title: Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: relation to neurofilament phosphorylation.
abstract: Neuronal cyclin-dependent kinase-5 (Cdk5) and its neuron-specific activator p35 play a major role in regulating the cytoskeleton dynamics. Since opioid addiction was associated with hyperphosphorylation of neurofilament (NF) in postmortem human brains, this study was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronic opioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontal cortex of opioid addicts compared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac and mu-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not that of p35, in the cerebral cortex. In contrast, chronic morphine (10-100 mg/kg for 5 days) induced marked decreases in cdk5 (40%) and p35 (47%) in rat brain. In brains of opioid addicts, the density of phosphorylated NF-H was increased (43%) as well as the ratio of phosphorylated to nonphosphorylated NF-H forms (two-fold). In these brains, phosphorylated NF-H significantly correlated with p35 (r=0.58) but not with cdk5 (r=0.03). The results suggest that opiate addiction is associated with downregulation of cdk5/p35 levels in the brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in the development of neural plasticity associated with opiate addiction in humans.
authors.affiliation: Clinical Research Unit, Department of Psychiatry, Faculty of Medicine, University of Geneva, HUG Belle-Idée, 2 Chemin du Petit-Bel-Air, CH-1225 Chêne-Bourg, Geneva, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ferrer-Alcón
authors.forename: Romano
authors.initials: R
authors.lastname: La Harpe
authors.forename: José
authors.initials: J
authors.lastname: Guimón
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
chemical_list: D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C089495:neuronal Cdk5 activator (p25-p35); C051774:neurofilament protein H; D009020:Morphine