Effects of donepezil on DOI-induced head twitch response in mice: implications for Tourette syndrome

Tourette syndrome (TS) is a neurological disorder characterized by persistent motor and phonic tics. Administration of the selective 5-HT(2A/2C) agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induces head twitches in mice that have been proposed to model tics seen in TS. Previous studies have demonstrated that nicotine markedly attenuates DOI-induced head twitch response (HTR). This and the reports that nicotine may have clinical efficacy in reducing symptoms of TS suggest possible involvement of the nicotinic cholinergic system in this disorder. Donepezil is an acetylcholinesterase inhibitor approved for use in mild to moderate Alzheimer's disease. The purpose of this study was to investigate whether donepezil might also reduce DOI-induced HTR, and whether its combination with nicotine might result in an additive or synergistic effect. Moreover, to elucidate the possible role of nicotinic receptors in this paradigm, the effects of mecamylamine, a nicotinic antagonist, was also evaluated. Acute and chronic administration of donepezil (0.1 mg/kg) or nicotine (0.5 mg/kg base), significantly reduced DOI-induced HTR. No additive or synergistic effects of donepezil and nicotine were observed. Acute mecamylamine administration (0.5-5.0 mg/kg) dose-dependently inhibited DOI-induced HTR. None of the mecamylamine doses blocked the inhibitory effects of donepezil or nicotine on DOI-induced HTR. These results suggest that donepezil may have therapeutic potential in treating motor tic symptoms of TS. Moreover, the action of donepezil and nicotine may be mediated through the same mechanism.