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.