John J. Wagner - US grants

DESCRIPTION: (Applicant's Abstract) The primary long-range objective of this application is to elucidate and characterize the actions of endogenous opioid peptides in their role as neurotransmitters in the CNS. If the medical and societal problems related to opiate use and abuse are to be fully appreciated, our understanding of the normal, physiological actions of the endogenous opioid peptide system must be increased. More specifically, this proposal investigates the neurophysiological effects of the dynorphin family of opioid peptides in the hippocampal region of the brain. The relatively well characterized anatomy and physiology of the hippocampus makes it an ideal preparation in which to determine fundamental mechanisms by which endogenous opioid peptides may elicit their effects throughout the nervous system. The specific aims address basic questions regarding the actions of dynorphin peptides, which are contained within granule cells of the dentate gyrus region in the hippocampal slice preparation: Under what conditions are these peptides released? What is the spatial extent of dynorphin influence on synaptic transmission in the molecular layer of the dentate gyrus? What is the mechanism involved in the release of these neurotransmitters from the dynorphin-containing granule cells? Electrophysiological techniques such as whole-cell voltage-clamp extracellular population responses, and dual intracellular recording methods will be applied in the in vitro hippocampal slice preparation to investigate these questions. It is expected that the information obtained from these studies will add to our understanding of how the nervous system normally utilizes endogenous opioids, and by extension, how it may respond under conditions of tolerance and/or addiction, where chronic opiate exposure has occurred.

DESCRIPTION (provided by applicant): 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.