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      Cortisol suppression and hearing thresholds in tinnitus after low-dose dexamethasone challenge

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          Abstract

          Background

          Tinnitus is a frequent, debilitating hearing disorder associated with severe emotional and psychological suffering. Although a link between stress and tinnitus has been widely recognized, the empirical evidence is scant. Our aims were to test for dysregulation of the stress-related hypothalamus-pituitary adrenal (HPA) axis in tinnitus and to examine ear sensitivity variations with cortisol manipulation.

          Methods

          Twenty-one tinnitus participants and 21 controls comparable in age, education, and overall health status but without tinnitus underwent basal cortisol assessments on three non-consecutive days and took 0.5 mg of dexamethasone (DEX) at 23:00 on the first day. Cortisol levels were measured hourly the next morning. Detection and discomfort hearing thresholds were measured before and after dexamethasone suppression test.

          Results

          Both groups displayed similar basal cortisol levels, but tinnitus participants showed stronger and longer-lasting cortisol suppression after DEX administration. Suppression was unrelated to hearing loss. Discomfort threshold was lower after cortisol suppression in tinnitus ears.

          Conclusions

          Our findings suggest heightened glucocorticoid sensitivity in tinnitus in terms of an abnormally strong glucocorticoid receptor (GR)-mediated HPA-axis feedback (despite a normal mineralocorticoid receptor (MR)-mediated tone) and lower tolerance for sound loudness with suppressed cortisol levels. Long-term stress exposure and its deleterious effects therefore constitute an important predisposing factor for, or a significant pathological consequence of, this debilitating hearing disorder.

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          Most cited references41

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          Tuning out the noise: limbic-auditory interactions in tinnitus.

          Tinnitus, the most common auditory disorder, affects about 40 million people in the United States alone, and its incidence is rising due to an aging population and increasing noise exposure. Although several approaches for the alleviation of tinnitus exist, there is as of yet no cure. The present article proposes a testable model for tinnitus that is grounded in recent findings from human imaging and focuses on brain areas in cortex, thalamus, and ventral striatum. Limbic and auditory brain areas are thought to interact at the thalamic level. While a tinnitus signal originates from lesion-induced plasticity of the auditory pathways, it can be tuned out by feedback connections from limbic regions, which block the tinnitus signal from reaching auditory cortex. If the limbic regions are compromised, this "noise-cancellation" mechanism breaks down, and chronic tinnitus results. Hopefully, this model will ultimately enable the development of effective treatment.
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            Dysregulation of limbic and auditory networks in tinnitus.

            Tinnitus is a common disorder characterized by ringing in the ear in the absence of sound. Converging evidence suggests that tinnitus pathophysiology involves damage to peripheral and/or central auditory pathways. However, whether auditory system dysfunction is sufficient to explain chronic tinnitus is unclear, especially in light of evidence implicating other networks, including the limbic system. Using functional magnetic resonance imaging and voxel-based morphometry, we assessed tinnitus-related functional and anatomical anomalies in auditory and limbic networks. Moderate hyperactivity was present in the primary and posterior auditory cortices of tinnitus patients. However, the nucleus accumbens exhibited the greatest degree of hyperactivity, specifically to sounds frequency-matched to patients' tinnitus. Complementary structural differences were identified in ventromedial prefrontal cortex, another limbic structure heavily connected to the nucleus accumbens. Furthermore, tinnitus-related anomalies were intercorrelated in the two limbic regions and between limbic and primary auditory areas, indicating the importance of auditory-limbic interactions in tinnitus. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.

              We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds. We show here that the mouse mdr1a and the human MDR1 P-glycoprotein actively transport ivermectin, dexamethasone, digoxin, and cyclosporin A and, to a lesser extent, morphine across a polarized kidney epithelial cell layer in vitro. Injection of these radio-labeled drugs in mdr1a (-/-) and wild-type mice resulted in markedly (20- to 50-fold) higher levels of radioactivity in mdr1a (-/-) brain for digoxin and cyclosporin A, with more moderate effects for dexamethasone (2- to 3-fold) and morphine (1.7-fold). Digoxin and cyclosporin A were also more slowly eliminated from mdr1a (-/-) mice. Our findings show that P-glycoprotein can be a major determinant for the pharmacology of several medically important drugs other than anti-cancer agents, especially in the blood-brain barrier. These results may explain a range of pharmacological interactions observed between various drugs in patients.
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                Author and article information

                Journal
                BMC Ear Nose Throat Disord
                BMC Ear Nose Throat Disord
                BMC Ear, Nose, and Throat Disorders
                BioMed Central
                1472-6815
                2012
                26 March 2012
                : 12
                : 4
                Affiliations
                [1 ]Cognitive Brain Research Unit, Cognitive Science, Department of Behavioural Sciences, University of Helsinki, Helsinki, P.O. Box 9 00014, Finland
                [2 ]Finnish Centre of Excellence in Interdisciplinary Music Research, Department of Music, University of Jyväskylä, Jyväskylä, Finland
                [3 ]BRAMS, International Laboratory for Brain, Music, and Sound research, Montreal, Canada
                [4 ]École d'orthophonie et d'audiologie, Faculté de médecine, Université de Montréal, Canada, and Centre de recherche de l'Institut universitaire de gériatrie de Montréal, Montréal, Canada
                [5 ]Université de Montréal BRAMS, Pavillon 1420, Mont-Royal C.P. 6128, succ. Centre-ville, Montréal, QC H3C 3J7, Canada
                Article
                1472-6815-12-4
                10.1186/1472-6815-12-4
                3328238
                22449242
                23a608a6-0a83-4ff4-9737-ac3dbdb4d032
                Copyright ©2012 Simoens and Hébert; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 July 2011
                : 26 March 2012
                Categories
                Research Article

                Otolaryngology
                hearing sensitivity,hpa axis,cortisol,tinnitus,low-dose dexamethasone suppression test,hearing threshold,stress

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