The Role of Orexin and Subthalamic Nucleus in Cocaine Demand

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DESCRIPTION (provided by applicant): Drug addiction remains a major public health issue. This is, in part, because drug abusers tend to display a pathologically low value for natural rewards, e.g. food, relationships, personal achievement, while simultaneously seeking drug regardless of the negative consequences. This pathological disparity between natural rewards and drug rewards is reversible in rats by lesioning subthalamic nucleus (STN) bilaterally or by deep brain stimulation (DBS) in STN, as is done for treatment of Parkinson's disease. Although DBS of STN may be a prospective treatment for drug abuse, its effects are nonspecific with side effects that dramatically limit its application. A more viable therapy would be one that selectivel targets the neuronal pathways that mediate the therapeutic effects of STN lesioning. Hence, this proposal outlines a series of experiments that will determine the role of STN, and its orexinergic inputs, in mediating motivation for cocaine. We hypothesize that inhibiting STN neural activity will decrease motivation to self-administer cocaine when effort required to obtain cocaine is high without decreasing motivation for sucrose or altering cocaine intake when effort required to obtain cocaine is low. We further hypothesize that orexinergic input to STN is involved in motivation for cocaine when effort required to obtain cocaine is high. These hypotheses, based upon preliminary data, will be tested through two specific aims. Aim 1 will employ a pharmacogenetic approach to determine the effects of specifically and transiently inhibiting the neurons within STN on motivation to self-administer cocaine or sucrose, and Aim 2 will determine the role of the hypothalamic orexinergic inputs to STN in the motivation to self-administer cocaine or sucrose. In both aims motivation to self-administer drug will be assessed via a behavioral-economic analysis that measures peak motivation an animal is willing to expend to self-administer drug as well as several other secondary measures. In addition to clarifying the role of STN and its orexinergic input in motivation to self-administer cocaine, this fellowship will train the applicant in the most cutting-edge techniques for analyzing behavioral functions of identified neural circuits.