Inhibiting Actin Cycling in the Nucleus Accumbens Prevents Stress Cross-Sensitization with Cocaine and Stress-induced Elevation in GluR1
Esparza, M.A.; Garcia Keller, C.; Virgolini, M.; Cancela L.M.
IFEC-CONICET, Universidad Nacional de Córdoba, Argentina
Haya de la Torre y Medina Allende, Ciudad Universitaria, Córdoba. CP:5000
Drug addiction is associated with long-term changes in the synaptic function, including the actin cytoskeleton. There is evidence about the proactive influence of stress on drug addiction. The present study investigated whether the neurobiological mechanisms that modulate repeated cocaine administration also occur in a stress-induced cocaine sensitization model. These experiments evaluated whether repeated stress induces alterations in actin rearrangement and AMPA receptors (AMPAR) expression in the Nucleus Accumbens (NAc). Male Wistar rats were restrained daily for 2 hours for 7 days. Three weeks after the last stress, animals were decapitated 45 min after saline or cocaine (30 mg/kg i.p.), and the Nac dissected. After subcellular fractionation, the immunoreactivity of the actin and actin binding proteins (ABPs) were determined by Western blot. For motor activity, animals receive latrunculin A or DMSO microinjections, which were followed by cocaine (15 mg/kg, i.p.) or saline, and behavior recorded for 120 min. For AMPAR expression, three weeks after chronic stress, rats were injected i.p. with saline, or cocaine 30 mg/kg and sacrificed 45 min later. In another experiment, the animals were injected with Latrunculin A or vehicle intra-NAc 5 min before cocaine 30 mg/kg i.p., and sacrificed 45 min later to determine the expression of AMPAR. Our experiments revealed that stress induced changes in protein levels involved in synaptic plasticity, such as actin and ABPs that regulate actin cytoskeleton in NAc. The stress-induced sensitization to cocaine was prevented by intra-NAc lantrunculin A (0.5 µg/µl). Interestingly, latrunculin A in the NAc also reversed the stress-induced increase in GluR1, indicating a potential role for actin cycling in the increased AMPAR accompanying cocaine cross-sensitization. This is the first evidence that the remodeling of the actin cytoskeleton contributes to the cross-sensitization between stress and cocaine.
Grants: FONCyT, SECyT, CONICET
