Tacrine is a potent and reversible inhibitor of
acetylcholinesterase (AChE) in the brain. It produces
tremor in animals, which is believed to be due to an increase in the brain
acetylcholine level following AChE inhibition. The present study was undertaken to investigate the involvement, if any, of
biogenic amines in the genesis of this motor dysfunction. Administration of
tacrine (10-20 mg/kg, i.p.) produced dose- and time-dependent
tremor in Balb/c mice. While in vivo inhibition of striatal AChE activity was observed only for the highest dose of
tacrine, a dose-dependent increase in striatal
choline acetyltransferase activity was obtained.
Serotonin (5-HT) levels, as assayed following a sensitive HPLC-electrochemical procedure, were significantly increased in nucleus caudatus putamen, nucleus accumbens, substantia nigra, nucleus raphe dorsalis, olivary nucleus and the cerebellum. However,
dopamine or
norepinephrine levels remained unaltered in these areas of the brain. In animals treated with
p-chlorophenylalanine, a specific
tryptophan hydroxylase inhibitor and
5-HT depletor,
tacrine failed to elevate the levels of
5-HT in the brain regions, and significantly attenuated
tremor response to the
drug.
Tacrine-induced
tremor was also significantly (83%) attenuated by 5-HT(2A/2C) receptor antagonist
mianserin (5 mg/kg, i.p.), but
methysergide (5 mg/kg, i.v.) could block
tacrine-induced
tremor only by 20%.
Atropine (5 mg/kg, i.p.) antagonized
tacrine-induced
tremor by about 53%, but a combination of
atropine and
mianserin completely blocked the
tremor response. These results indicate that the
cholinergic tremor produced by
tacrine in Balb/c mice is mediated via central serotonergic mechanisms, and stimulation of 5-HT(2A/2C) receptors plays a pivotal role in this motor dysfunction.