RT Journal Article SR Electronic T1 Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1309 OP 1316 DO 10.1124/mol.64.6.1309 VO 64 IS 6 A1 Laura A. Volpicelli-Daley A1 Anna Hrabovska A1 Ellen G. Duysen A1 Shawn M. Ferguson A1 Randy D. Blakely A1 Oksana Lockridge A1 Allan I. Levey YR 2003 UL http://molpharm.aspetjournals.org/content/64/6/1309.abstract AB 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 β2 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.