Stress‐induced sensitization to cocaine: actin cytoskeleton remodeling within mesocorticolimbic nuclei

Abstract

This study investigated whether the adaptations induced by repeated cocaine in the actin cytoskeleton, the surface expression of AMPA receptor subunit GluR1, dendritic spine morphology and the size of postsynaptic density (PSD) in nucleus accumbens (NAc) and prefrontal cortex (Pfc) are relevant to how repeated immobilization stress induces behavioural cross-sensitization to cocaine. Wistar rats were restrained daily (2 hours) for 7 days, and three weeks later, the NAc and Pfc were dissected from animals 45 min following acute saline or cocaine (30 mg/kg i.p.). F-actin, actin-binding protein (ABP) and GluR1 were determined by western blotting, and dendritic spines and the size of PSD measured by electron microscopy. In the NAc, a decrease in p-cofilin and p-cortactin, and an increase in GluR1 and PSD size was found in the stress plus cocaine group, while in the Pfc an increase in F-actin and Arp2, as well as the number of spines, was observed in the stress group. Inhibition of actin cycling with latrunculin A in NAc restored expression of GluR1, and both latrunculin A and the AMPAR antagonist CNQX inhibited the expression of motor cross-sensitization to cocaine (15 mg/kg i.p.). This study shows that cross-sensitization is associated with changes in the actin cytoskeleton, the size of the PSD and GluR1 expression that partly parallel the neuroadaptations elicited by sensitization to repeated cocaine. Also, the actin dynamics regulating GluR1 expression in the NAc contribute to the expression of cross-sensitization between stress and cocaine, but the changes in Pfc were not associated with cross-sensitization.