Central cholinergic effects of tricyclic antidepressants in mouse

The apparent rate of acetylcholine (ACh) turnover and levels of ACh and choline (Ch) in whole mouse brain were examined 30 min following i.p. injection of 25 mg/kg of three tricyclic antidepressants (TAD's): amitriptyline, chlorimipramine, and imipramine. The effects of these agents on high affinity choline uptake (HACU), a rate-limiting, regulatory step in ACh synthesis, were also examined. All three TAD's inhibited ACh turnover (by 27-40%), increased Ch levels (by 33-37%), and inhibited HACU (IC50's from 1.7 - 6.8 X 10(-5) M). Two of the three drugs produced significant decreases in ACh levels. It is concluded that these agents possess anticholinergic activity which is independent of their previously demonstrated muscarinic receptor blocking capabilities. As substantial evidence has accumulated linking increased cholinergic function with depression, it is speculated that this additional anticholinergic activity may contribute to the clinical efficacy of the TAD's.