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A major challenge for the successful treatment of drug addiction is the long-lasting susceptibility to relapse during abstinence. The goal of our studies is to advance the understanding of the implication of the orexin (Orx/Hcrt) system in cocaine and alcohol seeking. In addition to the Orx/Hcrt system, which includes the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA), the paraventricular nucleus of the thalamus (PVT), which receives projections from the LH and projects to regions integrated in the circuitry of addiction (i.e., nucleus accumbens shell, ventral pallidum, ventral tegmental area, central nucleus of the amygdala, and bed nucleus of the stria terminalis), has been recently identified as a structure involved in the modulation of reward function in general and drug-directed behavior in particular. Importantly, we recently characterized a correlation between cocaine-seeking behavior and activation of the PVT, but not in the case of natural reward (food)-seeking behavior. This suggests that cocaine dysregulates neurotransmission within the PVT. Capitalizing on these findings, our working hypothesis is that following repeated drug use, the Orx/Hcrt system acquires a preferential role in mediating the seeking of drugs of abuse vs. natural rewards (such as food). Therefore, the main effort of my laboratory is to study the neurobiological basis of chronic vulnerability to relapse by focusing on Orx/Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the distinctly compulsive nature of drug (cocaine or alcohol) seeking as opposed to behavior motivated by natural rewards. Specifically, we are (i) behaviorally characterizing the specific implication of the PVT in drug seeking, (ii) investigating drug-induced neuroplastic changes within Orx/Hcrt transmission, and (iii) investigating the effects of dysregulated Orx/Hcrt-PVT transmission on the mesolimbic system. Overall, this work will provide novel insights into the specific involvement of Orx/Hcrt-PVT transmission in drug-seeking behavior compared with natural reward-seeking behavior and will likely highlight a previously unrecognized neurotransmission system in the etiology of compulsive drug seeking during abstinence.