SUMMARY Despite considerable scientific efforts to discover effective treatments for cocaine use disorder, achieving abstinence and preventing relapse remain serious challenges. The orexin (Orx) system has been implicated in the regulation of motivation, arousal, and stress, making this system an ideal target for addiction treatment. Cocaine causes maladaptive changes in the Orx system that in turn might maintain cocaine intake and promote relapse. Our research has shown that knocking down the Orx gene in the hypothalamus attenuates extended-access cocaine self-administration in rats and that Orx neurons are strongly recruited during cocaine seeking. In particular, reward seeking has been primarily associated with the recruitment of Orx cells in the lateral hypothalamus (LH). The Orx system has been shown to play a role in mediating the effects of several drugs of abuse, including cocaine, via projections to key brain regions, such as the prefrontal cortex. Orexin neurons project densely to the infralimbic cortex (IL). The IL has been primarily implicated in response inhibition and is known to attenuate behaviors that depend on cocaine-related memories, such as cue-induced reinstatement. However, there is conflicting evidence of the role of the IL in cocaine seeking and its role in another aspect of cocaine-motivated behaviors, namely cocaine self-administration, has only recently begun to be investigated. The controversial data on cocaine conditioned reinstatement and the limited data on cocaine self-administration have hampered our understanding of the way in which the IL is involved in suppressing or promoting cocaine-motivated behaviors (e.g., intake and relapse). Moreover, the precise mechanisms that enable the IL to inhibit or facilitate cocaine-motivated behaviors are still unknown. Considering the function of the IL in response inhibition and LH Orx in reward seeking, we hypothesize that the activity of LH Orx inputs to the IL will influence reward-motivated behaviors by suppressing motivation toward cocaine intake and preventing cocaine relapse and that cocaine abuse engages and perturbs this circuitry. The present project will investigate the contribution of LH Orx projections to the IL in two different aspects of the cocaine addiction cycle: intake and relapse. This project will use new viral vectors that express a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) that can selectively target subpopulation of Orx neurons in rats: ORX- LV-hM3D(Gq) and ORX-LV-hM4D(Gi). Using these DREADDs, we will test whether the manipulation (activation or inhibition) of LH Orx inputs to the IL interferes with cocaine intake and cue-induced reinstatement. This proposal will provide unique information about the specific involvement of the LH[Orx]®IL circuit in the neurobiology of cocaine-motivated behaviors.