
Psychopathology and Clinical Biology Research Review Committee (PCB)
Project Start
1989-09-01
Project End
1992-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Uylings, Harry B M; Sanz-Arigita, Ernesto J; de Vos, Koos et al. (2010) 3-D cytoarchitectonic parcellation of human orbitofrontal cortex correlation with postmortem MRI. Psychiatry Res 183:1-20
Miguel-Hidalgo, Jose J; Overholser, James C; Meltzer, Herbert Y et al. (2006) Reduced glial and neuronal packing density in the orbitofrontal cortex in alcohol dependence and its relationship with suicide and duration of alcohol dependence. Alcohol Clin Exp Res 30:1845-55
Piletz, John E; Ordway, Gregory A; Rajkowska, Grazyna et al. (2003) Differential expression of alpha2-adrenoceptor vs. imidazoline binding sites in postmortem orbitofrontal cortex and amygdala of depressed subjects. J Psychiatr Res 37:399-409
Rajkowska, Grazyna (2003) Depression: what we can learn from postmortem studies. Neuroscientist 9:273-84
Stockmeier, Craig A (2003) Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 37:357-73
Klimek, Violetta; Roberson, Gary; Stockmeier, Craig A et al. (2003) Serotonin transporter and MAO-B levels in monoamine nuclei of the human brainstem are normal in major depression. J Psychiatr Res 37:387-97
Ordway, Gregory A; Schenk, Jane; Stockmeier, Craig A et al. (2003) Elevated agonist binding to alpha2-adrenoceptors in the locus coeruleus in major depression. Biol Psychiatry 53:315-23
Bissette, Garth; Klimek, Violetta; Pan, Jun et al. (2003) Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology 28:1328-35
Rajkowska, Grazyna (2002) Cell pathology in mood disorders. Semin Clin Neuropsychiatry 7:281-92
Stockmeier, Craig A; Shi, Xiaochun; Konick, Lisa et al. (2002) Neurokinin-1 receptors are decreased in major depressive disorder. Neuroreport 13:1223-7

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