This study was designed to investigate the central and peripheral activity profile of
cholinesterase inhibitors in rats.
Intravenous injection of
cholinesterase inhibitors caused
fasciculation, a fine involuntary muscular movement. This peripheral
cholinergic sign was tightly correlated with in vitro anti-
acetylcholinesterase activity by
cholinesterase inhibitors, suggesting that
fasciculation is a valid index of peripheral
cholinergic activation. Yawning, used as a marker of central
cholinergic activation, was also monitored.
E2030 (3-(2-(1-(1,3-dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2H-3,4-dihydro-1,3-benzoxazin-2,4-dione hydrochloride) elicited yawning at more than 4 mg/kg, while
fasciculation was significantly intensified only at a dose of 16 mg/kg.
Donepezil and
tacrine induced both yawning and
fasciculation at doses greater than 4 mg/kg, whereas
physostigmine induced both behaviors at a dose of 8 mg/kg and above. Finally,
ipidacrine elicited yawning at a dose of 16 mg/kg and
fasciculation at doses greater than 8 mg/kg. Thus, all putative centrally acting
cholinesterase inhibitors elicited yawning.
TAK-147 (3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-benzazepin-8-yl)-1-propanone
fumarate) did not significantly elicit yawning at doses under 16 mg/kg, but elicited
fasciculation at a dose of more than 4 mg/kg.
Distigmine, a peripherally acting
cholinesterase inhibitor, evoked
fasciculations, but not yawning. When mild to moderate
fasciculation was evoked,
donepezil and
E2030 elicited more than nine yawns over 30 min, while the other
cholinesterase inhibitors elicited approximately five yawns at most during this period. These results indicated that
E2030 and
donepezil exhibited the most marked preferential central
cholinergic activity, relative to peripheral activity, among
cholinesterase inhibitors tested.
Scopolamine, a centrally acting
antimuscarinic drug, completely inhibited E2030-induced yawning, while peripherally acting methylscopolamine did not.
Haloperidol, a
dopamine receptor antagonist, partially blocked E2030-induced yawning, but did not block
donepezil-induced yawning. These results suggest that central
cholinergic and, in part, dopaminergic mechanisms are involved in E2030-induced yawning.