title: Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice.
abstract: BACKGROUND
  The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine are used for the treatment of Alzheimer's disease. We previously demonstrated that donepezil and galantamine differentially affect isolation rearing-induced prepulse inhibition (PPI) deficits and that this might be due to differential effects on brain muscarinic acetylcholine (mACh) receptor function in mice.
  
  
  OBJECTIVE
  We examined the effects of rivastigmine on isolation rearing-induced PPI deficits, brain ACh levels, and mACh receptor function in mice.
  
  
  METHODS
  Acoustic startle responses were measured in a startle chamber. Microdialysis was performed, and the levels of dopamine and ACh in the prefrontal cortex were measured.
  
  
  RESULTS
  Rivastigmine (0.3 mg/kg) improved PPI deficits, and this improvement was antagonized by the mACh receptor antagonist telenzepine but not by the nicotinic ACh receptor antagonist mecamylamine. Rivastigmine increased extracellular ACh levels by approximately 2-3-fold, less than the increase produced by galantamine. Rivastigmine enhanced the effect of the mACh receptor agonist N-desmethylclozapine on prefrontal dopamine release, a marker of mACh receptor function, and this increase was blocked by telenzepine. In contrast, galantamine did not affect N-desmethylclozapine-induced dopamine release. Furthermore, rivastigmine did not affect cortical dopamine release induced by the serotonin1A receptor agonist osemozotan, suggesting that the effect of rivastigmine has specificity for mACh receptors.
  
  
  CONCLUSIONS
  Taken together with our previous finding that marked increases in ACh levels are required for the PPI deficit improvement induced by galantamine, our present results suggest that rivastigmine improves isolation rearing-induced PPI deficits by increasing ACh levels and by concomitantly enhancing mACh receptor function.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Higashino
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ago
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Umeki
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hasebe
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Onaka
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan.|United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, 565-0871, Japan. matsuda@phs.osaka-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000161:Acoustic Stimulation; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects*; D000068836:Rivastigmine / Q000494:pharmacology*; D012934:Social Isolation / Q000523:psychology*
chemical_list: D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D011976:Receptors, Muscarinic; C046338:telenzepine; D044282:Receptor, Serotonin, 5-HT1A; D010890:Pirenzepine; D008464:Mecamylamine; D000109:Acetylcholine; D000068836:Rivastigmine; D004298:Dopamine
keywords: ACh; Isolation rearing; Prepulse inhibition; Rivastigmine; Sensitization; mACh receptor