Transient enhanced expression of Cdk5 activator p25 after acute and chronic d-amphetamine administration.
The cellular and molecular mechanisms of sensitization in the addictive process are still unclear. Recently, chronic treatment with cocaine has been shown to upregulate the expression of cyclin-dependent kinase 5 (cdk5) and its specific activator, p35, in the striatum, as a downstream target gene of DeltaFosB, 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 the protease calpain, which results in the generation of a truncated product termed p25, which contains all elements necessary for cdk5 activation. The cdk5/p35 complex plays an essential role in neuronal development and survival. It has also been involved in neuronal trafficking and 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 d-amphetamine (AMPH)-evoked behavioral events, and we show a surprisingly transient enhanced expression of p25 and a lasting increased 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 upregulation 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.
Mlewski
Estela Cecilia
EC
Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Córdoba, Argentina.
Krapacher
Favio Ariel
FA
Ferreras
Soledad
S
Paglini
Gabriela
G
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology*; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D003913:Dextroamphetamine / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000378:metabolism; D014793:Visual Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
D000697:Central Nervous System Stimulants; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D054462:p21-Activated Kinases; D003913:Dextroamphetamine