Dopamine D2-receptor activation elicits akinesia, rigidity, catalepsy, and tremor in mice expressing hypersensitive {alpha}4 nicotinic receptors via a cholinergic-dependent mechanism.
Recent studies suggest that high-affinity neuronal nicotinic acetylcholine receptors (nAChRs) containing alpha4 and beta2 subunits (alpha4beta2*) 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 alpha4 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-alpha4*-nAChR functional interaction regulates cholinergic interneuron activity.
Zhao-Shea
Rubing
R
University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA 01604, USA.
Cohen
Bruce N
BN
Just
Herwig
H
McClure-Begley
Tristan
T
Whiteaker
Paul
P
Grady
Sharon R
SR
Salminen
Outi
O
Gardner
Paul D
PD
Lester
Henry A
HA
Tapper
Andrew R
AR
D000109:Acetylcholine / Q000502:physiology; D019943:Amino Acid Substitution; D000818:Animals; D002375:Catalepsy / Q000209:etiology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D004829:Epilepsy, Generalized / Q000209:etiology; D005260:Female; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009127:Muscle Rigidity / Q000209:etiology; D016297:Mutagenesis, Site-Directed; D020734:Parkinsonian Disorders / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014202:Tremor / Q000209:etiology
D000109:Acetylcholine; D018491:Dopamine Agonists; D019257:Quinpirole; D017448:Receptors, Dopamine D2; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins