Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines

Addict Biol. 2016 May;21(3):560-74. doi: 10.1111/adb.12238. Epub 2015 Mar 17.


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.

Keywords: Cellular morphology; chronic intermittent ethanol exposure; dendritic spines; nucleus accumbens; proteomics; structural plasticity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcoholism / metabolism*
  • Animals
  • Blotting, Western
  • Central Nervous System Depressants / administration & dosage
  • Central Nervous System Depressants / pharmacology*
  • Chromatography, Liquid
  • Dendritic Spines / drug effects*
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Ethanol / administration & dosage
  • Ethanol / pharmacology*
  • Male
  • Mice
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Post-Synaptic Density / drug effects*
  • Post-Synaptic Density / metabolism
  • Proteome / drug effects*
  • Proteome / metabolism
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / metabolism
  • Tandem Mass Spectrometry


  • Central Nervous System Depressants
  • Proteome
  • Ethanol