title: Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.
abstract: Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons.
authors: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
authors: Joachim D
authors: JD
authors: Uys
authors: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors: Natalie S
authors: NS
authors: McGuier
authors: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
authors: Justin T
authors: JT
authors: Gass
authors: Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors: William C
authors: WC
authors: Griffin
authors: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
authors: Lauren E
authors: LE
authors: Ball
authors: Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.|Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors: Patrick J
authors: PJ
authors: Mulholland
mesh_terms: D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D002853:Chromatography, Liquid; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D057907:Post-Synaptic Density / Q000187:drug effects* / Q000378:metabolism; D020543:Proteome / Q000187:drug effects* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D002492:Central Nervous System Depressants; D020543:Proteome; D000431:Ethanol
keywords: Cellular morphology; chronic intermittent ethanol exposure; dendritic spines; nucleus accumbens; proteomics; structural plasticity