Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice

https://doi.org/10.1016/j.ejphar.2004.03.066Get rights and content

Abstract

The effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition of acoustic startle response were determined in mice. The prepulse inhibition is associated with sensorimotor information processing in the brain. The anticholinergic agent scopolamine (0.3 mg/kg, s.c.) significantly attenuated prepulse inhibition, while the drug (1–10 mg/kg, s.c.) had no effects on startle amplitude as an indicator of startle response. The muscarinic M1 receptor antagonist pirenzepine (0.1–10 μg/mouse, i.c.v.) and the muscarinic M2 receptor antagonist AF-DX116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one) (0.1–10 μg/mouse, i.c.v.) had no effects on prepulse inhibition or startle amplitude. The muscarinic M3 receptor antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxy-piperidinium iodide) (30 μg/mouse, i.c.v.) and the muscarinic M4 receptor antagonist tropicamide (0.1 μg/mouse, i.c.v.) significantly attenuated prepulse inhibition, while tropicamide (0.01 μg/mouse, i.c.v.) but not 4-DAMP (10 and 30 μg/mouse, i.c.v.) produced a significant increase in startle amplitude. These results suggest that the blockade of muscarinic M3 and M4 receptors leads to the disruption of prepulse inhibition.

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.

References (27)

Cited by (37)

  • Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dt<sup>sz</sup>) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics

    2017, Neuroscience
    Citation Excerpt :

    This mechanism could contribute to inefficacy after striatal injections of tropicamide, because intrastriatal administration of dopamine receptor agonists aggravated dystonia in the dtsz mutant (Rehders et al., 2000). Tropicamide has been reported to penetrate the blood brain barrier (Potier and Psarropoulou, 2004; Ukai et al., 2004) and was therefore also used for systemic administration in the present study. Interestingly, tropicamide significantly retarded the onset of dystonia, as previously observed after i.p. administration of trihexyphenidyl (Löscher and Fredow, 1992).

  • Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs

    2016, Neurotoxicology and Teratology
    Citation Excerpt :

    For example, increasing cholinergic tone with sublethal exposures of GB increases startle amplitude in rats (Scremin et al., 2003), while reducing cholinergic tone with lesions of pontine cholinergic neurons reduces ASR (MacLaren et al., 2014). In contrast, however, other studies in rats (Sipos et al., 2001), guinea pigs (Philippens et al., 1996), and mice (Ukai et al., 2004) show that various anticholinergics also increase peak startle amplitude. Although methodological differences among these studies prohibit any direct comparisons, these studies suggest that increasing or decreasing cholinergic tone does not consistently affect startle behavior in a relative manner.

  • The muscarinic system, cognition and schizophrenia

    2015, Neuroscience and Biobehavioral Reviews
    Citation Excerpt :

    Scopolamine, a non-specific muscarinic antagonist, has been reported to evoke dose-dependent, antipsychotic medication-resistant cognitive impairments and psychotic-like symptoms in latent inhibition models of schizophrenia (Barak and Weiner, 2007, 2009, 2010). Likewise, various muscarinic antagonists have been reported to disrupt the prepulse inhibition of the startle reflex in rodents (e.g. Jones et al., 2005; Thomsen et al., 2010; Ukai et al., 2004), an index of sensorimotor gating commonly used to model schizophrenia. Locomotor activity and stereotypy, two animal indicators of psychotic activity, have also been evoked using muscarinic antagonists (Chintoh et al., 2003; Gholamreza et al., 2002; Mathur et al., 1997), further highlighting the role the central muscarinic system may play in the symptomology of schizophrenia.

  • Phospholipase C-β1 and schizophrenia-related behaviors

    2013, Advances in Biological Regulation
    Citation Excerpt :

    But M1 KO mice did not show disruption of PPI compared with wild type (Miyakawa et al., 2001). There has not been any report on PPI in M3 KO mice until today, but the pharmacological study an M3 receptor antagonist significantly attenuated prepulse inhibition, suggesting that the blockade of muscarinic M3 receptors can lead to the disruption of prepulse inhibition (Ukai et al., 2004). M5 mRNA expression is highest in the ventral tegmentum, striatum, and thalamus in wild-type mice.

View all citing articles on Scopus
View full text