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      Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT 1A receptor partial agonism and α 1-adrenoceptor antagonism

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          Abstract

          Trazodone is an antidepressant drug with considerable affinity for 5-HT 1A receptors and α 1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT 1A receptors (5-HT 1AARs) and α 1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α 1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α 1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1–10 μM) concentration-dependently silenced neurons through activation of 5-HT 1AARs. The effect was fully antagonized by the selective 5-HT 1A receptor antagonist Way-100635. With 5-HT 1A receptors blocked by Way-100635, trazodone (1–10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10–100 μM) indicated competitive antagonism at α 1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2 -/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT 1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT 1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT 1AARs and disfacilitation of firing through α 1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α 1-adrenoceptor stimulation.

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          Serotoninergic regulation of emotional and behavioural control processes.

          5-Hydroxytryptamine (5-HT, serotonin) has long been implicated in a wide variety of emotional, cognitive and behavioural control processes. However, its precise contribution is still not well understood. Depletion of 5-HT enhances behavioural and brain responsiveness to punishment or other aversive signals, while disinhibiting previously rewarded but now punished behaviours. Findings suggest that 5-HT modulates the impact of punishment-related signals on learning and emotion (aversion), but also promotes response inhibition. Exaggerated aversive processing and deficient response inhibition could underlie distinct symptoms of a range of affective disorders, namely stress- or threat-vulnerability and compulsive behaviour, respectively. We review evidence from studies with human volunteers and experimental animals that begins to elucidate the neurobiological systems underlying these different effects.
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            Current advances and trends in the treatment of depression.

            The pathophysiology of major affective illness is poorly understood. However, several lines of preclinical and clinical evidence indicate that an enhancement of 5-HT-mediated neurotransmission might underlie the therapeutic effect of most antidepressant treatments. This net effect would, however, be obtained via different mechanisms. A better understanding of the neurobiological basis for the delayed onset of action of antidepressant treatments has led to the elaboration of strategies that could accelerate the antidepressant response. These strategies are discussed in this article by Pierre Blier and Claude de Montigny.
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              Noradrenergic modulation of wakefulness/arousal.

              The locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus noradrenergic neurons has long-suggested a role of this system in the induction of an alert waking state. Work over the past two decades provides unambiguous evidence that the locus coeruleus, and likely other noradrenergic nuclei, exert potent wake-promoting actions via an activation of noradrenergic β- and α₁-receptors located within multiple subcortical structures, including the general regions of the medial septal area, the medial preoptic area and, most recently, the lateral hypothalamus. Conversely, global blockade of β- and α₁-receptors or suppression of norepinephrine release results in profound sedation. The wake-promoting action of central noradrenergic neurotransmission has clinical implications for treatment of sleep/arousal disorders, such as insomnia and narcolepsy, and clinical conditions associated with excessive arousal, such as post-traumatic stress disorder. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Investigation
                Role: ConceptualizationRole: Formal analysisRole: SupervisionRole: Writing – review & editing
                Role: Investigation
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 September 2019
                2019
                : 14
                : 9
                : e0222855
                Affiliations
                [1 ] NEUROFARBA—Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Università di Firenze, Firenze, Italia
                [2 ] Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A, S.Palomba-Pomezia (Roma), Italia
                Indiana University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Drs. L. Polenzani and M. Magnani are full-time employees of Angelini S.p.A. Dr. R. Corradetti has received research grants from Angelini S.p.A. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other Authors declare no conflict of interest.

                Author information
                http://orcid.org/0000-0002-2588-0484
                Article
                PONE-D-19-16674
                10.1371/journal.pone.0222855
                6763016
                31557210
                6ab03b09-1015-4d4e-8301-84ca960386a0
                © 2019 Montalbano et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 12 June 2019
                : 9 September 2019
                Page count
                Figures: 7, Tables: 0, Pages: 19
                Funding
                Funded by: Angelini S.p.A.
                Award ID: 039RD15382
                Award Recipient :
                This study was funded by Angelini S.p.A., by grant number 039RD15382 awarded to Prof. Renato Corradetti. The funder provided support in the form of salaries for authors L.P and M.M., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
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                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Neurons
                Biology and Life Sciences
                Neuroscience
                Cellular Neuroscience
                Neurons
                Biology and Life Sciences
                Biochemistry
                Proteins
                Transmembrane Receptors
                Serotonin Receptors
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                Cell Biology
                Signal Transduction
                Transmembrane Receptors
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                Biochemistry
                Neurochemistry
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                Biology and Life Sciences
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                Biogenic Amines
                Serotonin
                Medicine and Health Sciences
                Pharmacology
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