Advertisement

Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U

      Abstract

      Background

      Neuromedin U (NMU) is a neuropeptide enriched in the nucleus accumbens shell (NAcSh), a brain region associated with reward. While NMU and its receptor, NMU receptor 2 (NMUR2), have been studied for the ability to regulate food reward, NMU has not been studied in the context of drugs of abuse (e.g., cocaine). Furthermore, the neuroanatomical pathways that express NMUR2 and its ultrastructural localization are unknown.

      Methods

      Immunohistochemistry was used to determine the synaptic localization of NMUR2 in the NAcSh and characterize which neurons express this receptor (n = 17). The functional outcome of NMU on NMUR2 was examined using microdialysis (n = 16). The behavioral effects of NMU microinjection directly to the NAcSh were investigated using cocaine-evoked locomotion (n = 93). The specific effects of NMUR2 knockdown on cocaine-evoked locomotion were evaluated using viral-mediated RNA interference (n = 40).

      Results

      NMUR2 is localized to presynaptic gamma-aminobutyric acidergic nerve terminals in the NAcSh originating from the dorsal raphe nucleus. Furthermore, NMU microinjection to the NAcSh decreased local gamma-aminobutyric acid concentrations. Next, we evaluated the effects of NMU microinjection on behavioral sensitization to cocaine. When repeatedly administered throughout the sensitization regimen, NMU attenuated cocaine-evoked hyperactivity. Additionally, small hairpin RNA-mediated knockdown of presynaptic NMUR2 in the NAcSh using a retrograde viral vector potentiated cocaine sensitization.

