NICOTINE MECHANISMS IN ALZHEIMER’S DISEASE

Overview of Nicotinic Receptors and Their Roles in theCentral Nervous System

John A. Dani

Alzheimer’s disease is a complex disorder affecting mul-tiple neurotransmitters. In particular, the degenerativeprogression is associated with loss within the cholinergicsystems. It should be anticipated that both muscarinic andnicotinic mechanisms are affected as cholinergic neuronsare lost. This review focuses on the basic roles of neuronalnicotinic receptors, some subtypes of which decreaseduring Alzheimer’s disease. Nicotinic acetylcholine recep-tors belong to a superfamily of ligand-gated ion channelsthat play key roles in synaptic transmission throughout thecentral nervous system. Neuronal nicotinic receptors,however, are not a single entity, but rather there are manydifferent subtypes constructed from a variety of nicotinicsubunit combinations. This structural diversity and thepresynaptic, axonal, and postsynaptic locations of nico-tinic receptors contribute to the varied roles these recep-tors play in the central nervous system. Presynaptic andpreterminal nicotinic receptors enhance neurotransmitterrelease, and postsynaptic nicotinic receptors mediate asmall minority of fast excitatory transmission. In addition,some nicotinic receptor subtypes have roles in synapticplasticity and development. Nicotinic receptors are dis-tributed to influence many neurotransmitter systems atmore than one location, and the broad, but sparse,cholinergic innervation throughout the brain ensures thatnicotinic acetylcholine receptors are important modula-tors of neuronal excitability. Biol Psychiatry 2001;49:166–174 ©2001 Society of Biological Psychiatry

Key Words: Acetylcholine, nicotine, Alzheimer’s dis-ease, tobacco, addiction, plasticity

Introduction

Nicotinic acetylcholine receptors (nAChRs) belong tothe superfamily of ligand-gated ion channels that

includesg-aminobutyric acid A (GABAA), glycine, andserotonin 3 (5-HT3) receptors (Albuquerque et al 1997;Dani 2000; Dani and Heinemann 1996; Dani and Mayer1995; Jones et al 1999; Lena and Changeux 1998; Lind-strom 1997; Lindstrom et al 1996; Luetje et al 1990;McGehee and Role 1995; Role and Berg 1996; Sargent

1993; Wonnacott 1997). Agonists, such as endogenousacetylcholine or exogenous nicotine, stabilize the openconformation of the nAChR channel, which transientlypermeates cations before closing back to a resting state orto a desensitized state that is unresponsive to agonists.

Multiple Subunits Produce NicotinicReceptor Diversity

The structure of the nicotinic receptor–channel complexarises from five polypeptide subunits assembled likestaves of a barrel around a central water-filled pore(Cooper et al 1991). Although various subunit combina-tions can produce many different nAChR subtypes, thenicotinic receptor/channel family can be separated intothree general functional classes that are consistent withtheir evolutionary development and their pharmacologicand physiologic properties: muscle subunits (a1, b1, d, e,g), which are not discussed here; standard neuronalsubunits (a2–a6 and b2–b4) that form nAChRs inabcombinations; and subunits (a7–a9) capable of forminghomomeric nAChRs that are inhibited bya-bungarotoxin(Colquhoun and Patrick 1997; Le Nove`re and Changeux1995; McGehee and Role 1995). In the third classification,only thea7 subunit (nota8 or a9) is widely distributed inthe mammalian central nervous system (CNS). There isevidence that subunits from the separate classes maycombine to form nAChRs, possibly making these group-ings less than perfectly distinct (Girod et al 1999; Yu andRole 1998; Zoli et al 1998).

Heterologous expression systems have been used todetermine possible combinations of nAChR subunits ca-pable of forming active ion channels (McGehee and Role1995; Patrick et al 1993). Those studies indicated group-ings of nAChRs that are easily formed in theXenopusoocyte expression system:a7 homomeric receptors, het-erodimericab nAChRs formed by a combination ofasubunits (a2, a3, or a4) andb subunits (eitherb2 or b4),and complex receptors that include more than one type ofa or b subunit (e.g.,a4b2b4). This third group ofcomplex combinations also includes nAChRs containingsubunits such asa5 and b3 that do not form channelswhen they are expressed alone or in combination with anyother singlea or b subunit (e.g.,a4a5b2) (Conroy andBerg 1995; Conroy et al 1992; Ramirez-Latorre et al

From the Division of Neuroscience, Baylor College of Medicine, Houston, Texas.Address reprint requests to John A. Dani, Division of Neuroscience, Baylor College

of Medicine, Houston TX 77030-3498.Received May 25, 2000; accepted July 11, 2000.

