Long-term methadone treatment reduces phosphorylation of CaMKII in rat brain

Objectives To reveal a possible relationship between a previously reported impairment of novelty seeking in rats exposed to methadone and changes in intracellular molecules related to learning and memory. Methods Expression of phosphorylated Ca2+-calmodulin kinase II (pCaMKII), extracellular-signal-regulated kinase 2 (pERK2) and cAMP-responsive element binding protein (pCREB), as well as protein kinase A (PKA), was investigated in rat hippocampus one hour, one day and one week after a three-week methadone administration regime. Studies after an equivalent exposure to morphine, and in the frontal pole, were included for comparison. Key findings One day after the last methadone injection the hippocampal level of pCaMKII was significantly reduced. This coincides with a previously reported impairment of novelty seeking. At one hour and one week no significant changes were seen. There was no effect on the other proteins. Morphine affected pCaMKII similarly to methadone. Also in the frontal pole the two drugs reduced pCaMKII one day after the last injection. Conclusion The impaired novelty seeking previously found in rats administered methadone for three weeks coincides with a reduced level of pCaMKII in the brain. This finding implies that methadone treatment may affect learning and memory processes, and should stimulate further studies in a field with important knowledge gaps.