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J Pharm Pharmacol. 2012 Jun;64(6):843-7. doi: 10.1111/j.2042-7158.2012.01469.x. Epub 2012 Feb 21.

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

Author information

  • 1Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, Oslo, Norway.



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.


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.


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.


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.

© 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

[PubMed - indexed for MEDLINE]
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