Transient enhanced expression of cdk5 activator p25 after acute and chronic d-amphetamine administration

MLEWSKI ESTELA CECILIA; KRAPACHER FAVIO ARIEL; FERRERAS SOLEDAD; PAGLINI GABRIELA

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES.

Blackwell publishing and New York Academy of Sciences

Lugar: United States; Año: 2008 vol. 1139 p. 89 - 102

0077-8923

The cellular and molecular mechanisms of sensitization in addictive process are still unclear. Recently, the chronic treatment with cocaine has been shown to up-regulate the expression of cyclin-dependent kinase 5 (cdk5) and its specific activator, p35, in the striatum, as a downstream target gene of DFosB and has been implicated in compensatory adaptive changes associated with psychostimulants. Cdk5 is a serine/threonine kinase and its activation is achieved through association with a regulatory subunit, either p35 or p39. P35 is cleaved by a protease calpain, which results in the generation of a truncate product termed p25, which contains all elements necessary for cdk5 activation. Cdk5/p35 complex plays an essential role in neuron development and survival. It has also been involved in neuronal trafficking, transport and in dopaminergic transmission, indicating its role either in presynaptic and postsynaptic signaling. In this study we report that the cdk5/p35 complex participates in acute and chronic AMPH-evoked behavioral events and we show a surprisingly transient enhanced expression of p25 and a lasting raised expression of p35 in dorsal striatal synaptosomes after acute and chronic AMPH administration. Pak1, a substrate for cdk5, is also enriched in the synaptosomal fraction of acute AMPH-treated rats. Our data suggest that the transient up-regulation of p25 may regulate the activity of cdk5 in phosphorylating particular substrates, such as Pak1, implicated in the compensatory adaptive morphophysiologic changes associated with the process of behavioral sensitization to psychostimulants.