Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex

Navarro, Alvaro I; Mandyam, Chitra D.

doi:10.1016/j.neuroscience.2015.02.043

Cited by 44 publications

(36 citation statements)

References 86 publications

(110 reference statements)

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“…Importantly, these changes were also associated with deficits in cognitive flexibility, which lasted up to one week into abstinence. A subsequent study examining expression of GluN2B-containing NMDA receptors in the mPFC following three weeks of abstinence from chronic intermittent ethanol vapor exposure reported similar findings with unaltered total GluN2B levels despite the presence of significantly increased dendritic arborization of pyramidal neuron apical dendrites within this region (Navarro and Mandyam, 2015). Interestingly, while total GluN2B levels were unchanged at this time-point, the authors reported a significant reduction in the levels of phosphorylated GluN2B-containing receptors.…”

Section: Glutamatergic Adaptations Involved In Dependence-induced mentioning

confidence: 77%

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

Burnett

Chandler

Trantham-Davidson

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Introduction Alcohol dependence is characterized by a reduction in reward threshold, development of a negative affective state, and significant cognitive impairments. Dependence-induced glutamatergic neuroadaptations in the neurocircuitry mediating reward, affect and cognitive function are thought to underlie the neural mechanism for these alterations. These changes serve to promote increased craving for alcohol and facilitate the development of maladaptive behaviors that promote relapse to alcohol drinking during periods of abstinence. Objective To review the extant literature on the effects of chronic alcohol exposure on glutamatergic neurotransmission and its impact on reward, affect and cognition. Results Evidence from a diverse set of studies demonstrates significant enhancement of glutamatergic activity following chronic alcohol exposure and up-regulation of GluN2B-containing NMDA receptor expression and function is a commonly observed phenomenon that likely reflects activity-dependent adaptive homeostatic plasticity. However, changes in NMDA receptors and additional glutamatergic neuroadaptations are often circuit and cell-type specific. Discussion Dependence-induced alterations in glutamate signaling contribute to many of the symptoms experienced in addicted individuals and can persist well into abstinence. This suggests they play an important role in the development of behaviors that increase the probability for relapse. As our understanding of the complexity of the neurocircuitry involved in the addictive process has advanced, it has become increasingly clear that investigations of cell-type and circuit-specific effects are required to gain a more comprehensive understanding of the glutamatergic adaptations and their functional consequences in alcohol addiction. Conclusion While pharmacological treatments for alcohol dependence and relapse targeting the glutamatergic system have shown great promise in preclinical models, more research is needed to uncover novel, possibly circuit-specific, targets with improved efficacy and reduced side effects.

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Section: Glutamatergic Adaptations Involved In Dependence-induced mentioning

confidence: 77%

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

Burnett

Chandler

Trantham-Davidson

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…These results suggest that mPFC, in part via GR signaling, can modulate the mesocorticolimbic pathway and thereby regulate anxiety-like and aggression-like negative affect symptoms (Butts and Phillips, 2013; Miczek et al, 2015b). Previous research shows that acute withdrawal (2-10 h) from ethanol in CIE rats altered structural neuroplasticity in the mPFC pyramidal neurons (Kim et al, 2014) and decreased expression of GR mRNA in the mPFC without altering GR protein expression and signaling, among other regions (Navarro and Mandyam, 2015; Vendruscolo et al, 2012). Further, these studies do not reveal whether these changes persist into extended ethanol abstinence (24 h and longer).…”