      Conclusions

      Together, these data reveal that NMUR2 modulates a novel gamma-aminobutyric acidergic pathway from the dorsal raphe nucleus to the NAcSh to influence behavioral responses to cocaine.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Brighton P.J.
        • Szekeres P.G.
        • Wise A.
        • Willars G.B.
        Signaling and ligand binding by recombinant neuromedin U receptors: Evidence for dual coupling to Galphaq/11 and Galphai and an irreversible ligand-receptor interaction.
        Mol Pharmacol. 2004; 66: 1544-1556
        • Brighton P.J.
        • Szekeres P.G.
        • Willars G.B.
        Neuromedin U and its receptors: Structure, function, and physiological roles.
        Pharmacol Rev. 2004; 56: 231-248
        • Gartlon J.
        • Szekeres P.
        • Pullen M.
        • Sarau H.M.
        • Aiyar N.
        • Shabon U.
        • et al.
        Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats.
        Psychopharmacology (Berl). 2004; 177: 1-14
        • Guan X.M.
        • Yu H.
        • Jiang Q.
        • Van Der Ploeg L.H.
        • Liu Q.
        Distribution of neuromedin U receptor subtype 2 mRNA in the rat brain.
        Brain Res Gene Expr Patterns. 2001; 1: 1-4
        • Howard A.D.
        • Wang R.
        • Pong S.S.
        • Mellin T.N.
        • Strack A.
        • Guan X.M.
        • et al.
        Identification of receptors for neuromedin U and its role in feeding.
        Nature. 2000; 406: 70-74
        • Hosoya M.
        • Moriya T.
        • Kawamata Y.
        • Ohkubo S.
        • Fujii R.
        • Matsui H.
        • et al.
        Identification and functional characterization of a novel subtype of neuromedin U receptor.
        J Biol Chem. 2000; 275: 29528-29532
        • Budhiraja S.
        • Chugh A.
        Neuromedin U: Physiology, pharmacology and therapeutic potential.
        Fundam Clin Pharmacol. 2009; 23: 149-157
        • Volkow N.D.
        • Wang G.J.
        • Tomasi D.
        • Baler R.D.
        The addictive dimensionality of obesity.
        Biol Psychiatry. 2013; 73: 811-818
        • Volkow N.D.
        • Wang G.J.
        • Tomasi D.
        • Baler R.D.
        Obesity and addiction: Neurobiological overlaps.
        Obes Rev. 2013; 14: 2-18
        • Stice E.
        • Figlewicz D.P.
        • Gosnell B.A.
        • Levine A.S.
        • Pratt W.E.
        The contribution of brain reward circuits to the obesity epidemic.
        Neurosci Biobehav Rev. 2013; 37: 2047-2058
        • Domin J.
        • Ghatei M.A.
        • Chohan P.
        • Bloom S.R.
        Characterization of neuromedin U like immunoreactivity in rat, porcine, guinea-pig and human tissue extracts using a specific radioimmunoassay.
        Biochem Biophys Res Commun. 1986; 140: 1127-1134
        • Thomas M.J.
        • Kalivas P.W.
        • Shaham Y.
        Neuroplasticity in the mesolimbic dopamine system and cocaine addiction.
        Br J Pharmacol. 2008; 154: 327-342
        • Steketee J.D.
        • Kalivas P.W.
        Drug wanting: Behavioral sensitization and relapse to drug-seeking behavior.
        Pharmacol Rev. 2011; 63: 348-365
        • Koob G.F.
        • Volkow N.D.
        Neurocircuitry of addiction.
        Neuropsychopharmacology. 2010; 35: 217-238
        • Guillem K.
        • Ahmed S.H.
        • Peoples L.L.
        Escalation of cocaine intake and incubation of cocaine seeking are correlated with dissociable neuronal processes in different accumbens subregions.
        Biol Psychiatry. 2014; 76: 31-39
        • Loweth J.A.
        • Tseng K.Y.
        • Wolf M.E.
        Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving.
        Neuropharmacology. 2014; 76: 287-300
        • Cadet J.L.
        • Brannock C.
        • Krasnova I.N.
        • Ladenheim B.
        • McCoy M.T.
        • Chou J.
        • et al.
        Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.
        PLoS One. 2010; 5: e15643
        • Johnson C.
        • Drgon T.
        • Liu Q.R.
        • Walther D.
        • Edenberg H.
        • Rice J.
        • et al.
        Pooled association genome scanning for alcohol dependence using 104,268 SNPs: Validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism.
        Am J Med Genet B Neuropsychiatr Genet. 2006; 141B: 844-853
        • Noori H.R.
        • Spanagel R.
        • Hansson A.C.
        Neurocircuitry for modeling drug effects.
