Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking

Ashlie N. Reker, Alfredo Oliveros, John M. Sullivan, Lailun Nahar, David J. Hinton, Taehyun Kim, Robert C. Bruner, Doo Sup Choi, Nicholas E. Goeders, Hyung W. Nam

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Dysfunction of N-methyl-D-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng–/– mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng–/– mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng–/– mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng–/– mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng–/– mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.

Original languageEnglish (US)
Pages (from-to)58-67
Number of pages10
JournalNeuropharmacology
Volume131
DOIs
StatePublished - Mar 15 2018

Fingerprint

Neurogranin
Nucleus Accumbens
N-Methyl-D-Aspartate Receptors
Motivation
Ethanol
Metabotropic Glutamate 5 Receptor
Operant Conditioning
Rotarod Performance Test
Alcohols
Pharmacology
Calmodulin-Binding Proteins
Dependovirus
Neuronal Plasticity
Calmodulin
Reward
Synapses
Alcoholism
Cues

Keywords

  • Ethanol
  • Glutamate receptors
  • Motivation
  • Neurogranin
  • Nucleus accumbens
  • Operant conditioning

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Reker, A. N., Oliveros, A., Sullivan, J. M., Nahar, L., Hinton, D. J., Kim, T., ... Nam, H. W. (2018). Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking. Neuropharmacology, 131, 58-67. https://doi.org/10.1016/j.neuropharm.2017.12.008

Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking. / Reker, Ashlie N.; Oliveros, Alfredo; Sullivan, John M.; Nahar, Lailun; Hinton, David J.; Kim, Taehyun; Bruner, Robert C.; Choi, Doo Sup; Goeders, Nicholas E.; Nam, Hyung W.

In: Neuropharmacology, Vol. 131, 15.03.2018, p. 58-67.

Research output: Contribution to journalArticle

Reker, AN, Oliveros, A, Sullivan, JM, Nahar, L, Hinton, DJ, Kim, T, Bruner, RC, Choi, DS, Goeders, NE & Nam, HW 2018, 'Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking', Neuropharmacology, vol. 131, pp. 58-67. https://doi.org/10.1016/j.neuropharm.2017.12.008
Reker, Ashlie N. ; Oliveros, Alfredo ; Sullivan, John M. ; Nahar, Lailun ; Hinton, David J. ; Kim, Taehyun ; Bruner, Robert C. ; Choi, Doo Sup ; Goeders, Nicholas E. ; Nam, Hyung W. / Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking. In: Neuropharmacology. 2018 ; Vol. 131. pp. 58-67.
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abstract = "Dysfunction of N-methyl-D-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng–/– mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng–/– mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng–/– mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng–/– mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng–/– mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.",
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AU - Kim, Taehyun

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