Abstract
The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.
Highlights
During the last two decades, the primary approach to the symptomatic treatment of the cognitive decline in Alzheimer’s disease (AD) has been represented by the acetylcholinesterase inhibitors (AChEIs), aiming to relieve the cholinergic deficit by blocking the breakdown of the neurotransmitter acetylcholine (ACh)
The procognitive properties of antagonists of the 5-HT6 receptor have since been well-documented in preclinical animal models (Mitchell and Neumaier, 2005; Fone, 2008; Arnt et al, 2010; Meneses et al, 2011) that have suggested a potential benefit of combining a 5-HT6 receptor antagonist with an AChEI, as 5-HT6 receptor antagonism was shown to potentiate the neurochemical, electrophysiological, and procognitive effects of the AChEI donepezil (Marcos et al, 2008; Dawson, 2011; de Bruin et al, 2011)
The current data indicate that, whilst idalopirdine and donepezil recruit a discrete number of overlapping brain regions including one of the forebrain cholinergic nuclei, the synergistic effect of combining treatment extends beyond the effects of donepezil alone and the cholinergic system, toward recruitment of multiple neural circuits and neurotransmitter systems
Summary
During the last two decades, the primary approach to the symptomatic treatment of the cognitive decline in Alzheimer’s disease (AD) has been represented by the acetylcholinesterase inhibitors (AChEIs), aiming to relieve the cholinergic deficit by blocking the breakdown of the neurotransmitter acetylcholine (ACh). When combined with the use of 3D segmented, annotated, brain atlases, and computational analysis, it is possible to reconstruct distributed and integrated neural circuits or “finger prints” of brain activity These finger prints may be used to characterize the activity and function of new psychotherapeutics in preclinical development and to study the neurobiology of integrated neural circuits controlling cognition and emotion. To this end, the present study investigates the separate and combined effects of 5-HT6 receptor antagonism and AChE inhibition on general brain activity.
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