The Critical Importance of Nicotinic Receptors in Cognition

Alfred Maelicke, Institute of Physiological Chemistry and Pathobiochemi- stry, Institute of Physiological Chemistry and Pathobiochemistry, Guten -berg University Medical School, Mainz, Germany

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized, at the structural level, by amyloid plaques and neurofibrillary tangles, and at the functional level, by a loss of nicotinic acetylcholine receptors (nAChRs). The level of nAChR loss correlates with the severity of the disease at the time of death.

The cholinergic deficit in AD can be therapeutically addressed in three ways; by inhibitors of the ACh-degrading enzyme acetylcholinesterase (AChE), by direct nicotinic agonists, and by allosteric potentiating ligands (APLs). Whereas inhibition of AChE and exposure to nicotinic agonists always carry some risk of receptor desensitization and of system adaptation, APL therapy does not interfere with the physiology of the cholinergic system, but rather enhances natural ACh-controlled nicotinic neurotransmission. Galantamine (Reminyl) is the prototype of a nicotinic APL, in addition of acting also as a modest AChE inhibitor.

It has long been recognized that AD is not only associated with cognitive impairment but also with other behavioral disturbances. It is interesting in this regard that nicotinic receptors are often located presynaptically on glutamatergic and GABAergic neurons and are capable of modulating the release of these neurotransmitters. Recently, it was demonstrated in patch-clamp studies of rat hippocampal and human cerebral cortical slices that the APL, galantamine can potentiate, via action on nAChRs, both glutamatergic and GABAergic transmission.

These effects are unrelated to the inhibition of AChE and thus are not shared with rivastigmine, donepezil, and metrifonate, which do not act as nicotinic APLs. Nicotine can also enhance attention and vigilance. Nicotinic receptor activation can reduce choice reaction time in AD patients and reduce apathy, which is a common symptom in AD. Evidence is mounting that enhanced dopamine release, produced by activation of presynaptic nicotinic receptors may be involved in these effects.

Galantamine has been shown to improve speed and accuracy of cognitive processes in AD patients and animal models. Recent evidence from Spanish and Italian research groups suggests that the activation of nicotinic receptors may also have neuroprotective effects.

In summary, the evidence suggests that galantamine, by acting as an APL at nAChRs, may have a therapeutic role in patients with AD by facilitating neurotransmission not only in the cholinergic system, but also in the glutamatergic and GABAergic systems, and by reducing Aβ neurotoxicity.