THE EFFECTS OF CHRONIC TACRINE THERAPY ON D-TUBOCURARINE BLOCKADE IN THE SOLEUS AND TIBIALIS MUSCLES OF THE RAT

Tacrine (THA) is an anticholinesterase drug used to manage Alzheimer's dementia, but it is not clear how its chronic use might affect respon se to nondepolarizing muscle relaxants. We determined the magnitude an d time course of the effects of chronic oral THA and of intravenous (I V) THA on d-tubocurarine (dTC) blockade at the soleus and tibialis mus cles. Six groups of adult rats were given 10 mg/kg THA twice daily by gavage for 1, 2, 4, or 8 wk (chronic THA groups), or 1 mL of saline tw ice daily by gavage for 1-8 wk (control), or IV THA approximately 20 m in before (acute), and the cumulative dose-response curves of dTC at t he tibialis and soleus muscles were determined during indirect train-o f-four stimulation in the anesthetized, mechanically ventilated rat. T he 50% effective dose (ED50) and 95% effective dose (ED95) of dTC in c ontrol rats were (mean +/- SD) 30 +/- 10 and 61 +/- 18 mu g/kg in the tibialis and 32 +/- 8 and 75 +/- 19 mu g/kg in the soleus; respectivel y. IV THA increased the ED95 of dTC 2.5- to 3-fold (P < 0.05) but did not alter the ED50. Chronic THA increased both the ED50 and ED95 of dT C 1.5- to 2-fold (P greater than or equal to 0.05), and this effect te nded to decrease with duration of THA therapy. We conclude that chroni c THA therapy in rats causes resistance to dTC, with a tendency for th e resistance to decrease with time, probably because of down-regulatio n of postsynaptic acetylcholine receptors. The same may apply to Alzhe imer's patients taking THA chronically.