The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

Abstract

Rationale The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. Objectives The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Materials and methods Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). Results The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 μg/kg in the DMTS task. Conclusions The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

Amyrin Attenuates Scopolamine-Induced Cognitive Impairment in Mice

“…20) Furthermore, scopolamine-induced cognitive impairment is reversed by AChE inhibitors in animals, which is known to improve cognitive function in AD. 21) Consistent with other studies, we observed that the acute administration of scopolamine impaired fear-based contextual long-term memory in the passive avoidance test. 22) Furthermore, the scopolamine-induced memory impairments were reversed by the single administration of α-and β-amyrin.…”

The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys

“…Donepezil treatment significantly improved PAL performance for the moderately difficult 3-3 trials but not for the easiest (2-2) or the most difficult (4-4) trials. This pattern is similar to the effects of donepezil seen in the NHP delayed match to sample task (Buccafusco et al, 2008) in which donepezil only improved scopolamine deficits at the small to moderate delays but not at the longer, most demanding delays. We believe that the lack of significant effect on the demanding (4-4) trials might simply be due to the smaller dynamic range between the scopolamine-and vehicletreated animals for those trials.…”

Procyanidins extracted from the lotus seedpod ameliorate scopolamine‐induced memory impairment in mice

“…As a muscarinic receptor antagonist, scopolamine can impair learning and to some degree memory processing (Flood and Cherkin, 1986). Acute and systemic administration of scopolamine in young animals can offer a suitable substitute to the cholinergic deficit in AD and aging, and has been widely used in animal pharmacological models for the preliminary evaluation of potential cognitionenhancing agents (Buccafusco et al, 2007). Accordingly, in the present study, the scopolamine models had a worse performance in behavioral tests.…”