Methyllycaconitine- and scopolamine-induced cognitive dysfunction: differential reversal effect by cognition-enhancing drugs

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.

Keywords: Alzheimer’s disease; cognitive disorders; donepezil; galantamine; memantine; muscarinic receptors; nicotinic.

Figure 1

Dose–response curves of scopolamine (A) and MLA (B), showing dose-dependent reduction in spontaneous alternation of mice in the T-maze. Hatched horizontal bar shows the range of performance level of control mice in the T-maze. Data are expressed as mean ± SEM of n = 10–12 mice. **P ≤ 0.01; ***P ≤ 0.001, significantly different as compared with the performance of control mice.

Figure 2

Dose–response curves of donepezil reversal of a scopolamine-induced deficit (square symbol) and an MLA-induced deficit (circle symbol) as assessed by the change in spontaneous alternation of mice in the T-maze. Data are expressed as mean ± SEM of n = 10 mice. **P ≤ 0.01, indicate significant difference between curves.

Figure 3

Dose–response curves of galantamine reversal of a scopolamine-induced deficit (square symbol) and an MLA-induced deficit (circle symbol) as assessed by the change in spontaneous alternation of mice in the T-maze. Data are expressed as mean ± SEM of n = 10 mice. ***P ≤ 0.001, indicate significant difference between curves.

Figure 4

Dose–response curves of memantine reversal of a scopolamine-induced deficit (square symbol) and an MLA-induced deficit (circle symbol) as assessed by the change in spontaneous alternation of mice in the T-maze. Data are expressed as mean ± SEM of n = 10 mice. ***P ≤ 0.001, indicate significant difference between curves.