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Orexin-1 receptor signaling in ventral tegmental area mediates cue-driven demand for cocaine

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Abstract

Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area (VTA) is a major target by which orexin signaling modulates reward behaviors, but it is unknown whether this circuit is necessary for cue-driven motivation for cocaine. Here, we investigated the role of VTA orexin signaling in cue-driven motivation for cocaine using a behavioral economics (BE) paradigm. We found that infusion of the orexin-1 receptor (Ox1R) antagonist SB-334867 (SB) into VTA prior to BE testing reduced motivation when animals were trained to self-administer cocaine with discrete cues and tested on BE with those cues. SB had no effect when animals were trained to self-administer cocaine without cues or tested on BE without cues, indicating that learning to associate cues with drug delivery during self-administration training was necessary for cues to recruit orexin signaling in VTA. These effects were specific to VTA, as injections of SB immediately dorsal had no effect. Moreover, intra-VTA SB did not have an impact on locomotor activity, or low- or high-effort consumption of sucrose. Finally, we microinjected a novel retrograde adeno-associated virus (AAVretro) containing an orexin-specific short hairpin RNA (OxshRNA) into VTA to knock down orexin in the hypothalamus-VTA circuit. These injections significantly reduced orexin expression in lateral hypothalamus (LH) and decreased cue-driven motivation. These studies demonstrate a role for orexin signaling in VTA, specifically when cues predict drug reward.

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Fig. 1: Removal of discrete drug-paired cues reduced motivation in animals trained to associate drug delivery with cues.
Fig. 2: Intra-VTA SB lowered motivation for cocaine paired with discrete cues in animals trained to self-administer cocaine with cues.
Fig. 3: SB increased cocaine demand elasticity (decreased motivation) when microinjected into VTA specifically.
Fig. 4: SB did not have an impact on locomotor activity or motivation for natural (sucrose) reward.
Fig. 5: Retrograde knockdown of orexin in neurons projecting to VTA increased cocaine demand elasticity.

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Acknowledgements

We thank Drs. Brooke Schmeichel and Christopher Richie for critical and valuable input on viral vector expression experiments.

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CBP and GAJ designed the experiments. CBP, MHJ, SO, and NS performed the experiments, and acquired and analyzed experimental data. CBP, MHJ, and GAJ interpreted experimental data and wrote the manuscript. All authors reviewed and approved the manuscript prior to submission.

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Correspondence to Gary Aston-Jones.

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Pantazis, C.B., James, M.H., O’Connor, S. et al. Orexin-1 receptor signaling in ventral tegmental area mediates cue-driven demand for cocaine. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01173-5

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