Pharmacologic Interactions between the Muscarinic Cholinergic and Dopaminergic Systems in the Modulation of Prepulse Inhibition in Rats

Abstract

Prepulse inhibition (PPI) of the acoustic startle reflex is a sensorimotor gating process known to be deficient in a number of neurologic and psychiatric conditions, including schizophrenia. Multiple lines of evidence have indicated that the dopaminergic and muscarinic cholinergic systems play an important role in modulating PPI. Moreover, interactions between the dopaminergic and muscarinic cholinergic systems are well known; however, little is known about potential interactions between the two systems in modulating PPI. Therefore, the purpose of the present studies was to determine whether interactions occur between the muscarinic cholinergic and dopaminergic systems in modulating PPI. The efficacy of muscarinic cholinergic receptor agonists in reversing the disruption of PPI induced by apomorphine, a D1/D2 dopamine receptor agonist, was evaluated in male Sprague-Dawley rats. The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonistoctane oxalate] reversed the apomorphineinduced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine. The muscarinic agonists oxotremorine, RS86, pilocarpine, milameline, and sabcomeline also reversed the apomorphine-induced disruption of PPI. Moreover, the muscarinic antagonist scopolamine also disrupted PPI, and the D2-like receptor antagonist haloperidol, but not the D1-like receptor antagonist SCH23390 [R-(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], reversed the scopolamine-induced disruption. In addition, xanomeline produced a significant reversal of the disruption in PPI produced by scopolamine. Collectively, the present findings demonstrate that a functional interaction occurs between the muscarinic cholinergic and dopaminergic systems in modulating PPI and that muscarinic cholinergic agonists may be effective in the treatment of the PPI and other cognitive impairments observed in schizophrenia.Prepulse inhibition (PPI) of the acoustic startle reflex is one of the best-characterized models used to evaluate sensory information-processing deficits observed in a number of neurologic and psychiatric conditions, including schizophrenia (Braff et al., 1992). PPI theoretically represents a mechanism for the gating or filtering out of irrelevant or distracting stimuli and is operationally defined as the reduction in startle response produced by a low-intensity stimulus presented before a high-intensity, startle-inducing stimulus (Graham, 1975). The role of various neurotransmitter systems in modulating PPI (Geyer et al., 2001) has been reviewed, and multiple lines of evidence have indicated that D2 dopamine receptors are critical for modulating PPI in rats (Peng et al., 1990;Swerdlow et al., 1994). In addition, a synergistic interaction between D1 and D2 dopamine receptors in mediating PPI also exists (Wan et al., 1996). For example, administration of the mixed D1/D2 dopamine receptor agonist apomorphine, the selective D2 dopamine receptor agon...

Galantamine and donepezil attenuate pharmacologically induced deficits in prepulse inhibition in rats

“…Other animal data that support such a premise are evident in a recent study in which PPI deficits induced by immunolesions of cholinergic neurons of the nucleus basalis were reversed by the AChEI, rivastigmine (Ballmaier et al, 2002). Additional data to support the role of muscarinic receptors in PPI (and that these receptors could serve as targets for drug development in schizophrenia) have been reported in a recent study in which, xanomeline, an M 1 /M 4 AChR agonist (Jones et al, 2005;Stanhope et al, 2001), normalized apomorphine-reduced PPI levels.…”

Towards a muscarinic hypothesis of schizophrenia

“…Animal studies support both dopamine-dependent and dopamine-independent effects of muscarinic agents. 40,190 The muscarinic and dopaminergic system interact bidirectionally at different levels in the brain and the nature of these interactions is not fully understood. Depending on the brain region and muscarinic receptor subtype involved, stimulation and inhibition of the muscarinic system can result in different effects on the dopaminergic system.…”

“…189 Both BuTAC and xanomeline reverse a pharmacological disruption of the PPI in a way similar to dopamine D 2 -antagonists. 190 Sarter et al 191 recently suggested that an abnormal increase in the reactivity of the cholinergic neurotransmission results in an impaired regulation of the mesolimbic dopaminergic neurotransmission and thus in the symptoms of schizophrenia. It should be kept in mind that these effects are not unidirectional, as the release of dopamine also has an effect on the regulation of the muscarinic cholinergic system.…”

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…51 In summary, We propose that the attenuation of phosphoinositide hydrolysis due to the absence of PLC-b1 and feedback mechanisms regulating plasticity of muscarinic receptor expression in the adult neocortex may be responsible for the reduction of pirenzepine binding in standard housed KO animals. Muscarinic signaling has been demonstrated to modulate, and to be modulated by, other signaling systems, including dopaminergic 52 and GABAergic pathways. [53][54][55] More specifically, the observed phenotypes may be elicited as a result of decreased M1 receptor expression mediating an increase in striatal extracellular dopamine, as observed in the M1 KO mouse, 53 resulting in the impaired motor and sensorimotor phenotype recorded for these animals.…”