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      Increased Opioid Dependence in a Mouse Model of Panic Disorder

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          Abstract

          Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met 5-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

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          Most cited references79

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          Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

          This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
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            Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study.

            The prevalence of comorbid alcohol, other drug, and mental disorders in the US total community and institutional population was determined from 20,291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder, 13.5% for alcohol dependence-abuse, and 6.1% for other drug dependence-abuse. Among those with a mental disorder, the odds ratio of having some addictive disorder was 2.7, with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder, the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder, 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders, among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings, comorbidity of addictive and severe mental disorders was highest in the prison population, most notably with antisocial personality, schizophrenia, and bipolar disorders.
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              Brain-derived neurotrophic factor.

              Since the purification of BDNF in 1982, a great deal of evidence has mounted for its central roles in brain development, physiology, and pathology. Aside from its importance in neural development and cell survival, BDNF appears essential to molecular mechanisms of synaptic plasticity. Basic activity-related changes in the central nervous system are thought to depend on BDNF modification of synaptic transmission, especially in the hippocampus and neocortex. Pathologic levels of BDNF-dependent synaptic plasticity may contribute to conditions such as epilepsy and chronic pain sensitization, whereas application of the trophic properties of BDNF may lead to novel therapeutic options in neurodegenerative diseases and perhaps even in neuropsychiatric disorders.
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                Author and article information

                Journal
                Front Behav Neurosci
                Front. Behav. Neurosci.
                Frontiers in Behavioral Neuroscience
                Frontiers Research Foundation
                1662-5153
                07 June 2009
                22 February 2010
                2009
                : 3
                : 60
                Affiliations
                [1] 1simpleGenes and Disease Program, Genomic Regulation Center-CRG, Barcelona Biomedical Research Park-PRBB and CIBER de Enfermedades Raras Barcelona, Catalonia, Spain
                [2] 2simpleUnit of Neuropharmacology, Pompeu Fabra University, Barcelona Catalonia, Spain
                [3] 3simpleInstitute of Neuroscience, University of Miguel Hernández-CSIC Alicante, Spain
                [4] 4simpleDepartment of Pharmacology, University of the Basque Country Leioa, Spain
                [5] 5simpleDepartment of Cell Biology, Immunology and Neuroscience, University of Barcelona Barcelona, Catalonia, Spain
                Author notes

                Edited by: Agnes Gruart, University Pablo de Olavide, Spain

                Reviewed by: Shashana Eitan, Texas A&M University, USA

                *Correspondence: Mara Dierssen, Genes and Disease Program, Genomic Regulation Center-CRG, Barcelona Biomedical Research Park-PRBB, C/ Dr. Aiguader, 88, E-08003 Barcelona, Catalonia, Spain. e-mail: mara.dierssen@ 123456crg.es
                Article
                10.3389/neuro.08.060.2009
                2831706
                20204153
                a1066605-72fd-4b44-9f90-f48f21b4ce5c
                Copyright © 2010 Gallego, Murtra, Zamalloa, Canals, Pineda, Amador-Arjona, Maldonado and Dierssen.

                This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.

                History
                : 09 April 2009
                : 16 December 2009
                Page count
                Figures: 6, Tables: 3, Equations: 0, References: 83, Pages: 14, Words: 12045
                Categories
                Neuroscience
                Original Research

                Neurosciences
                trkb,bdnf,panic disorder,opiate withdrawal,trkc,tgntrk3,nt-3,locus coeruleus
                Neurosciences
                trkb, bdnf, panic disorder, opiate withdrawal, trkc, tgntrk3, nt-3, locus coeruleus

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