Phosphorylation of calcium/calmodulin-dependent protein kinase II in the rat dorsal medial prefrontal cortex is associated with alcohol-induced cognitive inflexibility

Addict Biol. 2018 Sep;23(5):1117-1129. doi: 10.1111/adb.12568. Epub 2017 Sep 22.


Repeated cycles of alcohol [ethanol (EtOH)] intoxication and withdrawal dysregulate excitatory glutamatergic systems in the brain and induce neuroadaptations in the medial prefrontal cortex (mPFC) that contribute to cognitive dysfunction. The mPFC is composed of subdivisions that are functionally distinct, with dorsal regions facilitating drug-cue associations and ventral regions modulating new learning in the absence of drug. A key modulator of glutamatergic activity is the holoenzyme calcium/calmodulin-dependent protein kinase II (CaMKII) that phosphorylates ionotropic glutamate receptors. Here, we examined the hypothesis that abstinence from chronic intermittent EtOH (CIE) exposure dysregulates CaMKII activity in the mPFC to impair cognitive flexibility. We used an operant model of strategy set shifting in male Long-Evans rats demonstrating reduced susceptibility to trial omissions during performance in a visual cue-guided task versus albino strains. Relative to naïve controls, rats experiencing approximately 10 days of abstinence from CIE vapor exposure demonstrated impaired performance during a procedural shift from visual cue to spatial location discrimination. Phosphorylation of CaMKII subtype α was upregulated in the dorsal, but not ventral mPFC of CIE-exposed rats, and was positively correlated with perseverative-like responding during the set shift. The findings suggest that abstinence from CIE exposure induces an undercurrent of kinase activity (e.g. CaMKII), which may promote aberrant glutamatergic responses in select regions of the mPFC. Given the role of the mPFC in modulating executive control of behavior, we propose that increased CaMKII subtype α activity reflects a dysregulated 'top-down' circuit that interferes with adaptive behavioral performance under changing environmental demands.

Keywords: cognition; ethanol; prelimbic.

Publication types

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

MeSH terms

  • Alcoholism / complications*
  • Alcoholism / genetics
  • Alcoholism / physiopathology
  • Animals
  • Behavior, Animal / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Central Nervous System Depressants / pharmacology
  • Cognition / drug effects
  • Cognitive Dysfunction / etiology*
  • Cognitive Dysfunction / physiopathology
  • Disease Models, Animal
  • Ethanol / pharmacology*
  • Male
  • Phosphorylation
  • Prefrontal Cortex / metabolism*
  • Rats
  • Rats, Long-Evans


  • Central Nervous System Depressants
  • Ethanol
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2