You Don't Know Nicotine: Novel Applications of Nicotinic Therapeutics in Aging

Abstract

Overall AbstractNicotine binds to nicotinic cholinergic receptors in the brain and the periphery. These receptors are ligand-gated ion channels that modulate other neurotransmitter systems and have important roles in cognitive and emotional functioning. Recent advances have expanded the understanding of how stimulation or blockade of nicotinic receptors affects brain activity, cortical networks, and behavior. While nicotine has been mostly thought of as a substance of abuse connected to tobacco smoking, the potential exists for utilizing nicotine and/or nicotinic stimulation as a therapeutic agent for the treatment of a variety of brain disorders. This symposium will present recent advances in the understanding of how nicotine and nicotinic drugs affect the brain and explore the possible utilization of nicotine for age-related brain disorders. While nicotinic therapeutics has a history dating back to the 1920s, work began in earnest in the 1980s with examining nicotine in Alzheimer's disease. This continued with the development of receptor-selective nicotinic agonists targeted towards Alzheimer’ disease, ADHD, and schizophrenia. These efforts failed, in part because of limited understanding of the appropriate brain system neural targets as well as lack of clarity as to whether the drugs engaged these targets in a meaningful way.Recent research has significantly expanded our understanding of the neural circuitry affected by nicotine and nicotinic stimulation and better human and animal models have offered new insights into the potential for nicotine therapeutics in areas as disparate as hearing loss and stress response mechanisms. Nicotine is now being investigated for its potential in age-related disorders including memory impairment, late life depression, cognitive impairment following cancer treatment and COVID, and age-related hearing loss. The symposium will examine how the effects of nicotine on cognitive functioning differ between older versus younger individuals to explore how nicotinic stimulation benefits may be age specific. We will also present the background and progress of the MIND study, a multi-center nicotine treatment study for mild cognitive impairment, the largest and longest nicotine study of non-smokers ever conducted. New clinical and neural evidence for nicotine as an augmentation treatment for late life depression and the cognitive deficits that accompany this condition will be discussed. Finally, the use of translational animal-human models for discerning the potential beneficial effects of nicotine and the potential for combination therapies to enhance the beneficial effects of nicotine will be presented. These studies of nicotine have broad clinical and scientific significance. If the hypotheses are validated, this will support a novel, broadly available, and inexpensive repurposed intervention for age-related brain disorders and would encourage early treatment to improve symptoms, retard progression of cognitive impairment or improve mood, and lead to combined trials with other agents for brain disorders of aging.