Galantamine improves apomorphine-induced deficits in prepulse inhibition via muscarinic ACh receptors in mice.
OBJECTIVE
Galantamine, a weak acetylcholine esterase (AChE) inhibitor and allosteric potentiator of nicotinic ACh receptors (nAChRs), improves apomorphine-induced deficits in prepulse inhibition (PPI), sensory information-processing deficits, via a nAChR-independent mechanism. The present study examined the role of muscarinic ACh receptors (mAChRs) in the effect of galantamine, and studied the mechanism of galantamine-induced increases in prefrontal ACh levels in mice.


METHODS
Apomorphine (1 mg kg(-1)) was administered to male ddY mice (9-10 weeks old) to create a PPI deficit model. Extracellular ACh concentrations in the prefrontal cortex were measured by in vivo microdialysis.


RESULTS
Galantamine- and donepezil-mediated improvements in apomorphine-induced PPI deficits were blocked by the preferential M(1) mAChR antagonist telenzepine. The mAChR agonist oxotremorine also improved apomorphine-induced PPI deficits. Galantamine, like donepezil, increased extracellular ACh concentrations in the prefrontal cortex. Galantamine-induced increases in prefrontal ACh levels were partially blocked by the dopamine D(1) receptor antagonist SCH23390, but not by antagonists of mAChRs (telenzepine) and nAChRs (mecamylamine). Galantamine increased dopamine, but not 5-HT, release in the prefrontal cortex.


CONCLUSIONS
Galantamine improves apomorphine-induced PPI deficits by stimulating mAChRs through increasing brain ACh levels via a dopamine D(1) receptor-dependent mechanism and AChE inhibition.
Yano
K
K
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
Koda
K
K
Ago
Y
Y
Kobayashi
H
H
Kawasaki
T
T
Takuma
K
K
Matsuda
T
T
D000109:Acetylcholine / Q000378:metabolism; D000161:Acoustic Stimulation; D000818:Animals; D021461:Animals, Outbred Strains; D001058:Apomorphine / Q000494:pharmacology*; D001522:Behavior, Animal; D001552:Benzazepines / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005702:Galantamine / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism
D001552:Benzazepines; D002800:Cholinesterase Inhibitors; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D007189:Indans; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C534628:SCH 23390; C046338:telenzepine; D005702:Galantamine; D012701:Serotonin; D010890:Pirenzepine; D010095:Oxotremorine; D008464:Mecamylamine; D000077265:Donepezil; D001058:Apomorphine; D000109:Acetylcholine; D004298:Dopamine