Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression - Postmortem evidence for decreased serotonin activity
Program in Basic and Clinical Neuroscience, Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/1998; 18(18):7394-401.
It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.
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- "Compared with the number of postmortem studies on the DRN in affective disorders and suicide (Lloyd et al., 1974; Stockmeier et al., 1998; Underwood et al., 1999; Bligh-Glover et al., 2000; Arango et al., 2001; Baumann et al., 2002; Austin et al., 2003; Bonkale et al., 2004, 2006; Bielau et al., 2005; Boldrini et al., 2005, 2008; Bach-Mizrachi et al., 2006, 2008; Gos et al., 2008; Matthews and Harrison, 2012), reports on the DRN in schizophrenia are scanty (Craven et al., 2005; Matthews and Harrison, 2012; Krzyżanowska et al., 2015; for a review of older studies see: Harrison, 1999). Discrepancies in these studies result from various factors. "
ABSTRACT: The central serotonergic system is implicated differentially in the pathogenesis of depression and schizophrenia. The dorsal raphe nucleus (DRN) is the main source of serotonergic innervation of forebrain limbic structures disturbed in both disorders. The study was carried out on paraffin-embedded brains from 27 depressed (15 major depressive disorder, MDD and 12 bipolar disorder, BD) and 17 schizophrenia (9 residual and 8 paranoid) patients and 28 matched controls without mental disorders. The transcriptional activity of ribosomal DNA (rDNA) in DRN neurons was evaluated by the AgNOR silver staining method. A significant effect of diagnosis on rDNA activity was found in the cumulative analysis of all DRN subnuclei. Further analysis revealed an increase in this activity in residual (but not paranoid) schizophrenia compared to depressed (both MDD and BD) patients. The effect was most probably neither confounded by suicide nor related to antidepressant and antipsychotic medication. Our findings suggest that increased activity of rDNA in DRN neurons is a distinct phenomenon in residual schizophrenia, related presumably to differentially disturbed inputs to the DRN and/or their local transformation compared with depressive episodes in patients with affective disorders.
- "Subsequently, Nagamine et al.  have performed a similar pharmacologic study and further confirmed this view. Evidence obtained in humans and other animal models have reported supersensitivity of the 5-HT1A autoreceptors in depression, which led to a reduction in central 5-HT transmission via a negative feedback mechanism   . However, antidepressants may down-regulate 5-HT1A and enhance 5-HT transmission, which in turn improves the symptoms of depression  . "
Article: Physiology & Behavior[Show abstract] [Hide abstract]
ABSTRACT: Binocular rivalry rate is slow in patients with depression. • Rivalry rate during depressive episodes was slower than during remission. • No significant correlation between the changes of HAMD scores and the rivalry rates. a b s t r a c t Binocular rivalry refers to a phenomenon in which, when different images are presented to each eye simultaneously , perception alternates spontaneously between monocular views rather than being a superposition of the two images. Recently, the involvement of serotonin systems has been reported to be related to the phenomenon. There is abundant evidence for abnormalities of the serotonin systems in depression and the antidepres-sants that enhance 5-HT transmission, which in turn improves mood and behavior. However, the available data with respect to rivalry rates in depression are less clear. Therefore, we aimed to explore whether perceptual rivalry was affected by a dysfunctional serotonin system in patients with depression and whether there was a rivalry rate difference between episode and remission states in depression patients. Twenty-eight patients with depression and 30 healthy controls were recruited in the study. We assessed the rivalry rate and the 17-item Hamilton Depression Rating Scale (HAMD) in patients with depression during clinical episode and remission states. The results suggested that alternation rates for patients during episodes were significantly slower than during remission and than in healthy controls. Also, alternation rates for patients during remission were slower than in healthy controls. These results may provide further clues to serotonergic neural systems contributing to the dynamics of perception rivalry and may foster enlightenment regarding the field of binocular rivalry in psychiatric disorders other than bipolar disorder.
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- "The neurotransmitter 5-Hydroxytryptamine (5-HT; serotonin) plays a key role in depression (Bruchas et al, 2011; Robinson et al, 1989; Stockmeier et al, 1998; Valentino et al, 2010). "
ABSTRACT: Cocaine addiction and depression are comorbid disorders. While it is well recognized that 5-Hydroxytryptamine (5-HT; serotonin) plays a central role in depression, our understanding of its role in addiction is notably lacking. The 5-HT system in the brain is carefully controlled by a combined process of regulating 5-HT neuron firing through 5-HT autoreceptors, neurotransmitter release, enzymatic degradation, and reuptake by transporters. The present study tests the hypothesis that activation of 5-HT1A autoreceptors, which would lessen 5-HT neuron firing, contributes to cocaine seeking behaviors. Using 5-HT neuron-specific reduction of 5-HT1A autoreceptor gene expression in mice, we demonstrate that 5-HT1A autoreceptors are necessary for cocaine conditioned place preference. Additionally, using designer receptors exclusively activated by designer drugs (DREADDs) technology, we found that stimulation of the serotonergic dorsal raphe nucleus (DRN) afferents to the nucleus accumbens (NAc) abolishes cocaine reward and promotes anti-depressive-like behaviors. Lastly, using a rat model of compulsive-like cocaine self-administration, we found that inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with 6 h extended access, but not 1 hour access to the drug. Therefore, our findings suggest an important role for 5-HT1A autoreceptors, and thus DRNNAc 5-HT neuronal activity, in the etiology and vulnerability to cocaine reward and addiction. Moreover, our findings support a strategy for antagonizing 5-HT1A autoreceptors for treating cocaine addiction.Neuropsychopharmacology accepted article preview online, 01 September 2015. doi:10.1038/npp.2015.268.
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