Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling

Abstract

Background: Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.Methods: Adult male CRF-tomato reporter mice were treatment-na€ ıve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.Results: We found that NE depolarized BNST CRF neurons in na€ ıve mice in a b-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE-or stress-exposed mice had significantly elevated basal resting membrane potential compared to na€ ıve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize b-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in na€ ıve mice, a mechanism previously shown to be a-AR-dependent.Conclusions: Altogether, these findings suggest that stress and CIE interact with b-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the a/b-AR balance of BNST CRF neuronal excitability. Restoration of a/b-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.

Impact of High Fat Diet and Ethanol Consumption on Neurocircuitry Regulating Emotional Processing and Metabolic Function

“…This consumption model has been the forerunner in the EtOH research field as a useful tool to study pathological disorders associated with AUD, such as alcoholic liver disease (Dolganiuc et al, 2009 ; Bhopale et al, 2017 ; Guo et al, 2018 ). Another commonly used exposure method is EtOH vapor inhalation which is useful to maintain constant, clinically relevant blood EtOH concentrations and to induce EtOH dependence (Healey et al, 2008 ; Snyder et al, 2019 ). In addition to these passive or forced consumption models, many rodent strains will self-administer to pharmacologically relevant blood EtOH concentrations.…”

Corticotropin Releasing Hormone Signaling in the Bed Nuclei of the Stria Terminalis as a Link to Maladaptive Behaviors

“…BST CRH infusion was also found to induce the reinstatement of cocaine-seeking behavior (Erb and Stewart, 1999), demonstrating the effect of CRH signaling on multiple forms of maladaptive behaviors. An important source of CRH in the BST comes from CRH projections from the CEA to the dorsolateral BST (BSTdl), and those projections are necessary for the induction Lateral ventricle Y2R antagonism ↓ Alcohol consumption (Thorsell et al, 2002) β-E µ and δ opioid receptors BST β-E deficient mice ↑ Alcohol consumption in female mice (Nentwig et al, 2019) NE α 2a -AR BSTd α 2a -AR agonist administration ↓ Anxiety-like behavior (Schweimer et al, 2005;Harris et al, 2018) β-AR BST NE administration ↑ CRH neuron activation (Snyder et al, 2019) DA D1R, D2R BSTdl DA administration ↑ glutamatergic transmission (Kash et al, 2008) eCB CB1R BSTd MAG lipase inhibitor administration Normalized BST CRH neuron activation following alcohol withdrawal (Centanni et al, 2019) -Indicates value not specified by cited paper.…”

“…HCRT is closely associated with wakefulness and narcolepsy ( Soya and Sakurai, 2020 ) because of its role in the regulation of vigilance and arousal states ( Boutrel and de Lecea, 2008 ), so it raises the question of if the BST-HCRT-LH pathway can help explain the sleep disruptions commonly associated with anxiety ( American Psychiatric Association, 2013 ). It is possible that upregulation of CRH neurons in the BST and subsequent activation of HCRT-LH neurons may therefore contribute to the increased arousal states associated with anxiety and other altered mood states, as well as contribute to the role of the BST in regulating addiction ( Snyder et al, 2019 ).…”

“…α 2 a -AR agonists administered during restraint stress decreased CRH activation in the BST, with sex-specific effects ( Fetterly et al, 2019 ). While α-ARs mediate glutamatergic inputs into BST CRH neurons in an inhibitory manner ( Fetterly et al, 2019 ), β-ARs have been shown to depolarize BST CRH neurons when treated with NE, leading to greater neuronal activation ( Snyder et al, 2019 ). β-AR activation occurs during both stress and EtOH administration, further tying the BST to AUDs ( Snyder et al, 2019 ).…”

“…The BST is involved in the development of other maladaptive behaviors beyond anxiety disorders. It has been implicated in binge drinking and alcohol use disorders (AUDs), particularly the stress-induced reinstatement of drug-seeking behaviors ( Silberman and Winder, 2013 ; Nentwig et al, 2019 ; Snyder et al, 2019 ). In this model of the addiction cycle, withdrawal produces negative affect and dysregulated BST CRH signaling.…”