Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice
Introduction
The startle response induced by acoustic stimulation has been demonstrated to be inhibited by prior acoustic stimulation with relatively small sound. This phenomenon is named prepulse inhibition, which is associated with sensorimotor information processing in the brain (Varty et al., 2001).
The prepulse inhibition has been reported to be impaired in schizophrenic patients (Braff et al., 1992). In particular, the nonselective dopamine receptor agonist apomorphine and the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine have been shown to impair prepulse inhibition in rodents Mansbach et al., 1988, Mansbach and Geyer, 1989, while antipsychotic drugs improve the impairment of prepulse inhibition (Swerdlow and Geyer, 1993). The dysregulation of dopamine and glutamate is generally considered to be central to the symptom of schizophrenia and the disturbance of prepulse inhibition. In contrast, there are multiple lines of evidence suggesting the possible involvement of muscarinic cholinergic systems in the mechanisms of prepulse inhibition with acoustic startle response. Although the original findings with carbachol have been reported by Caine et al. (1992), carbachol dose-dependently enhances prepulse inhibition and attenuates startle amplitude. Scopolamine dose-dependently reduces prepulse inhibition and enhances startle amplitude Jones and Shannon, 2000a, Geyer et al., 2001. Furthermore, trihexyphenidyl and benztropine have been demonstrated to significantly decrease prepulse inhibition, although muscarinic receptor agonists, such as pilocarpine, oxotremorine, and arecholine, as well as the cholinesterase inhibitors physostigmine and tacrine, have no effects on prepulse inhibition (Jones and Shannon, 2000b). Recently, the muscarinic receptor agonist xanomeline dose-dependently reverses the apomorphine-induced disruption of prepulse inhibition (Stanhope et al., 2001). At present, however, the contribution of muscarinic receptor subtypes to prepulse inhibition is inconclusive in rodents, particularly in rats.
In an attempt to further clarify the involvement of acetylcholine receptor subtypes in prepulse inhibition in mice, the effects of the muscarinic M1 receptor-preferring antagonist pirenzepine Ukai et al., 1995, Ukai et al., 1997, Eglen et al., 1996, the muscarinic M2 receptor-preferring antagonist AF-DX116 (11-[[2-diethylamino-O-methyl]-1-piperidinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one) Baratti et al., 1993, Billard et al., 1995, the muscarinic M3 receptor-preferring antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxy-piperidinium iodide) (Michel et al., 1989), and the muscarinic M4 receptor-preferring antagonist tropicamide (Lazareno et al., 1990), in addition to the anticholinergic agent scopolamine, on prepulse inhibition and startle amplitude, which is an indicator of startle response, were determined in mice, although it is possible that the pharmacology of prepulse inhibition in mice is very different from rats in many ways.
Section snippets
Animals
Male mice of ddY strain aged 6–8 weeks (Japan SLC, Hamamatsu, Shizuoka, Japan) were used in the study. Animals were at least kept for 4 days before starting the experiment. The temperature (24±1%), humidity (55±5%), and 12-h light/dark cycle (light period: 0730–1930 h) were set. Water and food were freely available. In addition, all efforts were made to minimize animal suffering, and to reduce the number of animals used according to the guiding principles for the care and use of laboratory
Effects of scopolamine
Scopolamine (0.3 mg/kg, s.c.) significantly decreased prepulse inhibition [H=12.633, P<0.05], but the drug (0.1–10 mg/kg, s.c.) failed to affect startle amplitude [H=2.091, P>0.05] (Fig. 1). Although all groups except the case of 0.3 mg/kg scopolamine consisted of 10 mice, a 0.3-mg/kg dose of scopolamine was administered to 20, but not 10, mice in an attempt to obtain conclusive results.
Effects of selective antagonists for cholinergic receptor subtypes
Pirenzepine (0.1–10 μg/mouse, i.c.v.) failed to affect prepulse inhibition [H=1.238, P>0.05] or startle
Discussion
Prepulse inhibition is one of the models of sensorimotor information processing (Swerdlow et al., 1992). Although prepulse inhibition is relevant to various nervous systems in the brain Furuya et al., 1999, Klamer et al., 2001, there are multiple lines of evidence suggesting the possible involvement of muscarinic cholinergic systems in the mechanisms of prepulse inhibition of acoustic startle response Fendt and Koch, 1999, Jones and Shannon, 2000a, Jones and Shannon, 2000b, Stanhope et al., 2001
Acknowledgements
The study was supported, in part, by Grants-in-Aid for Scientific Research, High-Tech Research Center Project, and Scientific Frontier Research Project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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