Stress-induced cocaine sensitization: changes in the actin cytoskeleton.

BOLLATTI F*, ESPARZA A*, GARCIA KELLER C, VIRGOLINI M. Y CANCELA L.M.

Coquimbo, Chile

Congreso; XVIII Congreso ALF. XXX Reunión Anual Sociedad de Farmacología de Chile. XXIII Sociedad Chilena de Ciencias Fisiológicas. III Congreso Iberoamericano de Farmacología; 2008

Drug addiction is associated with long-term changes in the synaptic function. Several evidences indicate that the proactive influence of stress on drug-addiction is exerted on excitatory synapses by the activation of common mechanisms between drugs and stress. The present study sought to investigate whether the neurobiological mechanisms that modulate repeated-cocaine administration also occur in a stress-induced cocaine sensitization model. These experiments have been designed to evaluate whether repeated-immobilization stress induces alterations in actin rearrangement in nucleus accumbens and frontal cortex.

Our experiments revealed that repeated stress induces changes in protein levels involved in synaptic plasticity, such as actin and proteins that regulate actin cytoskeleton, known as actin-binding proteins (ABPs). Specifically, we demonstrated that repeated stress induces a 30% reduction en F-actin levels in nucleus accumbens, values that returned to baseline after cocaine administration. In accordance with these results, we also observed a reduction in p-cofilin, the inactive protein form of cofilin. Cofilin is an actin-depolymerizing protein and a direct regulator of actin reorganization and dynamics. Cofilin activity is regulated by LIMK1 and its phosphorylation at a single site (ser 3) by LIMKs inhibits its binding to actin monomers and its actin-depolymerizing activity. Since the studied proteins that participate in the modulation of actin cytoskeleton are altered by chronic stress, we sought to determine the role of putative alterations in actin cytoskeleton for the development of expression of stress and drug cross sensitization. We will use a drug battery that act through actin and affect filament polymerization and evaluate the changes in cytoskeleton of actin, cofilin and LIMK1, a direct regulator of cofilin activity as well as actin-binding proteins (ABPs) implicated in the cytoskeleton reorganization and dynamics.