Elevated 5-HT2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Neuroscience (Impact Factor: 3.36). 02/2009; 158(4):1406-15. DOI: 10.1016/j.neuroscience.2008.11.036
Source: PubMed


Previous human postmortem brain tissue research has implicated abnormalities of 5-HT receptor availability in depression and suicide. Although altered abundance of 5-HT 1A, 5-HT 2A, and 5-HT 2C receptors (5-HT(1A), 5-HT(2A), and 5-HT(2C)) has been reported, the causes remain obscure. This study evaluated the availability of these three receptor subtypes in postmortem brain tissue specimens from persons with a history of major depression (MDD) and normal controls and tested the relationships to protein kinases A and C (PKA, PKC). Samples were obtained from postmortem brain tissue (Brodmann area 10) from 20 persons with a history of MDD and 20 matched controls as determined by a retrospective diagnostic evaluation obtained from family members. Levels of 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptor were quantitated via Western blot analyses. Basal and stimulated PKA and PKC activity were also determined. The depressed samples showed significantly increased 5-HT(2A) receptor abundance relative to controls, but no differences in 5-HT(1A) or 5-HT(2C) receptors. Basal and cyclic AMP-stimulated PKA activity was also reduced in the depressed sample; PKC activity was not different between groups. 5-HT(2A) receptor availability was significantly inversely correlated with PKC activity in controls, but with PKA activity in the depressed sample. Increased 5-HT(2A) receptor abundance and decreased PKA activity in the depressed sample are consistent with prior reports. The correlation of 5-HT(2A) receptor levels with PKA activity in the depressed group suggests that abnormalities of 5-HT(2A) receptor abundance may depend on receptor uncoupling and heterologous regulation by PKA.

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    • "Interestingly, both serotonin and 5-HT2a receptors were increased in the prefrontal cortex of Ts65Dn mice, and application of an 5-HT2a receptor antagonist rescued the nest building deficit (Heller et al., 2014). Some reports suggest that 5-HT2a receptor expression in the brain may be related to depression, and postmortem studies have shown increased levels of 5-HT2a receptor in the frontal cortices of subjects with major depression and suicide victims (Hrdina et al., 1993; Hrdina and Du, 2001; Pandey et al., 2002; Shelton et al., 2009). Buwalda et al. reported that social defeat stress alters serotonin receptor sensitivity in rodents (Buwalda et al., 2005); however, 2 days of subsequent social defeat stress did not change cortical or hippocampal 5-HT2a receptor levels in rats (Visser et al., 2014). "
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    ABSTRACT: Behavioral and physiological evaluations of animal models of depression are essential to thoroughly understand the mechanisms of depression in humans. Various models have been developed and characterized, and the socially defeated mouse has been widely used for studying depression. Here, we developed and characterized a mouse model of social aversion using a subchronic and mild social defeat stress (sCSDS) paradigm. Compared to control mice, sCSDS mice showed significantly increased body weight gain, water intake, and social aversion to dominant mice on the social interaction test. We observed nest building behavior in sCSDS mice using the pressed cotton as a nest material. Although sCSDS mice eventually successfully built nests, the onset of nest building was severely delayed compared to control mice. The underlying mechanism of this significant delay in nest building by sCSDS mice is unclear. However, our results demonstrate that nest building evaluation is a simple and useful assay for understanding behavior in socially defeated mice and screening drugs such as antidepressants.
