The primary long-range objective is to elucidate and characterize the actions of drugs of abuse as they influence and modify neuronal function. One of the crucial damaging aspects of drug addiction is the persistent wanting, or craving, that remains following rehabilitation that leads to relapse and a high failure rate in attempts to treat addiction. Because craving persists long after the cessation of withdrawal, and recovery from tolerance, it is often suggested that a drug-induced neural plasticity has occurred within the circuitry of the brain that sustains the potential for future triggering of drug craving. The neural underpinnings of the """"""""craving circuitry"""""""" of the brain are largely uncharacterized. The hippocampal formation is a region of the brain involved with memory formation and is crucial for the performance of several associative learning and memory tasks. The administration of addictive substances directly into the hippocampus has been shown to support self-administration behavior, and the activation of this brain region can prime, or reinstate, drug seeking behavior in animal models of addiction. Investigating the role of the hippocampus in drug addiction is therefore a reasonable pursuit. Electrophysiological recording techniques will be used to monitor neuronal responses from the in vitro hippocampal slice preparation. The acute and persisting effects of cocaine applied either directly to the tissue slice or systemically via in vivo injections prior to slice preparation are to be investigated. The central hypothesis of this proposal is the following: The neural adaptations resulting from exposure to drugs of abuse are likely to include modifications of normal synaptic plasticity mechanisms that are typically utilized to store information within neuronal networks. Thus an understanding of both the normal processes and the drug-induced changes are required to elucidate the long-term consequences of drug exposure. In this application, the mechanisms underlying the plasticity of synaptic plasticity (i.e. metaplasticity) in the hippocampal formation will be investigated, and the subsequent effects of exposure to cocaine on such processes will be assessed.
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