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 language | English (US) |
|---|---|
| Pages (from-to) | 1487-1497 |
| Number of pages | 11 |
| Journal | Journal of Neurochemistry |
| Volume | 114 |
| Issue number | 5 |
| DOIs | |
| State | Published - Sep 2010 |
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Keywords
- cocaine
- dopamine
- glutamate
- knockout
- plasticity
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience
Cite this
Altered neurotransmission in the mesolimbic reward system of Girk -/- mice. / Arora, Devinder; Haluk, Desirae M.; Kourrich, Saïd; Pravetoni, Marco; Fernández-Alacid, Laura; Nicolau, Joel C.; Luján, Rafael; Wickman, Kevin.
In: Journal of Neurochemistry, Vol. 114, No. 5, 09.2010, p. 1487-1497.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Altered neurotransmission in the mesolimbic reward system of Girk -/- mice
AU - Arora, Devinder
AU - Haluk, Desirae M.
AU - Kourrich, Saïd
AU - Pravetoni, Marco
AU - Fernández-Alacid, Laura
AU - Nicolau, Joel C.
AU - Luján, Rafael
AU - Wickman, Kevin
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - cocaine
KW - dopamine
KW - glutamate
KW - knockout
KW - plasticity
UR - http://www.scopus.com/inward/record.url?scp=77955150592&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955150592&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2010.06864.x
DO - 10.1111/j.1471-4159.2010.06864.x
M3 - Article
C2 - 20557431
AN - SCOPUS:77955150592
VL - 114
SP - 1487
EP - 1497
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 5
ER -