We provide evidence that cocaine evokes short- and long-lasting increases in activity-regulated cytoskeletal-associated protein (Arc) expression after a finely tuned, time-dependent and regional-selective expression profile. Acute experiments revealed that cocaine up-regulates Arc expression primarily in striatum and prefrontal cortex through a dopamine D1-dependent mechanism and a combination of D1- and D2-dependent mechanisms, respectively. Aside from cocaine-dependent Arc elevation, we show for the first time that D1 and D2 receptors tonically regulate basal Arc expression following a regional-selective profile. As opposed to the effects of a single cocaine injection on Arc expression, which dissipate within 24 h, subchronic (five daily injections) or chronic (14 daily injections) cocaine administration, with animals sacrificed hours or days after the last treatment, demonstrated that Arc expression is still up-regulated long after treatment cessation, suggesting that adaptive changes have been set in motion by the prolonged administration of the psychostimulant. In summary, our findings are the first to demonstrate that repeated exposure to cocaine leads to long-lasting dysregulation of Arc expression in the corticostriatal network, thus establishing a molecular basis to explain, at least partially, the impaired synaptic transmission caused by cocaine abuse at this level. Furthermore, given the role exerted by Arc in cytoarchitectural rearrangements, it is conceivable to speculate that it mediates changes in synaptic connectivity brought about by cocaine. Our findings thus pin-point this molecule as a neuropathological underpinning and molecular bridge that connects short- and long-term neuronal modifications associated with cocaine abuse.
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