        Addict Biol. 2012; 17: 827-864
        • Ferguson S.M.
        • Eskenazi D.
        • Ishikawa M.
        • Wanat M.J.
        • Phillips P.E.
        • Dong Y.
        • et al.
        Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization.
        Nat Neurosci. 2011; 14: 22-24
        • Baude A.
        • Nusser Z.
        • Molnár E.
        • McIlhinney R.A.
        • Somogyi P.
        High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus.
        Neuroscience. 1995; 69: 1031-1055
        • Chen L.
        • Boyes J.
        • Yung W.H.
        • Bolam J.P.
        Subcellular localization of GABAB receptor subunits in rat globus pallidus.
        J Comp Neurol. 2004; 474: 340-352
        • Medin T.
        • Owe S.G.
        • Rinholm J.E.
        • Larsson M.
        • Sagvolden T.
        • Storm-Mathisen J.
        • Bergersen L.H.
        Dopamine D5 receptors are localized at asymmetric synapses in the rat hippocampus.
        Neuroscience. 2011; 192: 164-171
        • Carlton S.M.
        • Hayes E.S.
        Dynorphin A(1-8) immunoreactive cell bodies, dendrites and terminals are postsynaptic to calcitonin gene-related peptide primary afferent terminals in the monkey dorsal horn.
        Brain Res. 1989; 504: 124-128
        • Hayes E.S.
        • Carlton S.M.
        Primary afferent interactions: Analysis of calcitonin gene-related peptide-immunoreactive terminals in contact with unlabeled and GABA-immunoreactive profiles in the monkey dorsal horn.
        Neuroscience. 1992; 47: 873-896
        • Benzon C.R.
        • Johnson S.B.
        • McCue D.L.
        • Li D.
        • Green T.A.
        • Hommel J.D.
        Neuromedin U receptor 2 knockdown in the paraventricular nucleus modifies behavioral responses to obesogenic high-fat food and leads to increased body weight.
        Neuroscience. 2014; 258: 270-279
        • Bolte S.
        • Cordelières F.P.
        A guided tour into subcellular colocalization analysis in light microscopy.
        J Microsc. 2006; 224: 213-232
        • Tsai W.-H.
        Moment-preserving thresholding: A new approach.
        Computer Vision Graphics and Image Processing. 1985; 29: 377-393
        • Kasper J.M.
        • Booth R.G.
        • Peris J.
        Serotonin-2C receptor agonists decrease potassium-stimulated GABA release in the nucleus accumbens.
        Synapse. 2015; 69: 78-85
        • Huang M.
        • Panos J.J.
        • Kwon S.
        • Oyamada Y.
        • Rajagopal L.
        • Meltzer H.Y.
        Comparative effect of lurasidone and blonanserin on cortical glutamate, dopamine, and acetylcholine efflux: Role of relative serotonin (5-HT)2A and DA D2 antagonism and 5-HT1A partial agonism.
        J Neurochem. 2014; 128: 938-949
        • Filip M.
        • Bubar M.J.
        • Cunningham K.A.
        Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: Acute and chronic pharmacological analyses.
        J Pharmacol Exp Ther. 2004; 310: 1246-1254
        • Land B.B.
        • Narayanan N.S.
        • Liu R.J.
        • Gianessi C.A.
        • Brayton C.E.
        • Grimaldi D.M.
        • et al.
        Medial prefrontal D1 dopamine neurons control food intake.
        Nat Neurosci. 2014; 17: 248-253
        • Paxinos G.
        • Watson C.
        The Rat.
        Brain in Stereotaxic Coordinates. Academic Press, San Diego2007
        • Ziv N.E.
        • Garner C.C.
        Cellular and molecular mechanisms of presynaptic assembly.
        Nat Rev Neurosci. 2004; 5: 385-399
        • Larsson M.
        • Broman J.
        Pathway-specific bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II at spinal nociceptive synapses after acute noxious stimulation.
        J Neurosci. 2006; 26: 4198-4205
        • Harris K.M.
        • Weinberg R.J.
        Ultrastructure of synapses in the mammalian brain. Cold Spring Harb Perspect.
        Biol. 2012; : 4
        • Baumert M.
        • Maycox P.R.
        • Navone F.
        • De Camilli P.
        • Jahn R.
        Synaptobrevin: An integral membrane protein of 18,000 daltons present in small synaptic vesicles of rat brain.
        EMBO J. 1989; 8: 379-384
        • Di Chiara G.
        • Bassareo V.
        • Fenu S.
        • De Luca M.A.
        • Spina L.
        • Cadoni C.
        • et al.
        Dopamine and drug addiction: The nucleus accumbens shell connection.
        Neuropharmacology. 2004; 47: 227-241
        • Xi Z.X.
