P4-352: The role of nicotinic receptors in human cognitive function

Abstract

In the 1970's evidence began to accumulate that nicotine was able to improve aspects of cognitive function in healthy volunteers. The definitive studies involved the administration of nicotine to non-smokers and required sensitive automated tests to identify these effects. This early work has been extensively replicated, and it is now widely accepted that nicotine improves various aspects of human attention and information processing. However, the evidence that nicotine can improve episodic memory in man remains weak. As the attentional enhancement produced by nicotine in volunteers can be blocked by scopolamine but not by haloperidol, this strongly supports a cholinergic mechanism underlying these effects. Such work has led to a closer scrutiny of the profile of cognitive deficits in dementias with a cholinergic basis, including Alzheimer's disease, Dementia with Lewy Bodies and Parkinson's dementia. Studies have shown attentional deficits to be central to all of the dementias with a cholinergic basis. Interest in nicotine has now given over to the selective receptor antagonists. Trials of α7 nicotinic agonists (eg GTS-21, MEM 3454) have found that besides enhancing attention in volunteers, these compounds also improve aspects of episodic secondary memory. A similar profile of effects has emerged from trials with α4β2 nicotinic agonists (eg TC-1734/AZD-3480). The therapeutic potential of these findings has now been confirmed, TC-1734/AZD-3480 has shown the ability to improve attention and memory in both AAMI and MCI populations, and MEM-3454 in Alzheimer's patients. This work which spans three and a half decades will be reviewed. Some possible explanations for the broader range of cognitive effects of more specific receptor agonists will be considered.