Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior

Abstract

Studies of the neurochemical pathology of Alzheimer's disease and Parkinson's disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with 10-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.