© 2001 Society of Biological Psychiatry 0006-3223/01/$20.00PII S0006-3223(00)01011-8

1996). a6 can rarely form anab receptor, and it alsoparticipates in more complex combinations (Gerzanich etal 1997). Evidence indicates that thea7 subunit can alsoform more complex combinations (Girod et al 1999; Yuand Role 1998; Zoli et al 1998). The basic conclusiondrawn from expression systems is that a limited number ofsubunit combinations are favored, but more rare combina-tions are possible. There is tremendous potential fornAChR diversity within the CNS.

There are some general rules, and these can be appliedwhen trying to simplify the influence of particular sub-units. For example,a7 homomeric nAChRs have highcalcium permeability and rapid activation and desensitiza-tion kinetics, and they are specifically inhibited bya-bun-garotoxin and methyllycaconitine (Alkondon et al 1992;Castro and Albuquerque 1995; Gray et al 1996). NicotinicAChRs with similar properties are found in the hippocam-pus and other neuronal regions, consistent with the hy-pothesis thata-bungarotoxin binding sites representa7-containing nAChRs (Albuquerque et al 1997; Alkondonand Albuquerque 1993; Lindstrom 1997; Lindstrom et al1996; Samuel et al 1997; Zarei et al 1999). Supporting thathypothesis,a-bungarotoxin binding sites were not de-tected ina7-knockout mice (Orr-Urtreger et al 1997). Thehigh-affinity [3H]nicotine binding sites, however, werestill present. Most high-affinity [3H]nicotine sites appearto containa4 and b2 subunits, and possibly some alsocontain additional subunits. These high-affinity sites arelost after knockout of theb2 subunit (Zoli et al 1998). Inmice lacking theb2 subunit, other lower affinity nicotinebinding sites are revealed, and these sites are likely tocontain thea3 subunit.

Expression of nAChRs in the CNS

Most nAChRs in the mammalian brain contain eithera4b2 or a7 (Charpantier et al 1998; Cimino et al 1992;Clarke et al 1985; Schoepfer et al 1990; Se´guela et al1993; Wada et al 1989, 1990). Although many of thenAChRs containa4 andb2 subunits, agonist and antago-nist profiles differ for cells derived from different nuclei.For example, both medial habenula and locus coeruleusneurons express functional nAChRs with a pharmacologicprofile that is consistent witha3 andb4 subunits in thoseregions (Mulle et al 1991). Studies indicate that there arefew b2 subunits contributing to medial habenular nAChRs(Quick et al 1999). Another example is thata7-containingnAChRs mediate the predominant nicotinic current inhippocampal neurons, but other nAChR responses may beattributable to a4b2-containing, a3b4-containing, andother nAChRs (Albuquerque et al 1997; Alkondon andAlbuquerque 1993; Zarei et al 1999; Zoli et al 1998).These electrophysiology results are consistent with in situ

hybridization studies that indicated high expression ofa7and b2 throughout the rat hippocampus and weakerexpression ofa3, a4, a5, andb4 (Seguela et al 1993;Wada et al 1989, 1990; Zoli et al 1998).

Radiolabeled nicotinic ligands and in situ hybridizationfor nAChR messenger RNA indicate a wide, nonuniformdistribution of various subunits, and nuclei often containsubgroups of nAChR subunits (Charpantier et al 1998;Cimino et al 1992; Clarke et al 1985; Lena et al 1999; LeNovere et al 1996; Schoepfer et al 1990; Se´guela et al1993; Sihver et al 1998; Wada et al 1989, 1990). Althoughone class of nAChRs often predominates within a region,more than one class or subclass of nAChRs is oftenpresent (e.g., Pidoplichko et al 1997). In addition, individ-ual neurons often express multiple classes of nAChRs, andeven related neighboring neurons can express nicotinicresponses that are significantly different (Dani et al 2000).

Basic Functions of Nicotinic Receptors

Upon binding ACh, the nAChR ion channel is stabilized inthe open conformation for several milliseconds. Then theopen pore of the receptor/channel closes to a resting stateor closes to a desensitized state that is unresponsive toACh or other agonists for many milliseconds or more.While open, nAChRs conduct cations, which can cause alocal depolarization of the membrane and produce anintracellular ionic signal.

Although sodium and potassium carry most of thenAChR current, calcium can also make a significantcontribution (Castro and Albuquerque 1995; Decker andDani 1990; Dani and Mayer 1995; Se´guela et al 1993;Vernino et al 1992, 1994). Calcium entry through nAChRscan be biologically important and is different from cal-cium influx mediated by voltage-gated calcium channelsor by theN-methyl-D-aspartate (NMDA) subtype of glu-tamate receptors. Both voltage-gated calcium channels andNMDA receptors require membrane depolarization to passcurrent freely. At hyperpolarized (negative) potentials,voltage-gated calcium channels generally do not open andNMDA receptors are blocked by extracellular magnesiumions. Nicotinic nAChRs do open and pass current freely atnegative potentials that provide a strong voltage forcedriving cations into the cell. