Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice

Laura A. Volpicelli-Daley, Anna Hrabovska, Ellen G. Duysen, Shawn M. Ferguson, Randy D. Blakely, Oksana Lockridge, Allan I. Levey

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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 high-affinity 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 down-regulation 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.

Original languageEnglish (US)
Pages (from-to)1309-1316
Number of pages8
JournalMolecular pharmacology
Volume64
Issue number6
DOIs
StatePublished - Dec 1 2003

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Corpus Striatum
Cholinergic Receptors
Muscarinic Receptors
Acetylcholinesterase
Knockout Mice
Cholinergic Agents
Down-Regulation
Cholinesterase Inhibitors
Acetylcholine
Vesicular Acetylcholine Transport Proteins
Neurons
Behavioral Symptoms
Choline O-Acetyltransferase
Dopamine Receptors
Nicotinic Receptors
Locomotion
Psychotic Disorders
Synapses
Dendritic Cells
Cognition

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Pharmacology

Cite this

Volpicelli-Daley, L. A., Hrabovska, A., Duysen, E. G., Ferguson, S. M., Blakely, R. D., Lockridge, O., & Levey, A. I. (2003). Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice. Molecular pharmacology, 64(6), 1309-1316. https://doi.org/10.1124/mol.64.6.1309

Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice. / Volpicelli-Daley, Laura A.; Hrabovska, Anna; Duysen, Ellen G.; Ferguson, Shawn M.; Blakely, Randy D.; Lockridge, Oksana; Levey, Allan I.

In: Molecular pharmacology, Vol. 64, No. 6, 01.12.2003, p. 1309-1316.

Research output: Contribution to journalArticle

Volpicelli-Daley, LA, Hrabovska, A, Duysen, EG, Ferguson, SM, Blakely, RD, Lockridge, O & Levey, AI 2003, 'Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice', Molecular pharmacology, vol. 64, no. 6, pp. 1309-1316. https://doi.org/10.1124/mol.64.6.1309
Volpicelli-Daley, Laura A. ; Hrabovska, Anna ; Duysen, Ellen G. ; Ferguson, Shawn M. ; Blakely, Randy D. ; Lockridge, Oksana ; Levey, Allan I. / Altered Striatal Function and Muscarinic Cholinergic Receptors in Acetylcholinesterase Knockout Mice. In: Molecular pharmacology. 2003 ; Vol. 64, No. 6. pp. 1309-1316.
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