Altered neurotransmission in the mesolimbic reward system of Girk -/- mice

Devinder Arora, Desirae M. Haluk, Saïd Kourrich, Marco Pravetoni, Laura Fernández-Alacid, Joel C. Nicolau, Rafael Luján, Kevin Wickman

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Mice lacking the Girk2 subunit of G protein-gated inwardly rectifying K+ (Girk) channels exhibit dopamine-dependent hyperactivity and elevated responses to drugs that stimulate dopamine neurotransmission. The dopamine-dependent phenotypes seen in Girk2-/- mice could reflect increased intrinsic excitability of or diminished inhibitory feedback to midbrain dopamine neurons, or secondary adaptations triggered by Girk2 ablation. We addressed these possibilities by evaluating Girk-/- mice in behavioral, electrophysiological, and cell biological assays centered on the mesolimbic dopamine system. Despite differences in the contribution of Girk1 and Girk2 subunits to Girk signaling in midbrain dopamine neurons, Girk1 -/- and Girk2-/- mice exhibited comparable baseline hyperactivities and enhanced responses to cocaine. Girk ablation also correlated with altered afferent input to dopamine neurons in the ventral tegmental area. Dopamine neurons from Girk1-/- and Girk2-/- mice exhibited elevated glutamatergic neurotransmission, paralleled by increased synaptic levels of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors. In addition, synapse density, α-amino-3-hydroxyl-5-methyl-4- isoxazole-propionate receptor levels, and glutamatergic neurotransmission were elevated in medium spiny neurons of the nucleus accumbens from Girk1 -/- and Girk2-/- mice. We conclude that dopamine-dependent phenotypes in Girk2-/- mice are not solely attributable to a loss of Girk signaling in dopamine neurons, and likely involve secondary adaptations facilitating glutamatergic signaling in the mesolimbic reward system.

Original languageEnglish (US)
Pages (from-to)1487-1497
Number of pages11
JournalJournal of Neurochemistry
Volume114
Issue number5
DOIs
StatePublished - Sep 1 2010

Keywords

  • cocaine
  • dopamine
  • glutamate
  • knockout
  • plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Arora, D., Haluk, D. M., Kourrich, S., Pravetoni, M., Fernández-Alacid, L., Nicolau, J. C., Luján, R., & Wickman, K. (2010). Altered neurotransmission in the mesolimbic reward system of Girk -/- mice. Journal of Neurochemistry, 114(5), 1487-1497. https://doi.org/10.1111/j.1471-4159.2010.06864.x