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.
