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Dopamine D 2 ‐receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic‐dependent mechanism
Author(s) -
Zhao-Shea Rubing,
Cohen Bruce N.,
Just Herwig,
McClure-Begley Tristan,
Whiteaker Paul,
Grady Sharon R.,
Salminen Outi,
Gardner Paul D.,
Lester Henry A.,
Tapper Andrew R.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-137034
Subject(s) - quinpirole , agonist , cholinergic , dopamine receptor d2 , dopamine , choline acetyltransferase , nicotinic agonist , receptor , chemistry , muscarinic acetylcholine receptor , endocrinology , acetylcholine receptor , medicine , dopamine receptor , catalepsy , neuroscience , pharmacology , biology , haloperidol
ABSTRACT Recent studies suggest that high‐affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing α4 and β2 subunits (α4β2*) functionally interact with G‐protein‐coupled dopamine (DA) D 2 receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9′Ala) rendering α4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D 2 ‐receptor agonist. When challenged with the D 2 R agonist, quinpirole (0.5–10 mg/kg), Leu9′Ala mice, but not wild‐type (WT) litter‐mates, developed severe, reversible motor impairment characterized by rigidity, catalepsy, akinesia, and tremor. While striatal DA tissue content, baseline release, and quinpirole‐induced DA depletion did not differ between Leu9′Ala and WT mice, quinpirole dramatically increased activity of cholinergic striatal interneurons only in mutant animals, as measured by increased c‐Fos expression in choline acetyltransferase (ChAT)‐positive interneurons. Highlighting the importance of the cho‐linergic system in this mouse model, inhibiting the effects of ACh by blocking muscarinic receptors, or by selectively activating hypersensitive nAChRs with nicotine, rescued motor symptoms. This novel mouse model mimics the imbalance between striatal DA/ACh function associated with severe motor impairment in disorders such as Parkinson's disease, and the data suggest that a D 2 R‐α4*‐nAChR functional interaction regulates cholinergic interneuron activity.—Zhao‐Shea, R., Cohen, B. N., Just, H., McClure‐Begley, T., Whiteaker, P., Grady, S. R., Salminen, O., Gardner, P. D., Lester, H. A., Tapper, A. R. Dopamine D2‐receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive α4 nicotinic receptors via a cholinergic‐dependent mechanism. FASEB J . 24, 49–57 (2010). www.fasebj.org