MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats

J Neural Transm (Vienna). 2008 Jul;115(7):1027-35. doi: 10.1007/s00702-008-0048-1. Epub 2008 Apr 30.

Abstract

The effect of MKC-231 on acetylcholine (ACh) synthesis and release was studied in the hippocampus of normal and AF64A-treated rats. AF64A (3 nmol/brain, i.c.v.) produced significant reduction of high-affinity choline uptake (HACU) and high K+-induced ACh release in hippocampal synaptosomes. Treatments with MKC-231 (10(-8) and 10(-7) M) showed significant reverse of the decrease in both HACU and ACh release. In hippocampal slices superfused with choline-containing artificial cerebro-spinal fluid (ACSF), high K+-induced ACh release was gradually decreased by repeated alteration of resting and high K+ stimulations in AF64A-treated rats. However, addition of MKC-231 (10(-8) to 10(-7) M) in the superfusate reduces this decrease. In vivo microdialysis studies indicate MKC-231 (10 mg/kg, p.o.) significantly reversed reduction of basal ACh concentrations in AF64A-treated rats, measured by radioimmunoassay without a cholinesterase inhibitor in the perfusate. These results indicate MKC-231 improves AF64A-induced cholinergic hypofunction by enhancing HACU, subsequently facilitating ACh synthesis and release in vitro and in vivo.

MeSH terms

  • Acetylcholine / metabolism*
  • Analysis of Variance
  • Animals
  • Aziridines / pharmacology*
  • Choline / analogs & derivatives*
  • Choline / metabolism
  • Choline / pharmacology
  • Cholinesterase Inhibitors / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Hippocampus / ultrastructure
  • In Vitro Techniques
  • Male
  • Microdialysis
  • Neuromuscular Blocking Agents / pharmacology*
  • Potassium / pharmacology
  • Quinolines / pharmacology*
  • Rats
  • Rats, Wistar
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism*
  • Tacrine / pharmacology
  • Tritium / metabolism

Substances

  • Aziridines
  • Cholinesterase Inhibitors
  • Neuromuscular Blocking Agents
  • Quinolines
  • Tritium
  • Tacrine
  • ethylcholine aziridinium
  • Choline
  • Acetylcholine
  • Potassium
  • MKC 231