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

James Kasper, David L. McCue, Adrianna J. Milton, Angelia Szwed, Catherine M. Sampson, Mei Huang, Susan Carlton, Herbert Y. Meltzer, Kathryn Cunningham, Jonathan Hommel

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiological Psychiatry
DOIs
StateAccepted/In press - Dec 18 2015

Fingerprint

Nucleus Accumbens
Cocaine
Microinjections
Locomotion
Reward
Presynaptic Receptors
Aptitude
Microdialysis
Viral RNA
Street Drugs
RNA Interference
neuromedin U
Dorsal Raphe Nucleus
Neuropeptides
gamma-Aminobutyric Acid
Small Interfering RNA
Immunohistochemistry
Neurons
Food
Brain

Keywords

  • AAV6
  • Cocaine
  • GABA
  • Neuropeptide
  • Nonserotonergic
  • RNAi

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U. / Kasper, James; McCue, David L.; Milton, Adrianna J.; Szwed, Angelia; Sampson, Catherine M.; Huang, Mei; Carlton, Susan; Meltzer, Herbert Y.; Cunningham, Kathryn; Hommel, Jonathan.

In: Biological Psychiatry, 18.12.2015.

Research output: Contribution to journalArticle

Kasper, James ; McCue, David L. ; Milton, Adrianna J. ; Szwed, Angelia ; Sampson, Catherine M. ; Huang, Mei ; Carlton, Susan ; Meltzer, Herbert Y. ; Cunningham, Kathryn ; Hommel, Jonathan. / Gamma-Aminobutyric Acidergic Projections From the Dorsal Raphe to the Nucleus Accumbens Are Regulated by Neuromedin U. In: Biological Psychiatry. 2015.
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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 = "AAV6, Cocaine, GABA, Neuropeptide, Nonserotonergic, RNAi",
author = "James Kasper and McCue, {David L.} and Milton, {Adrianna J.} and Angelia Szwed and Sampson, {Catherine M.} and Mei Huang and Susan Carlton and Meltzer, {Herbert Y.} and Kathryn Cunningham and Jonathan Hommel",
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AU - Kasper, James

AU - McCue, David L.

AU - Milton, Adrianna J.

AU - Szwed, Angelia

AU - Sampson, Catherine M.

AU - Huang, Mei

AU - Carlton, Susan

AU - Meltzer, Herbert Y.

AU - Cunningham, Kathryn

AU - Hommel, Jonathan

PY - 2015/12/18

Y1 - 2015/12/18

N2 - 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.

AB - 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.

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