An ultra low frequency spike timing dependent plasticity based approach for reducing alcohol drinking.

An ultra low frequency spike timing dependent plasticity based approach for reducing alcohol drinking.

Publication date: Dec 28, 2024

Alcohol use disorder (AUD) is a chronic relapsing brain disorder characterized by an impaired ability to stop or control alcohol consumption despite adverse social, occupational, or health consequences. AUD affects nearly one-third of adults at some point during their lives, with an associated cost of approximately $249 billion annually in the U. S. alone. The effects of alcohol consumption are expected to increase significantly during the COVID-19 pandemic, with alcohol sales increasing by approximately 54%, potentially exacerbating health concerns and risk-taking behaviors. Unfortunately, existing pharmacological and behavioral therapies for AUD are associated with poor success rates, with approximately 40% of individuals relapsing within three years of treatment. Pre-clinical studies have shown that chronic alcohol consumption leads to significant changes in synaptic function within the dorsal medial striatum (DMS), one of the brain regions associated with AUD and responsible for mediating goal-directed behavior. Specifically, chronic alcohol consumption has been associated with hyperactivity of dopamine receptor 1 (D1) medium spiny neurons (MSN) and hypoactivity of dopamine receptor 2 (D1) MSNs within the DMS. Optogenetic, chemogenetic, and transgenic approaches have demonstrated that reducing the D1/D2 MSN signaling imbalance decreases alcohol self-administration in rodent models of AUD. Here, we present an electrical stimulation approach that uses ultra-low (≤ 1 Hz) frequency (ULF) spike-timing-dependent plasticity (STDP) in mouse models of AUD to reduce DMS D1/D2 MSN signaling imbalances by stimulating D1-MSN afferents into the GPi and ACC glutamatergic projections to the DMS in a time-locked stimulation sequence. Our data suggest that GPi/ACC ULF-STDP selectively decreases DMS D1-MSN hyperactivity leading to reduced alcohol consumption without evoking undesired affective behaviors using electrical stimulation rather than approaches requiring genetic modification. This work represents a step towards fulfilling the unmet need for a reliable method of treating severe AUD through cell-type-specific control with clinically available neuromodulation tools.

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Concepts Keywords
249billion Action Potentials
Genetic Alcohol Drinking
Glutamatergic Alcoholism
Models Animals
Poor COVID-19
Male
Mice
Neuronal Plasticity
Optogenetics
Receptors, Dopamine D1
Receptors, Dopamine D1

Semantics

Type Source Name
drug DRUGBANK Ethanol
disease MESH Alcohol use disorder
disease MESH brain disorder
disease MESH COVID-19 pandemic
drug DRUGBANK Spinosad
drug DRUGBANK Succimer
drug DRUGBANK Dopamine
disease IDO cell
disease MESH psychiatric disorders
drug DRUGBANK Coenzyme M
drug DRUGBANK Glypromate
disease MESH neurologic disorders
drug DRUGBANK Trestolone
drug DRUGBANK Water
drug DRUGBANK Buprenorphine
drug DRUGBANK Ibuprofen
drug DRUGBANK Isoflurane
drug DRUGBANK Povidone-iodine
drug DRUGBANK Hydrogen peroxide
disease MESH infection
disease IDO site
disease MESH weight loss
drug DRUGBANK Aspartame
drug DRUGBANK Tricyclazole
drug DRUGBANK Pidolic Acid
disease MESH blood alcohol content
drug DRUGBANK Pentaerythritol tetranitrate
drug DRUGBANK Alpha-Linolenic Acid
drug DRUGBANK Albendazole
drug DRUGBANK Lidocaine
drug DRUGBANK Pentobarbital
drug DRUGBANK Phosphate ion
disease IDO blood
drug DRUGBANK Formaldehyde
drug DRUGBANK Sucrose
pathway KEGG Alcoholism

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