This is a revised application that focuses on the development of a novel medication for cocaine dependence--CDP-choline. This naturally occurring nucleotide is a major component in phospholipid metabolism and is an integral ingredient in membrane synthesis. It is approved for use in Europe to treat head trauma and a variety of neurological degenerative disorders. Interestingly, it also enhances dopamine activity. Thus, CDP-choline's efficacy as a treatment for cocaine dependence may be high because it repairs two putative consequences of chronic cocaine abuse: 1) membrane damage, and 2) depleted dopamine levels. Two experiments are proposed in this three year study. The first is a challenge study designed to assess the acute effects of cocaine administration in CDP-choline treated non-dependent, casual cocaine users. A multidisciplinary assessment battery including EEG, physiologic, subjective responses and plasma cocaine and metabolite levels will be conducted after cocaine or placebo challenge. This experiment will be conducted in the first six months of the project and will provide basic information on how cocaine's effects are altered by this medication. Study 2 is a 6-week placebo-controlled clinical trial of CDP-choline in cocaine dependent men and women. Follow-up assessments will be made at 8, 12 and 26 weeks. In an attempt to gain insight into the possible mechanism of CDP- choline's effects, two different assessments of CNS function will be conducted at baseline, after 6 weeks of treatment and at the 12 week follow-up visit. The first is a cue reactivity challenge using subjective reports of craving, physiologic and EEG activity after neutral, emotionally laden and cocaine-related stimuli. The second assessment is Magnetic Resonance Spectroscopy (MRS), which will be used to measure changes in brain chemistry that reflect neuronal damage. One of the major appeals of CDP-choline is its low inherent toxicity. Large doses have been given for relatively long periods of time with no adverse effects. The implication of this is that CDP-choline may be safe enough to treat cocaine dependence in pregnant women and adolescents and may even be useful for treating infants who are born to cocaine-dependent mothers. Although we have collected very encouraging preliminary data on CDP-choline's effects in cocaine-dependent male and female subjects, we recognize that it is not a """"""""magic bullet"""""""" and that CDP-choline may serve as an important adjunct to other psychotherapy or pharmacotherapy programs.
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