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

Modulation of alpha CaMKII expression and phosphorylation is a feature shared by drugs of abuse with different mechanisms of action. Accordingly, we investigated whether alpha CaMKII 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 alpha CaMKII-mediated signaling. alpha CaMKII 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 alpha CaMKII, 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 alpha CaMKII 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 alpha CaMKII autophosphorylation as a critical signature of ketamine self-administration providing an intracellular mechanism to explain the different effects caused by alpha CaMKII autophosphorylation on the post-synaptic GluN2B- and GluA1-mediated functions. These data add ketamine to the list of drugs of abuse converging on alpha CaMKII to sustain their addictive properties.