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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    • "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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    • "Other elements of the serotonergic system have also been related to the pathology of depression, including the 5-HT reuptake transporter, 5-HT synthesis pathway, and several 5- HT receptor subtypes, among others the 5-HT 2A receptor (5-HT 2A R). Postmortem studies indicate increased levels of 5- HT 2A R in frontal cortex (FC) of subjects with major depressive disorder and suicide victims (Hrdina and Du, 2001; Hrdina et al., 1993; Pandey et al., 2002; Shelton et al., 2009). These results are supported by imaging studies showing an increase in 5-HT 2A R binding in cortical regions of euthymic and "
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    ABSTRACT: It has been hypothesized that effects of uncontrollable stress on serotonin receptor expression contribute to the etiology of stress-related disorders like depression. While the serotonin-2A receptors (5-HT2AR) are thought to be important in this context, only few studies examined effects of stress on this receptor subtype. In the present study we therefore assessed acute and long-term changes in 5HT2AR binding after social defeat stress in rats.Male Wistar rats were subjected to social defeat by placing them in the home cage of an aggressive, dominant Long Evans rat. Acute social defeat suppressed growth, but did not affect anxiety-like behavior in an open field test. A PET scan with the 5-HT2AR tracer [11C]MDL 100907 one day and three weeks after defeat did not show significant changes in receptor binding. To verify these results, [3H]MDL 100907 binding assays were performed in homogenates of prefrontal cortex and hippocampus, which also did not indicate any changes in Bmax or Kd.These findings do not support the hypothesis that changes in 5-HT2AR function are a vital mechanism through which uncontrollable stress contributes to stress-related pathologies such as depression. It remains to be determined whether effects of stress on 5HT2AR binding depend on the nature of the stressor or on the characteristics of the rat strain. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 09/2014; 68(9). DOI:10.1002/syn.21750 · 2.13 Impact Factor
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    • "Notably, induction of learned helplessness in rats is associated with 5-HT 2A upregulation in cortical areas [Dwivedi et al. 2005]. Moreover, increased 5-HT 2A receptor densities in post-mortem PFCs of depressed patients are associated with decreased activity of protein kinase A, but not PKC [Shelton et al. 2009]. Although the psychedelic effects of classical hallucinogens appear likely to be due to agonist action on the 5-HT 2A receptor, binding to 5-HT 2C and 5-HT 1A receptors [Nichols, 2004] have also been implicated in depressive and anxiety disorders and treatment thereof. "
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    Therapeutic Advances in Psychopharmacology 07/2014; 4(4). DOI:10.1177/2045125314527985 · 1.53 Impact Factor
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