Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly neuropsychiatric...

To evaluate the possible differential responsivity of Alzheimer patients to cholinergic agents, a series of pharmacologic challenge studies in 83 neuropsychiatric patients and controls were performed contrasting a cholinergic antagonist (scopolamine) with two cholinergic agonists (arecoline and nicotine). Alzheimer patients displayed significantly greater behavioral and cognitive responses to central cholinergic blockade at lower scopolamine doses than age-matched controls or elderly depressives. These differential changes could not be explained by group differences in the sedative, physiologic, or pharmacokinetic effects of the drug. In addition, the elderly, age-matched control subjects did reveal a profile of cognitive deficits at the highest dose (0.5 mg), which temporarily mimicked the baseline impairments found in early Alzheimer's disease. Together, these findings with scopolamine suggest an increased sensitivity to cholinergic blockade in Alzheimer's disease and demonstrate the first direct evidence of anticholinergic modelling of dementia in normal elderly subjects. To investigate further the postsynaptic cholinergic responsivity in Alzheimer's disease, patients were studied with arecoline and nicotine. While the cognitive effects of both agents were modest at best, there were significant differences in mood and behavioral responses between arecoline and nicotine in Alzheimer subjects. These behavioral changes occurred at much lower doses in the Alzheimer patients than those required in normal controls, once more supporting the notion of increased behavioral sensitivity to cholinergic agents in Alzheimer's disease. In addition, the differential mood effects between these two cholinergic agonists raise new questions about receptor selectivity in the cholinergic regulation of mood.