Cocaine, Electroconvulsive Seizure and Neural Plasticity

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DESCRIPTION (provided by applicant): We speculate that the long-lasting nature of cocaine and other drug addiction may be due to drug-induced changes that ultimately produce a loss of plasticity in specific brain regions involved with craving and relapse. A novel conceptualization for the treatment of cocaine addiction is that restoration of neural plasticity during the period when the individual is learning to stay away from drugs (the extinction phase) may prevent relapse to drug-seeking or drug-taking behavior. The proposed studies focus on providing a new framework for suppressing relapse by manipulating the extinction period of drug-seeking behavior. Thus, we may take advantage of a critical window during which learning to avoid drug seeking/taking may be enhanced by simultaneous induction of neural plasticity. Electroconvulsive therapy (ECT) or seizure (ECS) is now viewed as successful in treating severe depression because of its ability to increase neural plasticity in the brain. Key molecules thought to be involved in ECS-induced plasticity are growth factors. Because extinction is new learning, alteration of growth factors during the extinction phase of cocaine-induced conditioned place preference (CPP) may reduce the reinstatement of drug-seeking behavior in rats. Our studies show that ECS given during the extinction phase suppresses reinstatement of cocaine-primed CPP compared with controls. The same ECS treatments delivered prior to the extinction phase did not alter reinstatement. The primary goal of these studies is to optimize the parameters of ECS treatment to produce maximal suppression of cocaine-primed reinstatement. The proposed studies center on the main hypothesis that ECS treatment is most effective in suppressing cocaine-primed reinstatement when given during the extinction phase. Specific Aim 1 will determine the effects of seizure duration and number of days of ECS treatment on reinstatement of cocaine-primed CPP. Seizure duration will be altered by changing the pulse dose and duration of ECS and depth of anesthesia during ECS treatments. Specific Aim 2 will optimize the timing of ECS treatment for its ability to suppress reinstatement of cocaine-primed CPP. The timing of ECS will be shifted to before, during or after the extinction phase. This Aim will also test ECS timing (in hours) relative to extinction to determine if the timing of ECS is important for the suppression of reinstatement. Our studies indicate that ECT in humans may be an option for some cases of cocaine addiction, as it is for severe depression in humans. However, our long term interest is to understand the critical neurobiological consequences of ECS that could lead to treatment for cocaine addiction.