Antipsychotic property of a muscarinic receptor agonist in animal models for schizophrenia.
Pharmacological evidence has implicated cholinergic dysfunction in the manifestation of psychotic symptoms. The purpose of the present study was to clarify the roles of muscarinic and nicotinic receptors in several animal models of schizophrenia. A muscarinic receptor agonist, oxotremorine (0.03-0.3 mg/kg), reversed hyperlocomotion in mice and disruption of prepulse inhibition (PPI) caused by methamphetamine in rats, similar to a typical antipsychotic drug, haloperidol (0.1-0.3 mg/kg). In addition to modulating hyperdopaminergic function, oxotremorine as well as clozapine (3-10 mg/kg) reversed the disruption of PPI caused by ketamine, an N-methyl-D-aspartate antagonist in rats, which mimics the clinical symptoms of schizophrenia. One of the spontaneous mouse models, DBA/2J exhibited lower PPI than C57BL/6J. Oxotremorine (0.03-0.06 mg/kg) increased PPI in DBA/2J but not C57BL/6J. On the other hand, a nicotinic receptor agonist, nicotine (0.06-0.6 mg/kg), exhibited no effects on the four animal models of symptoms of schizophrenia we tested. These findings suggest that muscarinic receptors play important roles in animal models to examine sensory gating which is known to be disrupted in schizophrenic patients, and hence activation of muscarinic receptors may provide an alternative approach for the treatment of psychotic symptoms in addition to classical antipsychotics.
Maehara
Shunsuke
S
Department of Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. shunsuke_maehara@merck.com
Hikichi
Hirohiko
H
Satow
Akio
A
Okuda
Shoki
S
Ohta
Hisashi
H
D000818:Animals; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D003024:Clozapine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D006948:Hyperkinesis / Q000139:chemically induced / Q000523:psychology; D008297:Male; D008694:Methamphetamine; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012565:Schizophrenic Psychology
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D008694:Methamphetamine; D010095:Oxotremorine; D009538:Nicotine; D003024:Clozapine; D006220:Haloperidol