Rivastigmine improves isolation rearing-induced prepulse inhibition deficits via muscarinic acetylcholine receptors in mice

• Published in: Psychopharmacology 2016-02, Vol.233 (3), p.521-528
• Main Authors: Higashino, Kosuke, Ago, Yukio, Umeki, Takahiro, Hasebe, Shigeru, Onaka, Yusuke, Hashimoto, Hitoshi, Takuma, Kazuhiro, Matsuda, Toshio
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine - metabolism; Acoustic Stimulation; Animals; Behavior; Biomedical and Life Sciences; Biomedicine; Brain Chemistry - drug effects; Cholinesterase Inhibitors - pharmacology; Dopamine - metabolism; Dosage and administration; Drug interactions; Health aspects; Male; Mecamylamine - pharmacology; Mice; Muscarinic Antagonists - pharmacology; Neurosciences; Nicotinic Antagonists - pharmacology; Observations; Original Investigation; Pharmacology/Toxicology; Pirenzepine - analogs & derivatives; Pirenzepine - pharmacology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Psychiatry; Psychopharmacology; Receptor, Serotonin, 5-HT1A - drug effects; Receptors, Muscarinic - drug effects; Reflex, Startle - drug effects; Rivastigmine; Rivastigmine - pharmacology; Rodents; Social Isolation - psychology; Studies
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-015-4123-7

Rationale 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. Objectives 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 serotonin 1A 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.