Background: Alcohol withdrawal syndrome (AWS) results from the sudden cessation of chronic alcohol use and is associated with high morbidity and mortality. Alcohol withdrawal-induced central nervous system (CNS) hyperexcitability results from complex, compensatory changes in synaptic efficacy and intrinsic excitability. These changes in excitability counteract the depressing effects of chronic ethanol on neural transmission and underlie symptoms of AWS, which range from mild anxiety to seizures and death. The development of targeted pharmacotherapies for treating AWS has been slow, due in part to the lack of available animal models that capture the key features of human AWS. Using a unique optogenetic method of probing network excitability, we examined electrophysiologic correlates of hyperexcitability sensitive to early changes in CNS excitability. This method is sensitive to pharmacologic treatments that reduce excitability and may represent a platform for AWS drug development.
Methods: We applied a newly developed method, the optogenetic population discharge threshold (oPDT), which uses light intensity response curves to measure network excitability in chronically implanted mice. Excitability was tracked using the oPDT before, during, and after the chronic intermittent exposure (CIE) model of alcohol withdrawal (WD).
Results: Alcohol withdrawal produced a dose-dependent leftward shift in the oPDT curve (denoting increased excitability), which was detectable in as few as three exposure cycles. This shift in excitability mirrored an increase in the number of spontaneous interictal spikes during withdrawal. In addition, Withdrawal lowered seizure thresholds and increased seizure severity in optogenetically kindled mice.
Conclusion: We demonstrate that the oPDT provides a sensitive measure of alcohol withdrawal-induced hyperexcitability. The ability to actively probe the progression of excitability without eliciting potentially confounding seizures promises to be a useful tool in the preclinical development of next-generation pharmacotherapies for AWS.
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http://dx.doi.org/10.1111/acer.15004 | DOI Listing |
Neurobiol Stress
January 2025
Department of Translational Neuroscience, Wake Forest University, School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
With the recent rise in the rate of alcohol use disorder (AUD) in women, the historical gap between men and women living with this condition is narrowing. While there are many commonalities in how men and women are impacted by AUD, an accumulating body of evidence is revealing sex-dependent adaptations that may require distinct therapeutic approaches. Preclinical rodent studies are beginning to shed light on sex differences in the effects of chronic alcohol exposure on synaptic activity in a number of brain regions.
View Article and Find Full Text PDFAddict Neurosci
December 2024
Department of Physiology and Pharmacology, University of Georgia, Athens, GA.
Chronic social defeat stress (SDS) is a widely employed preclinical model of depression involving repeated exposure to physical defeats using a resident-intruder model in male mice. Exposure to SDS induces depressive-like phenotypes including anhedonia, social withdrawal, and increased drug and alcohol consumption. Previously, we found that expression of the neurokinin-1 receptor (NK1R) is increased in the nucleus accumbens (NAC) of mice that are sensitive to this stressor and increase their alcohol intake.
View Article and Find Full Text PDFHarm Reduct J
January 2025
Department of Psychiatry and Neurosciences, CCM, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
Background: Gamma-hydroxybutyrate (GHB) and its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (BD) have become a significant concern due to the increase in their recreational use and the high risks associated with it (e.g., overdose, addiction, life-threatening withdrawal syndromes).
View Article and Find Full Text PDFAnaesthesia
January 2025
Consultant, Department of Peri-operative Medicine, University College London Hospitals NHS Trust, London, UK.
Introduction: This consensus statement gives practical advice for the safe management of patients with harmful alcohol intake undergoing elective and emergency surgery. The wide spectrum of alcohol-related organ dysfunction observed in this cohort of patients may have a profound impact on care, and the additional effects of alcohol withdrawal may further exacerbate postoperative morbidity and mortality.
Methods: A working party was assembled based on clinical and/or academic expertise in the area.
BMJ
January 2025
Division of Addiction Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
The covid-19 pandemic was associated with an unprecedented increase in alcohol consumption and associated morbidity, including hospitalizations for alcohol withdrawal. Clinicians based in hospitals must be ready to identify, assess, risk-stratify, and treat alcohol withdrawal with evidence based interventions. In this clinically focused review, we outline the epidemiology, pathophysiology, clinical manifestations, screening, assessment, and treatment of alcohol withdrawal in the general hospital population.
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