Tricyclic antidepressants and peripheral anticholinergic activity

Interference with cholinergic function produces disruption of memory/cognitive (M/C) performance in both animals and man. It is uncertain whether this disruption is due to a specific relation of cholinergic neurons to M/C functions, or whether the effect is nonspecific, resulting either from alteration of alertness and attention, or from a "mass action" effect, with loss of functioning neurons. Scopolamine was given to normal subjects to produce an M/C impairment. Half the test subjects then received physostigmine and half d-amphetamine. Physostigmine, a pharmacologic antagonist of scopolamine, markedly improved M/C functions; amphetamine failed to produce M/C improvement, although alertness was improved, and activity in catecholaminergic neurons presumably increased. This comparison supports a specific role for cholinergic neurons in M/C processes. Possible mechanisms of cholinergic neural functioning in memory include plasticity of cholinergic synapses, as well as other acetylcholine-depended operations of the limbic system crucial to memory.

Arecholine (4 milligrams), a cholinergic agonist, and choline (10 grams), a precursor of acetylcholine, significantly enhanced serial learning in normal human subjects. The subjects received methscopolamine prior to both arecholine and placebo injections. Conversely, scopolamine (0.5 milligram), a cholinergic antagonist, impaired learning and this impairment was reversed by arecholine and choline and the impairment after scopolamine were inversely proportional to the subject's performance on placebo; that is, "poor" performers were more vulnerable to both the enhancing effect of cholinergic agonist and precursor and the impairment after cholinergic antagonist than "good" performers.