        • Ramamoorthy S.
        • Shen H.
        • Lake R.
        • Samuvel D.J.
        • Kalivas P.W.
        GABA transmission in the nucleus accumbens is altered after withdrawal from repeated cocaine.
        J Neurosci. 2003; 23: 3498-3505
        • Grotewold S.K.
        • Wall V.L.
        • Goodell D.J.
        • Hayter C.
        • Bland S.T.
        Effects of cocaine combined with a social cue on conditioned place preference and nucleus accumbens monoamines after isolation rearing in rats.
        Psychopharmacology (Berl). 2014; 231: 3041-3053
        • Andrews C.M.
        • Lucki I.
        Effects of cocaine on extracellular dopamine and serotonin levels in the nucleus accumbens.
        Psychopharmacology (Berl). 2001; 155: 221-229
        • Torregrossa M.M.
        • Kalivas P.W.
        Microdialysis and the neurochemistry of addiction.
        Pharmacol Biochem Behav. 2008; 90: 261-272
        • Neisewander J.L.
        • Cheung T.H.
        • Pentkowski N.S.
        Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development.
        Neuropharmacology. 2014; 76: 301-319
        • Wren A.M.
        • Small C.J.
        • Abbott C.R.
        • Jethwa P.H.
        • Kennedy A.R.
        • Murphy K.G.
        • et al.
        Hypothalamic actions of neuromedin U.
        Endocrinology. 2002; 143: 4227-4234
        • Nakazato M.
        • Hanada R.
        • Murakami N.
        • Date Y.
        • Mondal M.S.
        • Kojima M.
        • et al.
        Central effects of neuromedin U in the regulation of energy homeostasis.
        Biochem Biophys Res Commun. 2000; 277: 191-194
        • Ikeda H.
        • Adachi K.
        • Fujita S.
        • Tomiyama K.
        • Saigusa T.
        • Kobayashi M.
        • et al.
        Investigating complex basal ganglia circuitry in the regulation of motor behaviour, with particular focus on orofacial movement.
        Behav Pharmacol. 2015; 26: 18-32
        • Salegio E.A.
        • Samaranch L.
        • Kells A.P.
        • Mittermeyer G.
        • San Sebastian W.
        • Zhou S.
        • et al.
        Axonal transport of adeno-associated viral vectors is serotype-dependent.
        Gene Ther. 2013; 20: 348-352
        • San Sebastian W.
        • Samaranch L.
        • Heller G.
        • Kells A.P.
        • Bringas J.
        • Pivirotto P.
        • et al.
        Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain.
        Gene Ther. 2013; 20: 1178-1183
        • Wydra K.
        • Golembiowska K.
        • Zaniewska M.
        • Kamińska K.
        • Ferraro L.
        • Fuxe K.
        • Filip M.
        Accumbal and pallidal dopamine, glutamate and GABA overflow during cocaine self-administration and its extinction in rats.
        Addict Biol. 2013; 18: 307-324
        • Sorg B.A.
        • Guminski B.J.
        • Hooks M.S.
        • Kalivas P.W.
        Cocaine alters glutamic acid decarboxylase differentially in the nucleus accumbens core and shell.
        Brain Res Mol Brain Res. 1995; 29: 381-386
        • Kennedy P.J.
        • Feng J.
        • Robison A.J.
        • Maze I.
        • Badimon A.
        • Mouzon E.
        • et al.
        Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation.
        Nat Neurosci. 2013; 16: 434-440
        • McDevitt R.A.
        • Tiran-Cappello A.
        • Shen H.
        • Balderas I.
        • Britt J.P.
        • Marino R.A.
        • et al.
        Serotonergic versus nonserotonergic dorsal raphe projection neurons: Differential participation in reward circuitry.
        Cell Rep. 2014; 8: 1857-1869
        • Bang S.J.
        • Commons K.G.
        Forebrain GABAergic projections from the dorsal raphe nucleus identified by using GAD67-GFP knock-in mice.
        J Comp Neurol. 2012; 520: 4157-4167
        • Vasudeva R.K.
        • Lin R.C.
        • Simpson K.L.
        • Waterhouse B.D.
        Functional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups.
        J Chem Neuroanat. 2011; 41: 281-293
        • Lobo M.K.
        • Nestler E.J.
        The striatal balancing act in drug addiction: Distinct roles of direct and indirect pathway medium spiny neurons.
        Front Neuroanat. 2011; 5: 41
        • Martin T.A.
        • Jayanthi S.
        • McCoy M.T.
        • Brannock C.
        • Ladenheim B.
        • Garrett T.
        • et al.
        Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens.
        PLoS One. 2012; 7: e34236