Neural mechanism of enduring cocaine effects on impulsive choice

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DESCRIPTION (provided by applicant): Drug addiction is a serious public health problem. Approximately 22 million Americans (9% of the population over 12 years of age) abuse or are addicted to alcohol and illicit drugs. Although the causes of drug addiction are multifaceted, it is becoming increasingly clear that cognitive deficits associated with drug use may contribute to the addiction process. In particular, drug addicts demonstrate poor decision-making and an abnormally increased preference for immediate over delayed gratification (i.e. - "impulsive choice"). This increased impulsive choice may contribute to the addiction process by rendering addicts more likely to choose the short-term rewards of further drug use over the delayed but ultimately more beneficial rewards (such as health, employment, and family) associated with abstinence. Because increased impulsive choice appears to persist long after cessation of drug use, this cognitive alteration may account in part for the high relapse rates that follow even the best currently available addiction therapies. Using animal models, in which clear cause-and-effect relationships can be determined, it has been established that chronic cocaine self-administration causes increased impulsive choice, just as is observed in human addicts, that can persist as long as 3 months after cocaine cessation. Cocaine self-administration also causes long-lasting neuroadaptations in a network of brain systems, including alterations in dopaminergic and glutamatergic signaling in the nucleus accumbens, a structure implicated in regulation of impulsive choice in drug-naove subjects. However, the role of these nucleus accumbens alterations in cocaine-induced increases in impulsive choice is unknown. The experiments in this proposal will test the hypothesis that alterations in dopaminergic and glutamatergic neurotransmission in the nucleus accumbens are involved in the long-lasting increases in impulsive choice caused by cocaine self-administration. Specifically, we will determine in a rat model: i) the procedural parameters under which cocaine self-administration increases impulsive choice, ii) the roles of nucleus accumbens dopaminergic and glutamatergic signaling in normal impulsive choice in drug-naove subjects, and iii) whether cocaine-induced increases in impulsive choice can be reversed by pharmacological targeting of alterations in nucleus accumbens dopaminergic and glutamatergic signaling known to result from cocaine self- administration. Knowledge gained from these experiments of the neural mechanisms by which cocaine self-administration increases impulsive choice is crucial for the development of novel effective treatments for addiction. Such treatments would have the potential to reduce the incidence of relapse and to enhance productivity and quality of life for addicted individuals. Cocaine use is associated with long-lasting increases in impulsive choice, (reflected in a preference for immediate over delayed rewards), which may contribute to addiction by rendering users more likely to choose the immediate rewards of further drug use (e.g., short-term euphoria, relief from withdrawal symptoms) over the delayed but ultimately more beneficial rewards of abstinence (better health, employment, family relationships). The experiments in this proposal will use a rat model to investigate brain mechanisms by which cocaine use causes persistent increases in impulsive choice. Knowledge gained from these experiments will be critical for development of novel treatments to reduce the likelihood of relapse and to enhance quality of life for addicted individuals.