Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 50 million people worldwide. Since it is known that the hypofunction of cholinergic system is one of pathologies associated with AD, acetylcholinesterase inhibitors (AChIs) such as donepezil are used for symptomatic treatment of AD; however, these drugs are broadly associated with increased risk for gastrointestinal adverse events, such as nausea and vomiting. Insufficient control of nausea and vomiting affects the ability to continue the AChIs therapy. We reported that pica, kaolin ingestion behavior, could be used to evaluate nausea and vomiting in mice. In this study, we investigated the effects of donepezil on pica in mice and the effects of anti-emetic drugs on inhibition of donepezil-induced pica.
Male mice were consecutively administered donepezil (5 mg/kg; i.p.) for 5 days, and their kaolin intakes were measured. Additionally, we examined the effects of a serotonin 5-HT₃ (granisetron: 0.5 or 1 mg/kg, i.p.), dopamine D₂ (metoclopramide 2.5 or 5 mg/kg; i.p.) and muscarinic (butylscopolamine 5 or 10 mg/kg: i.p.) receptor antagonists on the donepezil-induced pica. We found mice showed pica after 3 days of donepezil administration. Among the tested anti-emetic drugs, metoclopramide at the dose of 2.5 mg/kg significantly inhibited the pica in mice.
These results suggest donepezil-induced pica in mice has the potential to reflect donepezil-induced nausea and vomiting and dopaminergic pathway is involved in the development of in donepezil-induced nausea and vomiting human patients.