Cocaine increases actin cycling: effects in the reinstatement model of drug seeking.
Addiction to cocaine is associated with persistent changes in synaptic function. The cycling of actin between polymerized [F (for filamentous)] and depolymerized forms contributes to synaptic plasticity, and acute and withdrawal from repeated cocaine administration produced reversible and enduring elevations, respectively, in F-actin in the nucleus accumbens. Increased F-actin after 3 weeks withdrawal from repeated cocaine resulted from changes in the content or phosphorylation state of actin binding proteins (ABPs) that cosediment with F-actin. The profile of altered APBs was consistent with filopodia formation, including increased mammalian Enabled, phosphorylated (p)-cortactin, and p-vasodilator-stimulated phosphoprotein, and increased actin depolymerization [e.g., reduced LIM (Lin11/Isl-1/Mec3)-kinase and p-cofilin]. In contrast to repeated cocaine, the increase in F-actin after acute cocaine administration resulted from reduced depolymerization and actin cycling. The potential involvement of chronic cocaine-induced increases in actin cycling in cocaine addiction was examined using the reinstatement of cocaine seeking in rats previously trained to self-administer cocaine by inhibiting actin polymerization with intra-accumbens latrunculin A or by accelerating actin depolymerization with a LIM-kinase inhibitor. Disrupting actin cycling via either mechanism augmented cocaine-induced reinstatement of drug seeking but did not affect the locomotor response to acute cocaine administration. Thus, withdrawal from repeated cocaine induces a restructuring of actin-ABP complexes, which increases actin cycling and may modulate cocaine-induced reinstatement of drug seeking.
Toda
Shigenobu
S
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29464, USA.
Shen
Hao-Wei
HW
Peters
Jamie
J
Cagle
Stephanie
S
Kalivas
Peter W
PW
D000199:Actins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism* / Q000523:psychology; D004195:Disease Models, Animal; D008297:Male; D008840:Microfilament Proteins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000302:isolation & purification; D009473:Neuronal Plasticity; D009714:Nucleus Accumbens / Q000378:metabolism; D011554:Pseudopodia / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
D000199:Actins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C033652:postsynaptic density proteins; D003042:Cocaine