This is an A2 revision of a competing renewal proposal for continued funding of an ongoing program of research entitled """"""""Magnetic Resonance, EEC, and Behavior After Cocaine."""""""" The central motivation for this proposal is the belief that better knowledge of cocaine-induced alterations in brain chemistry may be useful in developing effective pharmacotherapies for cocaine dependence. In the last funding period, two-dimensional, J-resolved proton magnetic resonance spectroscopy (MRS) studies demonstrated marked decreases in frontal lobe gamma aminobutyric acid (GABA) and phosphorus- 31 MRS studies noted a pattern of neurochemical change consisting of increased phosphomonoesters (PME) and decreased brain beta nucleoside triphosphate levels ((3-NTP). As the NIH and NIDA have emphasized bench-to-bedside research, this grant proposal focuses on using a translational approach to further pursue the relationship between, as well as the significance of, these MRS findings in both non- human primates and humans. Non-human primate studies will be conducted prior to human studies in order to identify common neurochemical changes in animals and humans, who tend to use multiple drugs in variable amounts. Insights gained from the animal studies will inform the development of human studies. Recently developed methods for scanning awake, restrained monkeys will be used to determine cocaine- specific alterations in brain GABA, PME, and p-NTP levels without the confounds of additional substance or alcohol abuse that are characteristic of clinical populations. Changes in these neurochemical markers in monkeys administered cocaine daily for a period of 18 months are expected to be similar to those detected previously in humans. We also hypothesize that cocaine-induced GABA, p-NTP and PME alterations will not normalize with untreated abstinence, but will normalize with topiramate and CDP-choline treatment. Topiramate and CDP- choline are promising pharmacotherapies designed to increased brain GABA and high energy phosphates, respectively. The current funding period of this program explored the utility of CDP-choline as a treatment. Once the non-human primate studies have been completed, we will conduct multinuclear MRSI studies of human cocaine dependent and comparison subjects. This work will facilitate the direct comparison of neurochemical data across species.
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