Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice

Bin Li, Ellen G. Duysen, Laura A. Volpicelli-Daley, Allan I. Levey, Oksana Lockridge

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Acetylcholinesterase (AChE) hydrolyzes acetylcholine to terminate cholinergic neurotransmission. Overstimulation of cholinergic receptors by excess acetylcholine is known to be lethal. However, AChE knockout mice live to adulthood, although they have weak muscles, do not eat solid food, and die early from seizures. We wanted to know what compensatory factors allowed these mice to survive. We had previously shown that their butyrylcholinesterase activity was normal and had not increased. In this report, we tested the hypothesis that AChE-/- mice adapted to the absence of AChE by downregulating cholinergic receptors. Receptor downregulation is expected to reduce sensitivity to agonists and to increase sensitivity to antagonists. Physiological response to the muscarinic agonists, oxotremorine (OXO) and pilocarpine, showed that AChE-/- mice were resistant to OXO-induced hypothermia, tremor, salivation, and analgesia, and to pilocarpine-induced seizures. AChE+/- mice had an intermediate response. The muscarinic receptor binding sites measured with [3H]quinuclinyl benzilate, as well as the protein levels of M1, M2, and M4 receptors measured with specific antibodies on Western blots, were reduced to be approximately 50% in AChE-/- brain. However, mRNA levels for muscarinic receptors were unchanged. These results indicate that one adaptation to the absence of AChE is downregulation of muscarinic receptors, thus reducing response to cholinergic stimulation.

Original languageEnglish (US)
Pages (from-to)977-986
Number of pages10
JournalPharmacology Biochemistry and Behavior
Volume74
Issue number4
DOIs
StatePublished - Jan 1 2003

Fingerprint

Muscarinic Receptors
Acetylcholinesterase
Knockout Mice
Oxotremorine
Pilocarpine
Down-Regulation
Cholinergic Receptors
Cholinergic Agents
Acetylcholine
Benzilates
Seizures
Hypothermia
Butyrylcholinesterase
Salivation
Induced Hypothermia
Muscarinic Agonists
Tremor
Synaptic Transmission
Analgesia
Muscle

Keywords

  • Acetylcholinesterase
  • Knockout mice
  • Muscarinic receptor
  • Oxotremorine
  • Pilocarpine
  • Seizures

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Clinical Biochemistry
  • Biological Psychiatry
  • Behavioral Neuroscience

Cite this

Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. / Li, Bin; Duysen, Ellen G.; Volpicelli-Daley, Laura A.; Levey, Allan I.; Lockridge, Oksana.

In: Pharmacology Biochemistry and Behavior, Vol. 74, No. 4, 01.01.2003, p. 977-986.

Research output: Contribution to journalArticle

Li, Bin ; Duysen, Ellen G. ; Volpicelli-Daley, Laura A. ; Levey, Allan I. ; Lockridge, Oksana. / Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. In: Pharmacology Biochemistry and Behavior. 2003 ; Vol. 74, No. 4. pp. 977-986.
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