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The Journal of Neuroscience, February 1, 2006, 26(5):1579-1587; doi:10.1523/JNEUROSCI.4132-05.2006

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Behavioral/Systems/Cognitive
Cocaine Increases Actin Cycling: Effects in the Reinstatement Model of Drug Seeking

Shigenobu Toda, Hao-Wei Shen, Jamie Peters, Stephanie Cagle, and Peter W. Kalivas

Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29464

Correspondence should be addressed to Dr. Peter W. Kalivas, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 403, Charleston, SC 29464. Email: kalivasp{at}musc.edu

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.

Key words: actin; cocaine; cofilin; reinstatement; LIM-kinase; accumbens

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Received Aug. 8, 2005; revised Nov. 27, 2005; accepted Dec. 18, 2005.

Correspondence should be addressed to Dr. Peter W. Kalivas, Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, BSB 403, Charleston, SC 29464. Email: kalivasp{at}musc.edu

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