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Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice

Center for Neurodegenerative Disease and Department of Neurology, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, Georgia (L.A.V.-D., A.I.L.); Eppley Institute, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (A.H., E.G.D., O.L.); and Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tennessee (S.M.F., R.D.B.)

Cholinesterase inhibitors are commonly used to improve cognition and treat psychosis and other behavioral symptoms in Alzheimer's disease, Parkinson's disease, and other neuropsychiatric conditions. However, mechanisms may exist that down-regulate the synaptic response to altered cholinergic transmission, thus limiting the efficacy of cholinomimetics in treating disease. Acetylcholinesterase knockout (AChE-/-) mice were used to investigate the neuronal adaptations to diminished synaptic acetylcholine (ACh) metabolism. The striatum of AChE-/- mice showed no changes in choline acetyltransferase activity or levels of the vesicular ACh transporter but showed striking 60% increases in the levels of the highaffinity choline transporter. This transporter takes choline from the synapse into the neuron for resynthesis of ACh. In addition, the striata of AChE-/- mice showed dramatic reductions in levels of the M₁, M₂, and M₄ muscarinic ACh receptors (mAChRs), but no alterations in dopamine receptors or the 2 subunit of nicotinic receptors. M₁, M₂, and M₄ also showed decreased dendritic and cell surface distributions and enhanced intracellular localizations in striatal neurons of AChE-/- mice. mAChR antagonist treatment reversed the shifts in mAChR distribution, indicating that internalized receptors in AChE-/- mice can recover to basal distributions. Finally, AChE-/- mice showed increased sensitivity to mAChR antagonist-induced increases in locomotor activity, demonstrating functional mAChR down-regulation. mAChR downregulation in AChE-/- mice has important implications for the long-term use of cholinesterase inhibitors and other cholinomimetics in treating disorders characterized by perturbed cholinergic function.

Address correspondence to: Dr. A. I. Levey, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael St., 5th Floor, Atlanta, GA 30322. E-mail: alevey{at}emory.edu

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