Cocaine-induced ischemia in prefrontal cortex is associated with escalation of cocaine intake in rodents.

Abstract

Cocaine-induced vasoconstriction reduces blood flow, which can jeopardize neuronal function and in the prefrontal cortex (PFC) it may contribute to compulsive cocaine intake. Here we used integrated optical imaging in a rat self-administration and a mouse non-contingent model, to investigate whether changes in the cerebrovascular system in the PFC contribute to cocaine self-administration, and whether they recover with detoxification. In both animal models, cocaine induced severe vasoconstriction and marked reductions in cerebral blood flow (CBF) in the PFC, which were exacerbated with chronic exposure and with escalation of cocaine intake. Though there was a significant proliferation of blood vessels in areas of vasoconstriction (angiogenesis), CBF remained reduced even after one month of detoxification. Treatment with Nifedipine (Ca2+ antagonist and vasodilator) prevented cocaine-induced CBF decreases and neuronal Ca2+ changes in the PFC, and decreased cocaine intake and blocked reinstatement of drug seeking. These findings provide support for the hypothesis that cocaine-induced CBF reductions lead to neuronal deficits that contribute to hypofrontality and to compulsive-like cocaine intake in addiction, and document that these deficits persist at least one month after detoxification. Our preliminary data showed that nifedipine might be beneficial in preventing cocaine-induced vascular toxicity and in reducing cocaine intake and preventing relapse.