Abstract
There is a growing body of evidence pointing to the pivotal role of alpha-7 nicotinic acetylcholine receptor (α7 nAchR) dysfunction in cognitive disorders such as Alzheimer’s disease or schizophrenia. This study was undertaken to establish and characterize an in vivo model for cognitive disorder secondary to the blockade of α7 nAChR by its specific antagonist, methyllycaconitine (MLA). The results show that MLA elicited cognitive dysfunction as assessed by reduced spontaneous alternation of mice in the T-maze. The maximal effect of MLA produced 25–30% reduction in the spontaneous alternation of mice, a level comparable with that induced by the muscarinic antagonism of scopolamine. Donepezil and galantamine fully reversed both MLA and scopolamine-induced cognitive dysfunction. However, the ED50 of donepezil and galantamine was significantly shifted to the left in the MLA- compared to scopolamine-treated mice (0.0005 and 0.002 mg/kg for donepezil; 0.0003 and 0.7 mg/kg for galantamine). Moreover, memantine elicited marked reversion of cognitive dysfunction (up to 70%) in MLA-treated mice while only a weak reversal effect at high dose of memantine (less than 20%) was observed in scopolamine-treated mice. The above findings indicate that MLA-induced cognitive dysfunction in the mouse is highly sensitive and more responsive to the current procognitive drugs than the traditional scopolamine-based assay. Thus, it can be of value for the preclinical screening and profiling of cognition-enhancing drugs.
Highlights
It is widely accepted that alpha-7 nicotinic acetylcholine receptor (a7 nAChR) plays a central role in cognitive deficits associated with neurodegenerative and cognitive disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia
The muscarinic antagonism of scopolamine remains the standard method for inducing cognitive deficits in animals and in healthy volunteers despite the accrued data pointing to the importance of a7 nAChR in cognitive dysfunction
We sought to characterize the cognitive dysfunction induced by MLA, a specific antagonist of the a7 nAChR
Summary
It is widely accepted that alpha-7 nicotinic acetylcholine receptor (a7 nAChR) plays a central role in cognitive deficits associated with neurodegenerative and cognitive disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia (for review see Conejero-Goldberg et al 2008; Pohanka 2012). In support of this concept, changes in the brain expression of a7 nAChR have been reported in patients with neurodegenerative diseases (Banerjee et al 2000; Guan et al 2000; Court et al 2001; Teaktong et al 2003; Yu et al 2005; Counts et al 2007; Olincy and Freedman 2012). Side by side comparison between cognitive deficit induced by scopolamine and by MLA was conducted with emphasis to the reversal effect of current cognitive-enhancing drugs, namely donepezil, galantamine, and memantine
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