title: Long-term methadone treatment reduces phosphorylation of CaMKII in rat brain.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Forensic Medicine and Drug Abuse Research, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Jannike M
authors.initials: JM
authors.lastname: Andersen
authors.forename: Christine
authors.initials: C
authors.lastname: Klykken
authors.forename: Jørg
authors.initials: J
authors.lastname: Mørland
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects; D008691:Methadone / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000701:Analgesics, Opioid; D017362:Cyclic AMP Response Element-Binding Protein; D009020:Morphine; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019950:Mitogen-Activated Protein Kinase 1; D008691:Methadone