CNS NICOTINIC RECEPTORS - POSSIBLE THERAPEUTIC TARGETS IN NEURODEGENERATIVE DISORDERS

CNS nicotinic acetylcholine receptors are a family of ligand-gated cation channels that allow the passage of calcium ions. They are structurally and functionally distinct from nicotinic receptors at the neuromuscular junction, CNS nicotinic receptors show a variation in distribution and pharmacology. The number of these receptors is reduced with normal aging, and a further reduction in number occurs in dementing conditions that err common in elderly individuals. A comparison of receptor loss in the substantia nigra of patients with Parkinson's disease and Lewy body dementia indicates that this process may occur early in the disease and precede cell loss. In addition, nicotine binding sites in humans are concentrated in the entorhinal cortex and subicular formation, areas that are affected early in the course of Alzheimer-type disease. The number of nicotine binding sites is high in human neonatal brain, at which stage exposure to nicotine and tobacco smoke is deleterious. Conversely, epidemiological evidence suggests that later in life tobacco smoking may offer some protection against Parkinson's and Alzheimer's diseases. Exposure to nicotinic agonists and tobacco smoke increases the number of brain nicotinic receptors both in humans and experimental animals, although the functional significance of this and its precise relationship to receptor desensitisation is not completely understood. Acute exposure to nicotine and nicotinic antagonists has beneficial and adverse effects, respectively, on cognitive function. Subcutaneous administration of nicotine to patients with Alzheimer's disease improves discriminative sensitivity and reaction times. Available nicotinic agonists appear to induce diverse functional responses, and models for the testing of such novel compounds are needed.