Section: Introductionmentioning

confidence: 99%

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors

Somkuwar

Vendruscolo

Fannon

et al. 2017

Psychoneuroendocrinology

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Alcohol dependence is linked to dysregulation of the hypothalamic-pituitary-adrenal axis. Here, we investigated effects of repeated ethanol intoxication-withdrawal cycles (using chronic intermittent ethanol vapor inhalation; CIE) and abstinence from CIE on peak and nadir plasma corticosterone (CORT) levels. Irritability- and anxiety-like behaviors as well as glucocorticoid receptors (GR) in the medial prefrontal cortex (mPFC) were assessed at various intervals (2h-28d) after cessation of CIE. Results show that peak CORT increased during CIE, transiently decreased during early abstinence (1-11d), and returned to pre-abstinence levels during protracted abstinence (17-27d). Acute withdrawal from CIE enhanced aggression- and anxiety-like behaviors. Early abstinence from CIE reduced anxiety-like behavior. mPFC-GR signaling (indexed by relative phosphorylation of GR at Ser211) was transiently decreased when measured at time points during early and protracted abstinence. Further, voluntary ethanol drinking in CIE (CIE-ED) and CIE-naïve (ED) rats, and effects of CIE-ED and ED on peak CORT levels and mPFC-GR were investigated during acute withdrawal (8h) and protracted abstinence (28d). CIE-ED and ED increased peak CORT during drinking. CIE-ED and ED decreased expression and signaling of mPFC-GR during acute withdrawal, an effect that was reversed by systemic mifepristone treatment. CIE-ED and ED demonstrate robust reinstatement of ethanol seeking during protracted abstinence and show increases in mPFC-GR expression. Collectively, the data demonstrate that acute withdrawal from CIE produces robust alterations in GR signaling, CORT and negative affect symptoms which could facilitate excessive drinking. The findings also show that CIE-ED and ED demonstrate enhanced relapse vulnerability triggered by ethanol cues and these changes are partially mediated by altered GR expression in the mPFC. Taken together, transition to alcohol dependence could be accompanied by alterations in mPFC stress-related pathways that may increase negative emotional symptoms and increase vulnerability to relapse.

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“…Particularly interesting is the long-lasting effect of withdrawal on OPCs in the mPFC, visualized as increases in proliferation and survival of progenitors in CIE-ED animals that also demonstrated enhanced drinking after prolonged abstinence, suggesting a permanent dysregulation in the oligodendroglial niche maintaining oligodendroglial homeostasis (Somkuwar et al, 2015). Protracted abstinence from CIE is also associated with increases in myelin associated proteins in the mPFC indicating additional compensatory changes in myelinating glia (Navarro and Mandyam, 2015). Such alterations in the expression of oligodendroglia and myelinating glia during withdrawal and abstinence in the mPFC may be regulated by neuroinflammatory response during withdrawal, as interactions between oligodendroglia, myelin, endothelial cells and neuroinflammatory proteins have been demonstrated in models of brain injury, including, stroke and ischemia (Pham et al, 2012, Ortega et al, 2015).…”

Section: 0 Introductionmentioning

confidence: 99%

Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex

Somkuwar

Fannon-Pavlich

Ghofranian

et al. 2016

Brain, Behavior, and Immunity

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The therapeutic effects of wheel running (WR) during abstinence on reinstatement of ethanol seeking behaviors in rats that self-administered ethanol only (ethanol drinking, ED) or ED with concurrent chronic intermittent ethanol vapor experience (CIE-ED) were investigated. Neuronal activation as well as oligodendroglial and neuroinflammatory factors were measured in the medial prefrontal cortex (mPFC) tissue to determine cellular correlates associated with enhanced ethanol seeking. CIE-ED rats demonstrated escalated and unregulated intake of ethanol and maintained higher drinking than ED rats during abstinence. CIE-ED rats were more resistant to extinction from ethanol self-administration, however, demonstrated similar ethanol seeking triggered by ethanol contextual cues compared to ED rats. Enhanced seeking was associated with reduced neuronal activation, and increased number of myelinating oligodendrocyte progenitors and PECAM-1 expression in the mPFC, indicating enhanced oligodendroglial and neuroinflammatory response during abstinence. WR during abstinence enhanced self-administration in ED rats, indicating a deprivation effect. WR reduced reinstatement of ethanol seeking in CIE-ED and ED rats, indicating protection against relapse. The reduced ethanol seeking was associated with enhanced neuronal activation, reduced number of myelinating oligodendrocyte progenitors, and reduced PECAM-1 expression. The current findings demonstrate a protective role of WR during abstinence in reducing ethanol seeking triggered by ethanol contextual cues and establish a role for oligodendroglia-neuroinflammatory response in ethanol seeking. Taken together, enhanced oligodendroglia-neuroinflammatory response during abstinence may contribute to brain trauma in chronic alcohol drinking subjects and be a risk factor for enhanced propensity for alcohol relapse.

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Protracted abstinence from chronic ethanol exposure alters the structure of neurons and expression of oligodendrocytes and myelin in the medial prefrontal cortex

Cited by 44 publications

References 86 publications

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

Abstinence from prolonged ethanol exposure affects plasma corticosterone, glucocorticoid receptor signaling and stress-related behaviors

Wheel running reduces ethanol seeking by increasing neuronal activation and reducing oligodendroglial/neuroinflammatory factors in the medial prefrontal cortex

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