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.

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

“…Notably, in males, only 4.2% (or 49 out of 1157) of regions that gain ΔFosB binding after chronic cocaine exposure overlap with a region that gains accessibility after acute cocaine exposure (Figure 5D). These regions include an intronic region of Pdpk1, encoding 3-phosphoinositide-dependent protein kinase-1, and a region upstream of Nmur2 (Figure 5D), encoding a neuropeptide receptor whose activity is linked to addiction-related phenotypes (62) and whose expression in the NAc is dysregulated following repeated cocaine administration (63). Together, these data show that acute cocaine exposure sex-specifically increases chromatin accessibility in AP1 motif-containing regions that exhibit sexspecific ΔFosB binding after chronic cocaine.…”

Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine

“…These regions include an intronic region of Pdpk1 , encoding 3-phosphoinositide-dependent protein kinase-1, and a region upstream of Nmur2 ( Figure 4F ), encoding a neuropeptide receptor whose NAc expression is dysregulated following repeated cocaine administration. 73 , 74 …”