Oral tremor induced by galantamine in rats: A model of the parkinsonian side effects of cholinomimetics used to treat Alzheimer's disease

Abstract

Anticholinesterases are the most common treatment for Alzheimer's disease, and, in recent years, a new group of cholinesterase inhibitors (i.e. rivastigmine, galantamine, and donepezil) has become available. Although these drugs improve cognitive symptoms, they also can induce or exacerbate parkinsonian symptoms, including tremor. The present studies were conducted to determine if galantamine induces tremulous jaw movements, a rodent model of parkinsonian tremor, and to investigate whether these oral motor impairments can be reversed by co-administration of adenosine A2A antagonists. The first experiment demonstrated that systemic injections of galantamine (0.75–6.0mg/kg I.P.) induced a dose-related increase in tremulous jaw movements in rats. In a second study, co-administration of the muscarinic antagonist scopolamine (0.0156–0.25mg/kg I.P.) produced a dose dependent suppression of tremulous jaw movements induced by a 3.0mg/kg dose of galantamine, indicating that galantamine induces these tremulous oral movements through actions on muscarinic acetylcholine receptors. In two additional studies, analyses of freeze-frame video and electromyographic activity recorded from the lateral temporalis muscle indicated that the local frequency of these galantamine-induced jaw movements occurs in the 3–7Hz frequency range that is characteristic of parkinsonian tremor. In the final experiment, the adenosine A2A antagonist MSX-3 significantly attenuated the tremulous jaw movements induced by the 3.0mg/kg dose of galantamine, which is consistent with the hypothesis that co-administration of adenosine A2A antagonists may be beneficial in reducing parkinsonian motor impairments induced by anticholinesterase treatment.