Milameline

Abstract  RU 35926/CI‐979 (milameline) is a partial muscarinic agonist with promnestic effects in animal models. Preliminary animal studies suggest that this agent has the capacity to reverse cholinergic dysfunction and that it may impact on regional cerebral blood flow (rCBF). A total of 10 subjects with Alzheimer’s disease (AD) of mild severity underwent high resolution split‐dose single photon emission computed tomography (SPECT) during performance of a verbal recognition and control task, both before and after 18 weeks treatment with melameline or placebo. SPECT images were coregistered with individual’s magnetic resonance imaging scans allowing extraction of rCBF values from multiple anatomical regions of interest (ROI). The effect of milameline was examined in eight individuals who were found after unblinding to be taking active drug. Effects of milameline were most apparent in the frontal regions, basal ganglia and thalamus. In the group as a whole, the greatest increase in rCBF due to milameline treatment was observed in the left globus pallidus. Response to milameline treatment was associated with increases in rCBF in the cingulate gyrus bilaterally, and less so for the left thalamus. Milameline‐related increases in rCBF values were exaggerated by the verbal recognition task. Milameline has a demonstrable effect on cerebral blood flow in mild AD. Consistent with emerging animal data, the effects on rCBF appear most prominent in frontal and subcortical regions in AD subjects. The effects on rCBF appear to be augmented by the performance of a cognitively demanding task, raising the possibility that such tasks could assist in building an awareness of the functional neuropsychopharmacology of drugs designed for cognitive enhancement.

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.