Zhao-Shea, Rubing and Cohen, Bruce N. and Just, Herwig and McClure-Begley, Tristan and Whiteaker, Paul and Grady, Sharon R. and Salminem, Outi and Gardner, Paul D. and Lester, Henry A. and Tapper, Andrew R. (2010) Dopamine D_2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism. FASEB Journal, 24 (1). pp. 49-57. ISSN 0892-6638 http://resolver.caltech.edu/CaltechAUTHORS:20100119-103312477
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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 4 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) littermates, 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 cholinergic 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.
|Additional Information:||© 2010 Federation of American Societies for Experimental Biology. Received for publication May 26, 2009; accepted for publication August 6, 2009.|
|Subject Keywords:||acetylcholine; striatum; nicotine; parkinsonian; interneuron|
|Official Citation:||Rubing Zhao-Shea, Bruce N. Cohen, Herwig Just, Tristan McClure-Begley, Paul Whiteaker, Sharon R. Grady, Outi Salminen, Paul D. Gardner, Henry A. Lester, and Andrew R. Tapper Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive 4 nicotinic receptors via a cholinergic-dependent mechanism FASEB J. 24: 49-57; published online as doi10.1096/fj.09-137034|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Jason Perez|
|Deposited On:||25 Jan 2010 20:10|
|Last Modified:||20 Dec 2012 22:53|
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