Galantamine (Reminyl) represents the first of a new class of medications for the treatment of disorders involving abnormalities of transduction of the acetylcholine signal at nicotinic receptors--a category of disorders that includes Alzheimer's disease (AD). These disorders could result, in part, from pathologic conditions associated with a reduced density of nicotinic receptors--including receptors containing specific polypeptide subunits--due to cell death or diminished expression.

Alternatively, the disorders could result from expression of mutant receptor subunits with altered pharmacological properties, such as the affinity of ligand binding or channel characteristics. In addition to its ability to inhibit acetylcholinesterase, an enzyme mediating the hydrolytic cleavage of acetylcholine and termination of its synaptic actions, galantamine is a positive allosteric modulator of acetylcholine at nicotinic receptors (Erkinjuntti et al., 2002; Raskind et al., 2000). Thus, while galantamine cannot elicit ionic currents across nicotinic receptor-associated ionophores by itself, it does potentiate the receptor's responsiveness to acetylcholine at nonsaturating concentrations (Albuquerque et al., 1997). In this respect, galantamine's action resembles that of benzodiazepines; essentially, benzodiazepines such as diazepam (Valium) increase the likelihood that g-aminobutyric acid (GABA) will be successful at promoting chloride ion conductance. Similarly, galantamine increases the likelihood that acetylcholine will be successful in promoting channel opening and cationic conductance changes.

Nicotinic receptors are examples of ligand-gated ion channels, mediating fast-synaptic neurotransmission (i.e., cell-to-cell signaling changes occurring in a millisecond time frame). A ligand-gated channel is a potential pore or hole in the lipid bilayer membrane; the binding of a specific neurotransmitter to its agonist recognition site on the extracellular domain of the receptor determines whether the receptor-associated channel or potential pore will transiently assume an open or activated configuration (Albuquerque et al., 1997).

Most ligand-gated channels are complex pentameric proteins whose individual polypeptide subunits are derived from a common ancestral polypeptide. The polypeptide subunits are integral membrane proteins with extracellular, four transmembranous hydrophobic and intracytoplasmic domains. Transmembranous hydrophobic domains from each of the five constituent polypeptide subunits align themselves to create a potential pore or channel. The extracellular domains can be glycosylated at specific sites, and the intracytoplasmic domains have consensus amino acid sequences that serve as substrates for phosphorylation by a variety of protein kinases. Channel conductance and binding properties of the receptor can be modified by both glycosylation and phosphorylation. In fact, phosphorylation of intracytoplasmic domains may be a mechanism of "cross-talk" between different types of receptors. Specifically, the actions of some receptors mediating slow-synaptic neurotransmission (i.e., signaling events that may take seconds to minutes to evolve and are dependent on the synthesis of small soluble intracytoplasmic molecules) may modulate the channel properties of ligand-gated receptors by influencing the extent to which these latter receptors are enzymatically phosphorylated.

Further, regulation of ligand-gated ionic conductance can be influenced by allosteric modulators (e.g., in the case of the GABA_A receptors, these allosteric modulators can include benzodiazepines, barbiturates, neurosteriods and ethanol). Finally, channel properties can be influenced by the selective expression and incorporation of specific polypeptide receptor subunits into the functional channel. Thus, within given areas of the brain, the subunit composition of channels change as a function of normal brain development and in response to stress, hormonal, pharmacological and behavioral manipulations. The ability to change channel properties, including the binding characteristics of neurotransmitters and allosteric modulators, by glycosylation, phosphorylation, allosteric modulation and gene expression represents an enormous opportunity for plasticity or experience-dependent changes in neurotransmission.

The inclusion of the α7 receptor polypeptide subunit in the pentameric receptor protein confers upon the nicotinic receptor unique electrophysiological and pharmacological properties (Albuquerque et al., 2000, 1997; Mike et al., 2000). For example, the α7-containing channel can be distinguished from other subunits of nicotinic receptors by its increased sensitivity to inhibition by α-bungarotoxin and methyllycaconitine, permeability to calcium ions, and rapid kinetics of channel opening and receptor desensitization. In fact, electrophysiological recording of conductance changes mediated by acetylcholine through α7-containing nicotinic receptors, showing both rapid onset and decay, has a unique signature or tracing, referred to as type 1A currents. Interestingly, choline--the hydrolytic split product and precursor of acetylcholine--has been shown to be a selective agonist of α7-containing nicotinic receptors, mimicking type 1A electrophysiological responses. Apart from its important roles as a precursor of acetylcholine biosynthesis and constituent of cell membranes, choline may have an important role as a neurotransmitter, selectively stimulating nicotinic receptor-gated calcium ion entry into cells. Further, choline's selective neurotransmitter actions may arise rapidly and very locally within the region of cholinergic synapses as a result of hydrolytic cleavage of acetylcholine by acetylcholinesterase, an enzyme with remarkable catalytic efficiency and high substrate turnover number.