    Behavioural processes 11/2015; DOI:10.1016/j.beproc.2015.10.018 · 1.57 Impact Factor
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    • "One problem that affects the interpretation of post-mortem studies on this topic is the occurrence of suicide in many of the depression cohorts reported in literature. For instance, postmortem studies that claimed to have determined molecular alterations in relation to depression had in fact selected, in the diagnosis group, depressed patients who (nearly) all committed suicide, and compared them with control subjects without any psychiatric disorder and who did not commit suicide (Bernard et al., 2011; Cotter et al., 2001; Dwivedi et al., 2006b; Martins-de-Souza et al., 2012; Rajkowska et al., 1999; Shelton et al., 2009). Vice versa, the studies focused on suicide appeared to compare suicide cases to matched controls without any psychiatric disorder (Dwivedi et al., 2006a, 2006b; Poulter et al., 2008; Thalmeier et al., 2008). "
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    ABSTRACT: Suicide occurs in some, but not all depressed patients. So far, it remains unknown whether the studied stress-related candidate genes change in depression, suicide or both. The prefrontal cortex (PFC) is involved in, among other things, impulse control and inhibitory behavior and plays an important role in both suicide and depression. We have employed qPCR to study 124 anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) brain samples, obtained from two brain banks, from: i) young depressed patients (average age 43 years) who committed suicide (MDD-S) and depressed patients who died from causes other than suicide (MDD-NS) and from ii) elderly depressed patients (average age 75 years) who did not commit suicide (DEP). Both cohorts were individually matched with non-psychiatric non-suicide control subjects. We determined the transcript levels of hypothalamic-pituitary-adrenal axis-regulating molecules (corticotropin-releasing hormone (CRH), CRH receptors, CRH binding protein, mineralocorticoid receptor/glucocorticoid receptor), transcription factors that regulate CRH expression, CRH-stimulating cytokines, chaperone proteins, retinoid signaling, brain-derived neurotrophic factor and tropomyosin-related kinase B, cytochrome proteins, nitric oxide synthase (NOS) and monoamines. In the MDD-S group, expression levels of CRH and neuronal NOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) were increased. Other changes were only present in the DEP group, i.e. decreased NIDD, and increased and 5-hydroxytryptamine receptor 1A (5-HT1A) expression levels. Changes were found to be more pronounced in the anterior cingulate cortex than in the dorsolateral PFC. Depressed patients who committed suicide have different gene expression patterns than depressed patients who died of causes other than suicide. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Psychiatric Research 09/2015; 68:176-185. DOI:10.1016/j.jpsychires.2015.06.010 · 3.96 Impact Factor
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    • "The 5-HT 2A receptor is thought to play an important role in regulating mood and cognition and has been implicated in the pathology of several psychiatric disorders (Gray and Roth, 2001; Carr and Lucki, 2011). In humans, depression and schizophrenia have been associated with increased expression of 5-HT 2A receptors in the brain (Gurevich and Joyce, 1997; Shelton et al., 2009), and effective treatment strategies have been shown to decrease 5-HT 2A receptor expression and/or function (Gray and Roth, 2001). For example, atypical antipsychotics are thought to exert their therapeutic benefit, in part, by acting as inverse agonists that reduce 5-HT 2A receptor constitutive activity (Meltzer, 2012). "
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    ABSTRACT: The serotonin 2A (5-HT2A) receptor and the pro-inflammatory cytokine, interleukin-6 (IL-6), have both been implicated in psychiatric disorders. Previously, we demonstrated that these molecules both facilitate cognitive flexibility, a prefrontal cortex-mediated executive function impaired in multiple mental illnesses. In this study, we tested the hypothesis that IL-6 influences 5-HT2A receptor signaling, providing a potential mechanism by which this cytokine may influence behavior. We first demonstrated that 5-HT2A receptors and IL-6-mediated STAT3 phosphorylation co-localize in cells of the prefrontal cortex, providing the neuroanatomical substrate for a potential interaction. In the neuronally derived A1A1 cell line, which expresses both IL-6 and 5-HT2A receptors, we found that IL-6 attenuates inositol phosphate (IP) accumulation in response to the 5-HT2 agonist, DOI, suggesting that IL-6 can regulate 5-HT2A receptor function. To identify the signaling pathway(s) that mediate this effect, we measured DOI-mediated IP accumulation in the presence of IL-6 and either the JAK-STAT inhibitor, JSI-124, or the ERK inhibitor, PD-98059. The IL-6 effect was blocked by JSI-124, but not PD-98059. Further, siRNA knockdown of either JAK or STAT blocked the IL-6 effect, suggesting that IL-6-induced JAK-STAT activation can regulate 5-HT2A receptor signaling. Finally, to determine if IL-6 specifically regulates the 5-HT2A receptor system, we measured IP production mediated by another Gq-coupled receptor, bradykinin B2. IL-6 had no effect on bradykinin-mediated IP accumulation, suggesting that regulation may occur at the 5-HT2A receptor. These results may provide clues to the pathological mechanisms underlying certain psychiatric disorders and may suggest novel therapeutic strategies for their treatment. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 12/2014; 87(3). DOI:10.1124/mol.114.096289 · 4.13 Impact Factor
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