The limbic system is of central importance in the experience of sensation, affect, and memory. Cocaine has been shown to stimulate the limbic system in both preclinical and clinical studies, and the euphorigenic effects of cocaine have been correlated with limbic system activation. Previous investigators have suggested that a state of permanent limbic neuronal hyperexcitability may be present in cocaine addicts, such that spontaneous or cue-related episodes of limbic neuronal discharge may occur. Limbic discharge may subsequently induce craving in cocaine dependent patients, precipitating relapse to drug use. Thus, limbic sensitization may be an important etiologic component of cocaine addiction. The existence of limbic system hyperexcitability in cocaine-addicted patients, however, has not been demonstrated. The principal aim of this exploratory study is to compare limbic sensitivity in cocaine addicted patients to limbic sensitivity in age- and sex-matched healthy controls. Twelve female and twelve male patients, ages 25-45 years, with cocaine abuse or dependence will be compared to 24 age- and sex-matched healthy controls. The limbic system will be activated by the local anesthetic, procaine, a relatively specific stimulant of the limbic system. Limbic sensitivity will be assessed following the intravenous administration, on two separate study days, of both procaine and saline. Limbic system activation will be measured following each infusion by assessing regional cerebral blood flow (rCBF) using Single Photon Emission Computerized Tomography (SPECT) neuroimaging techniques. Differences in brain images will be analyzed using both traditional Region of Interest (ROI) and two newer statistical approaches: T-Image Analysis and Statistical Parametric Mapping (SPM). Subjects will also be assessed for changes in mood and sensorium and the similarity of the experience to other drug experiences. We hypothesize that (1) patients with a history of cocaine abuse or dependence will demonstrate greater procaine-induced limbic activation compared to healthy controls, and (2) there will be a positive correlation between procaine-induced limbic activation and the amount of previous life-time cocaine use. A secondary hypothesis is that mood and sensory disturbances during procaine administration will be increased in cocaine addicted patients compared to controls. The clinical and technical expertise of investigators in the study of biologic disturbances in substance abusers, the neuroimaging of procaine responses, and SPECT methodology will be brought together in the development and execution of this proposal. The demonstration of limbic system hyperexcitability in cocaine addicted patients would offer important insights into potential etiologic mechanisms of the addiction process. An association between limbic system sensitivity and previous cocaine use would provide the framework for subsequent studies to examine the relationship between procaine-induced limbic response and relapse, as well as suggesting novel pharmacologic approaches to treat cocaine addiction.
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