Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine.
In the present study, we investigated the role of cyclin-dependent kinase 5 (cdk5) in the brain dynamics changed by repeated in vivo treatment with morphine. The level of phosphorylated-cdk5 was significantly increased in the cingulate cortex of mice showing the morphine-induced rewarding effect. Under these conditions, roscovitine, a cdk5 inhibitor, given intracerebroventricularly (i.c.v.) caused a dose-dependent and significant inhibition of the morphine-induced rewarding effect. In addition, the dose-response effect of the morphine-induced rewarding effect was dramatically attenuated in cdk5 heterozygous (+/-) knockout mice. Furthermore, the development of behavioral sensitization by intermittent administration of morphine was virtually abolished in cdk5 (+/-) mice. These findings suggest that the induction and/or activation of cdk5 are implicated in the development of psychological dependence on morphine.
Narita
Minoru
M
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan. narita@hoshi.ac.jp
Shibasaki
Masahiro
M
Nagumo
Yasuyuki
Y
Narita
Michiko
M
Yajima
Yoshinori
Y
Suzuki
Tsutomu
T
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000201:enzymology* / Q000235:genetics; D009294:Narcotics / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D012201:Reward; D000077546:Roscovitine; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D004791:Enzyme Inhibitors; D009294:Narcotics; D011687:Purines; D000077546:Roscovitine; D009020:Morphine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases