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BEHAVIORAL PHARMACOLOGY

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

Program of Medical Neurobiology, Indiana University School of Medicine, Indianapolis, Indiana (C.K.J., D.L.M., H.E.S.); and The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.K.J., E.L.E., D.B.S., D.L.M., H.E.S.)

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 agonist BuTAC [([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl-]-1-azabyciclo-[3.2.1])octane oxalate] reversed the apomorphine-induced 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 [[2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride], 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-(+)-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.

Address correspondence to: Dr. Harlan E. Shannon, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: h.shannon{at}lilly.com

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