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

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Abstract

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.

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Acknowledgements

We would like to thank the Zardi-Gori Foundation for funding this project through a grant to FF.

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Authors and Affiliations

  1. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy

    Lucia Caffino, Francesca Mottarlini, Giuseppe Giannotti & Fabio Fumagalli

  2. Neuropsychopharmacology Laboratory, Section Pharmacology, Department of Diagnostic and Public Health, P.le Scuro 10, University of Verona, Verona, Italy

    Alessandro Piva, Marzia Di Chio & Cristiano Chiamulera

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  1. Lucia Caffino
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  2. Alessandro Piva
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Correspondence to Fabio Fumagalli.

Ethics declarations

All animal procedures were carried out in accordance with the principles of laboratory animal care (NIH publication No. 85-23, revised 1985), the European Communities Council Directive (2010/63/UE). All efforts were made to minimize animal suffering and to keep the lowest number of animals used.

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The authors declare that they have no conflicts of interest.

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Cristiano Chiamulera and Fabio Fumagalli share the senior authorship

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Caffino, L., Piva, A., Mottarlini, F. et al. Ketamine Self-Administration Elevates αCaMKII Autophosphorylation in Mood and Reward-Related Brain Regions in Rats. Mol Neurobiol 55, 5453–5461 (2018). https://doi.org/10.1007/s12035-017-0772-3

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