5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: increase in 5-HT2 sites in cortex and amygdala

Abnormalities in serotonin (5-HT) receptors and 5-HT receptor-mediated signal transduction systems have been widely reported in mood disorders. This study was intended to evaluate 5-HT 2A receptor-coupled activation of phosphatidylinositol (PI) hydrolysis in subtypes of depression. Samples for fibroblast culture were obtained from patients with major depression with or without melancholia, and normal controls. Dose response curves were determined for 5-HT-induced PI hydrolysis. PI response was determined for bradykinin and l-a-lysophosphatidic acid (LPA), alternative Gq-coupled receptor agonists. [ 125 I]LSD binding for 5-HT 2A also was conducted. Finally, Western blot analysis was performed for phospholipase C b1 (PLC b1 ) and Ga q/11 proteins. The maximum PI response observed with 5-HT was significantly lower in melancholics but not nonmelancholic patients relative to controls. Activation of PI hydrolysis by bradykinin and LPA was not reduced in melancholic vs melancholics and controls; responses to both agonists actually were increased in the melancholic group. [ 125 I]LSD binding, PLC b1 , and Ga q/11 protein levels did not differ between groups. The data raise the possibility that the reduced 5-HT 2A receptor-induced PI hydrolysis is intrinsic to the receptor itself or its coupling to Gq protein, and is not related to altered availability of the 5-HT 2A receptor, Gq or PLC.

Section: Introductionmentioning

confidence: 67%

Decreased Serotonin 5-HT2A Receptor-Stimulated Phosphoinositide Signaling in Fibroblasts from Melancholic Depressed Patients

Akın

Manier

Sanders‐Bush

et al. 2004

“…Greater 5-HT 2A binding has been reported in post-mortem brain tissue from individuals with major depression and suicide victims by some but not all studies (Stanley and Mann 1983;Mann et al, 1986;Hrdina and Du 2001;Kato et al, 1996;Ono et al, 2001;Hrdina et al, 1993;Arora and Meltzer 1989;Yates et al, 1990). Pandey et al (1995) found that higher prefrontal cortical 5-HT 2A binding was associated with greater gene expression in youth suicide.…”

Section: Introductionmentioning

confidence: 94%

Association of Serotonin 5-HT2A Receptor Binding and the T102C Polymorphism in Depressed and Healthy Caucasian Subjects

Khait

Huang

Zalsman

et al. 2004

Serotonin 5-HT 2A receptor (5-HT 2A ) binding is reported to be altered in individuals with suicidal behavior, mood disorders, and aggressive-impulsive traits. Genetic association with major depression, suicidal behavior, and aggressive-impulsive traits has not been established. This study examines the possible association of the 5-HT 2A gene C102T polymorphism with the receptor binding kinetics, and clinical overt phenotypes. The study population included 63 healthy volunteers and 152 subjects with mood disorders, 56 of whom had a history of suicide attempts. All were Caucasian. Platelet 5-HT 2A binding kinetics (B max and K D ) were assayed and adjusted for seasonal variation. All subjects were genotyped for the T102C polymorphism. Clinical phenotype was determined by structured clinical interview. The TT genotype was associated with higher B max in all subjects (F ¼ 3.53, df ¼ 2,211; p ¼ 0.03), controlling for diagnosis. Bonferroni-adjusted post hoc testing showed higher binding in the TT compared with TC genotype in the control group (F ¼ 7.56, df ¼ 2,60, p ¼ 0.001), but not in the mood-disordered subjects. No difference was found in genotype and allele distribution between the mood-disordered subjects, with and without suicide attempt history, and controls. B max was not related to a diagnosis of mood disorders.The TT genotype appears associated with higher platelet 5-HT 2A B max in the healthy population, but this genotypic effect appears absent in mood disorders and unrelated to psychopathology.

“…Neuroendocrine studies find blunted serotoninmediated prolactin release related to aggressive and suicidal behavior (see Dulchin et al, 2001;Malone et al, 1996;Weiss and Coccaro, 1997). Furthermore, in postmortem serotonin receptor-binding studies, presynaptic alterations are identified in the brainstem (Arango et al, 2001) and pre-and postsynaptic alterations are described in the prefrontal cortex (Arango et al, 1995;Hrdina et al, 1993;Mann et al, 2000;Pandey et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Tryptophan Hydroxylase mRNA Expression in the Human Dorsal and Median Raphe Nuclei: Major Depression and Suicide

Bach-Mizrachi

Underwood

Kassir

et al. 2005

171

124

Major depressive disorder (MDD) and suicide are associated with deficient serotonergic neurotransmission. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme for serotonin. Previously, we reported elevated levels of TPH protein in the dorsal raphe nucleus (DRN) of depressed suicides and now examine expression of neuronal TPH2 mRNA in a cohort of matched controls and depressed suicides (n ¼ 11 pairs). DRN TPH2 mRNA was measured by densitometric analysis of autoradiograms from in situ hybridization histochemistry experiments. TPH2 mRNA is confirmed as the raphe-specific isoform of TPH in human brain, and is expressed in neurons throughout the anteroposterior extent of the DRN and median raphe nucleus (MRN). TPH2 mRNA expression correlates with TPH protein distribution in the DRN, and has a negative correlation with age. In drug-free suicides, TPH2 expression is 33% higher in the DRN and 17% higher in the MRN as compared to matched nonpsychiatric controls. Higher levels of TPH2 mRNA were found throughout the entire extent of the rostrocaudal axis of the DRN, and were not specific to any single subnucleus. Higher TPH2 mRNA expression may explain more TPH protein observed in depressed suicides and reflect a homeostatic response to deficient brain serotonergic transmission.