Why an M1 Antagonist Could Be a More Selective Model for Memory Impairment than Scopolamine

Citation: Blokland A, Sambeth A, Prickaerts J and Riedel WJ (2016) Why an M1 Antagonist Could Be a More Selective Model for Memory Impairment than Scopolamine. Since the early studies of Deutsch (1), the non-selective muscarinic receptor antagonist sco-polamine has been used as a drug that impairs memory performance in man. The notion that scopolamine could be used as a pharmacological model of age-associated memory impairment and dementia further strengthened the cholinergic hypothesis of geriatric memory dysfunction by Bartus et al. (2). Since then, a vast amount of studies applied this model to induce memory impairments in young healthy subjects to model age-related memory disorders. At present, scopolamine is still considered to be the best model for inducing cognitive impairments in healthy subjects (3). Scopolamine is therefore used as a pharmacological model to test novel cognition-enhancing drugs in animals [e.g., Ref. (4–6)] and in humans [e.g., Ref. (7, 8)]. In clinical trials, scopolamine is in particular being used as a model for AD in which novel cognition-enhancing drugs are tested (see https://ClinicalTrials.gov). Further efforts have been made to compare human and animal data with scopolamine to further validate the scopolamine as a model of cognitive impairments. For example, comparable tests were developed for humans and animals to allow cross-species comparison [e.g., Ref. (9, 10)]. Another effort is comparing scopolamine effects on brain imaging parameters (11, 12). These studies reveal great cross-species similarities in the effects of scopolamine in comparable cognitive tasks in humans and animals, and that the effects on central blood flow is also comparable. These studies have resulted in a huge database in which the effects of scopolamine on cognitive and non-cognitive functions have been documented. This also relates to doses and routes of administration. Furthermore, interactions with various other drugs (also non-cholinergic) have been documented, which supports the notion of drug interactions in memory functions. Taken together, scopolamine is considered as a golden standard for cholinergic deficits and the existing data were used as a reference for evaluating novel cognition-enhancing drugs. Although scopolamine has this established (gold standard) status, there are also some important issues related with this drug. A first point is that scopolamine is binding to both peripheral and central muscarinic receptors [see Ref. (13)]. Thus, scopolamine binds to all five different muscarinic receptors which are located in the brain as well in the peripheral system. This may relate to the various side effects that …