Issue: The many types of nicotinic cholinergic receptors differ in their structure, function, location, response to drugs, and involvement in cognitive disorders such as Alzheimer's disease and schizophrenia.
In
this second part of a 2-part series, we present the role
of nicotinic cholinergic receptors in regulating
neurotransmission and in mediating cognitive functions in
health and disease. In part 1,
we discussed the structure of nicotinic
cholinergic receptors.1 Nicotinic Receptor Molecular SubtypesNicotinic receptors have an ever-increasing array of subtypes defined by which 5 of the many possible subunits are grouped together.1-3 Some of the best known examples and their hypothetical functions are shown in Figures 1 and 2. For example, outside the brain, unique nicotinic receptors are located postsynaptically in skeletal muscle where they mediate contraction of skeletal muscle.2,3 Other types of nicotinic receptors are located in the autonomic ganglia of the peripheral nervous system where they regulate the autonomic nervous system.2,3 In the brain, there are many subtypes of nicotinic receptors, and 2 of the most important are shown in Figures 3 and 4. The alpha4-beta2 subtype may be involved postsynaptically in excitatory neurotransmission.4 More of these receptors may be lost early in Alzheimer's disease than other nicotinic receptor subtypes.5 The alpha7 subtype is predominantly presynaptic6 and is located not only on cholinergic terminals, but also on the terminals of numerous noncholinergic neurons.7 These presynaptic alpha7 nicotinic receptors are responsible for generating very fast calcium currents and, when they do so, causing neurotransmitter release. Thus, alpha7 nicotinic receptors enhance not only acetylcholine release, but also the release of glutamate, serotonin, and other neurotransmitters.7 In addition, they may mediate dopamine release in response to nicotine, particularly in the nucleus accumbens, thereby activating the classic "reward" pathway and causing addiction to cigarettes.8 Nicotinic Receptor Pharmacologic SubtypesSince the molecular configurations of nicotinic receptors differ in various sites of the body and in various sites within the brain, it is theoretically possible that therapeutic agents could be found that would act at nicotinic receptors at some sites but not at others.2 If so, this might allow desirable CNS-mediated cognitive actions without undesirable peripherally mediated side effects.2,3 Although some drugs bind more readily to certain nicotinic receptors than to others, this pharmacologic binding affinity does not necessarily correlate specifically with molecular configurations.3 Nicotinic Receptors and CognitionNicotinic agonists improve attention in normal people and may improve cognitive function in patients with Alzheimer's disease.9 The alpha7 nicotinic receptors may inhibit beta-amyloid-induced neuronal death and thereby confer a neuroprotective action in Alzheimer's disease.10 In addition, strong genetic and pharmacologic evidence suggests that the alpha7 nicotinic receptor is involved in the attentional and cognitive deficit associated with schizophrenia, known as an auditory-gating deficit.11 Agonists of the alpha7 nicotinic receptor might reverse this dysfunction in schizophrenic patients, thereby improving cognition. SummaryDiscoveries of the functions of nicotinic receptors are occurring at a fast pace. A great deal of attention is being directed to one specific receptor subtype, the alpha7 nicotinic receptor, as a potential target for improving cognition in both Alzheimer's disease and schizophrenia.
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References1. Stahl SM. Paying attention to your acetylcholine, pt 1: structural organization of nicotinic receptors. J Clin Psychiatry 2000;61:547-548 2. Halladay MW, Dart MJ, Lynch JK. Neuronal nicotinic acetylcholine receptors as targets for drug discovery. J Med Chem 1997;40:4169-4194 3. Picciotto MR, Caldarone BJ, King SL, et al. Nicotinic receptors in the brain: links between molecular biology and behavior. Neuropsychopharmacology 2000;22:451-465 4. Clarke PBS, Schwartz RD, Paul SM, et al. Nicotinic binding in rat brain: autoradiographic comparison of 3H-acetylcholine, 3H-nicotine, and 125I-bungarotoxin. J Neurosci 1985;5:1307-1315 5. Martin-Ruiz CM, Court JA, Molnar E, et al. Alpha 4 but not alpha 3 or alpha 7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer's disease. J Neurochem 1999;73:1635-1640
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6. Albuquerque EX, Alkondon
M, Pereira EFR, et al. Properties of neuronal nicotinic
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