Ketamine Self-Administration Elevates αCaMKII Autophosphorylation in Mood and Reward-Related Brain Regions in Rats

Mol Neurobiol. 2018 Jul;55(7):5453-5461. doi: 10.1007/s12035-017-0772-3. Epub 2017 Sep 25.


Modulation of αCaMKII expression and phosphorylation is a feature shared by drugs of abuse with different mechanisms of action. Accordingly, we investigated whether αCaMKII expression and activation could be altered by self-administration of ketamine, a non-competitive antagonist of the NMDA glutamate receptor, with antidepressant and psychotomimetic as well as reinforcing properties. Rats self-administered ketamine at a sub-anesthetic dose for 43 days and were sacrificed 24 h after the last drug exposure; reward-related brain regions, such as medial prefrontal cortex (PFC), ventral striatum (vS), and hippocampus (Hip), were used for the measurement of αCaMKII-mediated signaling. αCaMKII phosphorylation was increased in these brain regions suggesting that ketamine, similarly to other reinforcers, activates this kinase. We next measured the two main targets of αCaMKII, i.e., GluN2B (S1303) and GluA1 (S831), and found increased activation of GluN2B (S1303) together with reduced phosphorylation of GluA1 (S831). Since GluN2B, via inhibition of ERK, regulates the membrane expression of GluA1, we measured ERK2 phosphorylation in the crude synaptosomal fraction of these brain regions, which was significantly reduced suggesting that ketamine-induced phosphorylation of αCaMKII promotes GluN2B (S1303) phosphorylation that, in turn, inhibits ERK 2 signaling, an effect that results in reduced membrane expression and phosphorylation of GluA1. Taken together, our findings point to αCaMKII autophosphorylation as a critical signature of ketamine self-administration providing an intracellular mechanism to explain the different effects caused by αCaMKII autophosphorylation on the post-synaptic GluN2B- and GluA1-mediated functions. These data add ketamine to the list of drugs of abuse converging on αCaMKII to sustain their addictive properties.

Keywords: Glutamate receptors; Hippocampus; Ketamine; Medial-prefrontal cortex; Nucleus accumbens; αCaMKII.

MeSH terms

  • Affect* / drug effects
  • Animals
  • Brain / enzymology*
  • Brain / pathology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Ketamine / administration & dosage*
  • Male
  • Models, Biological
  • Phosphorylation / drug effects
  • Rats, Sprague-Dawley
  • Reward*
  • Self Administration
  • Synaptosomes / metabolism


  • Ketamine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2