@article{bdc3761b29f4439ca928e27e667e118e,
title = "Role of neuropeptide neuromedin U in the nucleus accumbens shell in cocaine self-administration in male rats",
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.",
author = "Kasper, {James M.} and Smith, {Ashley E.} and Miller, {Sierra N.} and Ara and Russell, {William K.} and Cunningham, {Kathryn A.} and Hommel, {Jonathan D.}",
note = "Funding Information: Our research demonstrates that experimenter-administered cocaine increased NAcSh GABA efflux, similar to published studies [35]. In addition, the elevated levels of GABA in the NAc following a history of cocaine self-administration support the connection between NAc GABA and motivation for cocaine [35, 38–40]. Previously, we reported that intra-NAcSh NMU decreases basal GABA, and our work here demonstrated that NMU decreases cocaine-evoked GABA as well. There are numerous sources of GABAergic projections to the NAcSh [41], including the DRN → NAcSh [15, 42, 43], that express presynaptic NMUR2 [15]. Indeed, the DRN → NAcSh pathway was found to colocalize with almost 50% of the NMUR2 in the NAcSh as visualized with confocal microscopy [15]. The NMU-evoked decrease in NAcSh GABA is supported by the corresponding increase in NAcSh phosphorylated c-Fos (Fig. 2D). Tract-tracing identified greater phosphorylated c-Fos presence in the NAcSh → VP pathway compared to the NAcSh → VTA pathway in NMU-treated rats, suggesting the decreased NAcSh GABA preferentially disinhibited the NAcSh → VP pathway. In addition, other neurotransmitters, such as dopamine, may also be involved as NMU blocks amphetamine-evoked dopamine in the NAc and intra-NAc NMU blocks alcohol-evoked dopamine release in the NAc [17, 37]. Thus, the NMU microdialysis studies presented here potentially correspond with a hypothesized blunting of cocaine-evoked dopamine release as well as the reported decrease in GABA, and this research is the subject of future studies. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.",
year = "2022",
month = oct,
doi = "10.1038/s41386-021-01234-9",
language = "English (US)",
volume = "47",
pages = "1875--1882",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "11",
}