If this is so, there is a very real theoretical possibility that massive and almost complete inhibition of acetylcholinesterase activity, which is a major therapeutic target for AD, would have a very real downside (i.e., potential depletion of choline for the purposes of neurotransmission and selective α7-nicotinic stimulation) (Albuquerque et al., 1997). Further, in the healthy human brain, rapid desensitization of α7-containing nicotinic receptors in response to prolonged exposure to acetylcholine and choline serves an important regulatory mechanism of receptor-gated calcium ion entry. Alterations of intracytoplasmic concentrations of calcium must be carefully regulated because of the large number of calcium ion-dependent processes, including neurotransmitter release from presynaptic nerve terminals, the synthesis of important "retrograde" messengers such as nitric oxide, and the phosphorylation of proteins, among many others. However, in a diseased brain characterized by deficient or pathologic α7-containing nicotinic receptors, desensitization can exacerbate an already existing problem of defective receptor-mediated transduction of the acetylcholine signal. In addition to improving signal transduction, galantamine can also retard or prevent receptor desensitization; thus, nicotinic receptors will have a prolonged responsiveness to acetylcholine (Albuquerque et al., 1997).

This latter property of galantamine may be especially important in conditions associated with deficient numbers and/or defective receptors. The therapeutic efficacy of the dietary administration of choline in AD in earlier clinical trials may have been limited by the rapid desensitization of α7-containing nicotinic receptors to this selective ligand. In view of the availability of galantamine and its positive allosteric modulatory actions on nicotinic receptors, there may be renewed interest in dietary choline administration.

Galantamine may be the first representative of nicotinic receptor agonists, a new class of medications whose primary therapeutic action involves stimulation of acetylcholine/choline-gated ionic conductance. These medications might include other compounds with allosteric modulatory properties, in addition to selective full and partial nicotinic agonists. As noted, galantamine is distinguished from the other currently available cholinesterase inhibitors (donepezil [Aricept], rivastigmine [Exelon] and tacrine [Cognex]) by its positive allosteric modulatory properties at nicotinic acetylcholine receptors. Theoretically, this added property of galantamine should confer advantage over other cholinesterase inhibitors and encourage its exploration for both novel indications and therapeutic targets. However, as a group, empirical data support the efficacy of current cholinesterase inhibitors for the stabilization and reduction of the rate of progressive cognitive decline and functional impairment, and improvement of noncognitive behavioral and psychotic symptoms in patients with AD (Cummings, 2000; Trinh et al., 2003).

Due to its unique mechanism of action, galantamine is likely to be actively explored for a variety of expanded indications in addition to its approved indication for AD (Erkinjuntti et al., 2002). These expanded indications will likely include neuropsychiatric disorders with presumptive deficiencies or defects of nicotinic receptor-mediated neurotransmission.

Dr. Stephen Deutsch is professor and associate chair for the clinical neurosciences in the department of psychiatry at the Georgetown University School of Medicine. He is also director of the Mental Health Service Line at the Veterans Affairs Capitol Health Care Network.

Dr. Rosse is a facility service line manager at the VA Capitol Health Care Network's Mental Health Service Line.

Dr. Lynn Deutsch is professor in the department of psychiatry at the Georgetown University School of Medicine.

Ms. Eller is a program analyst at the VA Capitol Health Care Network's Mental Health Service Line.

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Albuquerque EX, Pereiria EF, Mike A et al. (2000), Neuronal nicotinic receptors in synaptic function in humans and rats: physiological and clinical relevance. Behav Brain Res 113(1-2):131-141.

Cummings JL (2000), Cholinesterase inhibitors: a new class of psychotropic compounds. Am J Psychiatry 157(1):4-15.

Erkinjuntti T, Kurz A, Gauthier S et al. (2002), Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial. Lancet 359(9314):1283-1290 [see comments].

Mike A, Castro NG, Albuquerque EX (2000), Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res 882(1-2):155-168.

Raskind MA, Peskind ER, Wessel T, Yuan W (2000), Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 54(12):2261-2268.

Trinh NH, Hoblyn J, Mohanty S, Yaffe K (2003), Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer disease: a meta-analysis. JAMA 289(2):210-216[see comments].

A Galantamine Mechanism Primer