Downregulation of neuronal cdk5/p35 in opioid addicts and opiate-treated rats: Relation to neurofilamentphosphorylation

Abstract

Neuronalcyclin-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, thisstudy was undertaken to assess the status of the cdk5/p35 complex and its relation with NF-H phosphorylation in brains of chronicopioid abusers. Decreased immunodensities of cdk5 (18%) and p35 (26-44%) were found in the prefrontalcortex of opioid addictscompared with matched controls. In the same brains, the densities of p25 (a truncated neurotoxic form of p35), phosphatase PP2Ac andm-calpain were found unaltered. Acute treatment of rats with morphine (30 mg/kg, 2 h) increased the density of cdk5 (35%), but not thatof p35, in the cerebralcortex. 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 wellas the ratio ofphosphorylated 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 inthe brain. This downregulation and the aberrant hyperphosphorylation of NF-H proteins might have important consequences in thedevelopment of neuralplasticity associated with opiate addiction in humans. © 2003 American College of Neuropsychopharmacology.