Galantamine ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine: involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic-ERK1/2 systems.
Galantamine, a drug used to treat Alzheimer's disease, inhibits acetylcholinesterase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs) resulting in stimulation of catecholamine neurotransmission. In this study, we investigated whether galantamine exerts cognitive-improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine (Meth) psychosis. The mice treated with Meth (1 mg/kg.d) for 7 d showed memory impairment in a novel object recognition test. Galantamine (3 mg/kg) ameliorated the memory impairment, and it increased the extracellular dopamine release in the prefrontal cortex (PFC) of Meth-treated mice. Donepezil, an AChE inhibitor (1 mg/kg) increased the extracellular ACh release in the PFC, whereas it had no effect on the memory impairment in Meth-treated mice. The nAChR antagonist, mecamylamine, and dopamine D1 receptor antagonist, SCH 23390, blocked the ameliorating effect of galantamine on Meth-induced memory impairment, whereas the muscarinic AChR antagonist, scopolamine, had no effect. The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine. Galantamine attenuated the defect of the novelty-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). The ameliorating effect of galantamine on recognition memory in Meth-treated mice was negated by microinjection of an ERK inhibitor, PD98059, into the PFC. These results suggest that the ameliorating effect of galantamine on Meth-induced memory impairment is associated with indirect activation of dopamine D1 receptor-ERK1/2 following augmentation with dopaminergic neurotransmission in the PFC through the allosteric activation of nAChRs. Galantamine could be a useful therapeutic agent for treating cognitive deficits in schizophrenia/Meth psychosis, as well as Alzheimer's disease.
Noda
Yukihiro
Y
Division of Clinical Sciences and Neuropsychopharmacology, Meijo University, Graduate School of Pharmaceutical Science, Nagoya, Japan.
Mouri
Akihiro
A
Ando
Yu
Y
Waki
Yukari
Y
Yamada
Shin-Nosuke
SN
Yoshimi
Akira
A
Yamada
Kiyofumi
K
Ozaki
Norio
N
Wang
Dayong
D
Nabeshima
Toshitaka
T
D000109:Acetylcholine / Q000032:analysis; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D000077265:Donepezil; D004298:Dopamine / Q000032:analysis; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D005702:Galantamine / Q000378:metabolism / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D002800:Cholinesterase Inhibitors; D018491:Dopamine Agonists; D007189:Indans; D010880:Piperidines; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D005702:Galantamine; D008694:Methamphetamine; D000077265:Donepezil; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine; D004298:Dopamine