Dopamine D2-Receptor Activation Elicits Akinesia Rigidity Catalepsy And Tremor In Mice Expressing Hypersensitive Î±4 Nicotinic Receptors Via A Cholinergic-Dependent Mechanism
Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing Î±4 and Î²2 subunits (Î±4Î² 2*) functionally interact with G-protein-coupled dopamine (DA) D2 receptors in basal ganglia. We hypothesized that if a functional interaction between these receptors exists, then mice expressing an M2 point mutation (Leu9â€²Ala) rendering Î±4 nAChRs hypersensitive to ACh may exhibit altered sensitivity to a D2-receptor agonist. When challenged with the D2R agonist, quinpirole (0.5-10 mg/kg), Leu9â€²Ala 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 Leu9â€²Ala 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 D2R- Î±4*-nAChR functional interaction regulates cholinergic interneuron activity. Â© FASEB.
Digital Object Identifier (DOI)
Zhao-Shea, Rubing; Cohen, Bruce N.; Just, Herwig; McClure-Begley, Tristan; Whiteaker, Paul; Grady, Sharon R.; Salminen, Outi; Gardner, Paul D.; Lester, Henry A.; and Tapper, Andrew R., "Dopamine D2-Receptor Activation Elicits Akinesia Rigidity Catalepsy And Tremor In Mice Expressing Hypersensitive Î±4 Nicotinic Receptors Via A Cholinergic-Dependent Mechanism" (2010). Neurobiology. 385.