Gap junction channels as potential targets for the treatment of major depressive disorder

Ren, Qian; Wang, Zhenzhen; Chu, Shifeng; Xia, Changfa; Chen, Nai‐Hong

doi:10.1007/s00213-017-4782-7

Cited by 41 publications

(26 citation statements)

References 145 publications

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“…The infusion into the prefrontal cortex of both the gap junction blocker carbenoxolone and the Cx43 mimetic, antagonistic peptide Gap27 caused anhedonia. Similarly, exposure to chronic unpredictable stress of rats also caused a decrease in the expression of prefrontal cortical connexins, while long-lasting treatment with antidepressants with unrelated structure and mode of action invariably increased the expression of connexins (Ren et al, 2018).…”

Section: Inhibited Astrocytic Atp Release In the Prefrontal Cortex Anmentioning

confidence: 98%

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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The mood disorders, major depression (MD) and bipolar disorder (BD), have a high lifetime prevalence in the human population and accordingly generate huge costs for health care. Efficient, rapidly acting, and side-effect-free pharmaceuticals are hitherto not available, and therefore, the identification of new therapeutic targets is an imperative task for (pre)clinical research. Such a target may be the purinergic P2X7 receptor (P2X7R), which is localized in the central nervous system (CNS) at microglial and neuroglial cells mediating neuroinflammation. MD and BD are due to neuroinflammation caused in the first line by the release of the pro-inflammatory cytokine interleukin-1β (IL-1β) from the microglia. IL-1β in turn induces the secretion of corticotropin-releasing hormone (CRH) and in consequence the secretion of adrenocorticotropic hormone (ACTH) and cortisol, which together with a plethora of further cytokines/chemokines lead to mood disorders. A number of biochemical/molecular biological measurements including the use of P2X7R-or IL-1β-deficient mice confirmed this chain of events. More recent studies showed that a decrease in the astrocytic release of ATP in the prefrontal cortex and hippocampus is a major cause of mood disorders. It is an attractive hypothesis that compensatory increases in P2X7Rs in these areas of the brain are the immediate actuators of MD and BD. Hence, blood-brain barrier-permeable P2X7R antagonists may be promising therapeutic tools to improve depressive disorders in humans.

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Section: Inhibited Astrocytic Atp Release In the Prefrontal Cortex Anmentioning

confidence: 98%

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Illéš

Verkhratsky

Tang

2020

Front. Mol. Neurosci.

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“…It can be argued, however, that while self-reports provide an overview of an individual’s general tendency to be impulsive, behavioral tasks capture in-the-moment fluctuations in components of impulsivity, as well as variations that might arise in response to various stimuli ( Cyders and Coskunpinar, 2011 ; Gullo and Potenza, 2014 ). Although both self-report and behavioral impulsivity have been implicated in substance use disorder pathology ( Verdejo-García et al , 2008 ; Gullo et al , 2014 ; Gullo and Potenza, 2014 ; Weafer et al , 2014 ), it is fluctuations in aspects of impulsivity and how these might map onto variations in substance intake that often attracts the interest of cognitive psychologists ( Jones et al , 2018 ), particularly as this might provide insight into when and how to intervene.…”

Section: Impulsivitymentioning

confidence: 99%

Transition to substance use disorders: impulsivity for reward and learning from reward

Poulton

Hester

2019

Social Cognitive and Affective Neuroscience

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Abstract Substance dependence constitutes a profound societal burden. Although large numbers of individuals use licit or illicit substances, few transition to dependence. The specific factors influencing this transition are not well understood. Substance-dependent individuals tend to be swayed by the immediate rewards of drug taking, but are often insensitive to delayed negative consequences of their behavior. Dependence is consequently associated with impulsivity for reward and atypical learning from feedback. Behavioral impulsivity is indexed using tasks measuring spontaneous decision-making and capacity to control impulses. While evidence indicates drug taking exacerbates behavioral impulsivity for reward, animal and human studies of drug naïve populations demonstrate it might precede any drug-related problems. Research suggests dependent individuals are also more likely to learn from rewarding (relative to punishing) feedback. This may partly explain why substance-dependent individuals fail to modify their behavior in response to negative outcomes. This enhanced learning from reward may constitute a further pre-existing risk factor for substance dependence. Although impulsivity for reward and preferential learning from rewarding feedback are both underpinned by a compromised dopaminergic system, few studies have examined the relationship between these two mechanisms. The interplay of these processes may help enrich understanding of why some individuals transition to substance dependence.

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“…Because hyperactivity of the noradrenergic system is also identified as a neurobiological mechanism underlying AUD [21,31,40], the findings from the collective prazosin literature lend support to the notion that alpha-1 adrenergic antagonists may also be effective in the treatment of co-occurring PTSD and AUD. One limitation of prazosin is its relatively short half-life, which commonly results in challenges to medication adherence in order to obtain a therapeutic dose.…”

Section: Discussionmentioning

confidence: 99%

“…The studies conducted to date have examined a variety of medications (e.g., sertraline, topiramate, naltrexone, nacetylcysteine) with modest therapeutic effects observed and significant room for improvement [4,9,14,44,63]. The noradrenergic system has been implicated in PTSD, withdrawal states from chronic substance use, and in response to substance-related cues [21,25,31,61], suggesting that therapeutic interventions targeting the noradrenergic system may represent a promising avenue for the treatment of comorbid PTSD and SUD. Previous studies have examined the use of prazosin, an alpha-1 noradrenergic blocker approved by the U.S. Food and Drug Administration (FDA) for hypertension and benign prostatic hyperplasia, in the treatment of PTSD, AUD and comorbid AUD/PTSD.…”

Section: Introductionmentioning

confidence: 99%

Doxazosin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in military veterans

Back¹,

Flanagan²,

Jones³

et al. 2018

Contemporary Clinical Trials

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Posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD) are two of the most common mental health disorders affecting civilians as well as military populations. If left untreated, individuals with co-occurring PTSD/AUD are at increased risk for developing other mental health problems (e.g., depression, anxiety), physical health problems, reduced resiliency and military readiness, and vocational and social impairment. Substantial gaps in the treatment of co-occurring PTSD/AUD exist and there is a critical need to develop more effective pharmacological treatments. The current study addresses this gap in the literature by testing the efficacy and safety of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared to placebo in reducing PTSD and AUD severity among U.S. military veterans. Noradrenergic dysregulation has been implicated in the development and maintenance of PTSD and AUD, and pilot studies examining doxazosin in PTSD-only or AUD-only samples have shown promise. This is the first study, however, to evaluate doxazosin in a comorbid PTSD/AUD sample. This paper describes the rationale, design and methodology of a randomized, double-blind, placebo-controlled trial of doxazosin (16 mg/day) delivered over 12 weeks among military veterans with current PTSD and AUD. In addition, functional magnetic resonance imaging (fMRI) is applied at pre- and post-treatment to investigate the underlying pathophysiology of comorbid PTSD/AUD and identify prognostic indicators of treatment outcome. This study is designed to accelerate research on co-occurring PTSD/AUD and provide empirical evidence to inform clinical practice.

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Gap junction channels as potential targets for the treatment of major depressive disorder

Abstract: This review supports the hypothesis that the regulation of GJCs between astrocytes could be an underlying mechanism for the therapeutic effect of antidepressants.

Cited by 41 publications

References 145 publications

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Pathological ATPergic Signaling in Major Depression and Bipolar Disorder

Transition to substance use disorders: impulsivity for reward and learning from reward

Doxazosin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in military veterans

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