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 a process that is exerted on excitatory synapses by the activation of common mechanisms between drugs and stress. 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, AMPA receptors (AMPAR) expression and the size of postsynaptic density (PSD) in the nucleus accumbens (NAc). Wistar rats were restrained daily (2 hours) for 7 days, and three weeks later, the NAc was dissected from animals 45 min following acute saline or cocaine administration. F-actin, actin-binding protein (ABP) and AMPAR were determined by western blotting, and dendritic spines and the size of PSD measured by electron microscopy. Locomotor activity was monitored in a photocell apparatus (actographs). For these sessions, animals were allowed to habituate to the activity chambers for 60 min before latrunculin A, CNQX or DMSO (1%) microinjections, which were followed by cocaine or saline, and behavior recorded was for 120 min. Our experiments revealed that repeated stress induces changes in actin and actin binding proteins. In the NAc, a decrease in p-cofilin and p-cortactin, concomitant to an increase in AMPAR and the size of PSD, was found in the stress plus cocaine group. The stress-induced sensitization to cocaine was prevented by administering either latrunculin A or CNQX. Interestingly, latrunculin A in the NAc also reversed the stress/cocaine-induced increase in GluR1, indicating a potential role for actin cycling in the increased AMPAR accompanying cocaine cross-sensitization. This study shows that stress-induced changes in the actin cytoskeleton, the size of PSD and AMPAR partly parallel the alterations elicited by sensitization to repeated cocaine and that actin dynamics regulate AMPAR expression in the NAc and underlie the expression of cross-sensitization between stress and cocaine.
