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Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats

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Abstract

The nucleus accumbens shell (NAcSh) and its afferent and efferent neuronal projections control key aspects of motivation for cocaine. A recently described regulator of γ-aminobutyric acid (GABA) projections from the dorsal raphe nucleus (DRN) to the NAcSh (DRN → NAcSh) is the neuropeptide neuromedin U (NMU). Here, we find that systemic administration of NMU decreases breakpoint for cocaine on a progressive ratio schedule of reinforcement in male rats. Employing a retrograde adeno-associated virus (AAV), we found that RNAi-mediated knockdown of the NMU receptor 2 (NMUR2) in afferent DRN projections to the NAcSh increases the breakpoint for cocaine. Our previous studies demonstrated that NMU regulates GABA release in the NAcSh, and our current investigation found that systemic NMU administration suppresses cocaine-evoked GABA release in the NAcSh and increases phosphorylated c-Fos expression in neurons projecting from the NAcSh to the ventral pallidum (VP). To further probe the impact of NMU/NMUR2 on neuroanatomical pathways regulating motivation for cocaine, we employed multi-viral transsynaptic studies. Using a combination of rabies virus and retrograde AAV helper virus, we mapped the impact of NMU across three distinct brain regions simultaneously and found a direct connection of GABAergic DRN neurons to the NAcSh → VP pathway. Together, these data reveal that NMU/NMUR2 modulates a direct connection within the GABAergic DRN → NAcSh → VP circuit that diminishes breakpoints for cocaine. These findings importantly advance our understanding of the neurochemical underpinnings of pathway-specific regulation of neurocircuitry that may regulate cocaine self-administration, providing a unique therapeutic perspective.

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Fig. 1: NMU and NMUR2 controls breakpoints for cocaine.
Fig. 2: NMU prevented cocaine-induced increase in GABA and preferentially increased phosphorylated c-Fos on NAcSh→VP projection neurons.
Fig. 3: The schematic diagram of transsynaptic study to label all neurons that project onto the NAcSh → VP pathway is presented.
Fig. 4: GABAergic and serotonergic DRN → NAcSh neurons differentially innervated NAcSh → VTA and NAcSh → VP pathways.

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Acknowledgements

This work was possible thanks to the facilities and expertize of the University of Texas Medical Branch (UTMB) Center for Addiction Research Rodent In Vivo Assessment Core and the UTMB Mass Spectrometry Facility. We thank Ms. Reyna Collura for her graphic design contributions.

Funding

This work was supported by the National Institute on Drug Abuse (R03DA033437, P30DA028821, and T32DA07287), Peter F. McManus Charitable Trust, and Clinical and Translational Science Award (UL1TR001439 and KL2TR001441) from the National Center for Advancing Translational Science. The UTMB Mass Spectrometry Facility is supported in part by CPRIT grant RP190682.

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JMK and AES preformed the surgeries, behavior experiments, and microdialysis. JMK and SNM performed the immunohistochemistry. WKR quantified the microdialysis samples. JMK, SNM and JDH performed the data analysis. JMK, A13, KAC and JDH drafted the paper. JMK, KAC, WKR, and JDH conceived the experiments. All have edited the paper.

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Correspondence to Kathryn A. Cunningham or Jonathan D. Hommel.

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Dr. Cunningham has current research funding from VidaLibreBio, Inc., for research unrelated to this study. Additional authors declare no competing interests. 

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Kasper, J.M., Smith, A.E., Miller, S.N. et al. Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats. Neuropsychopharmacol. 47, 1875–1882 (2022). https://doi.org/10.1038/s41386-021-01234-9

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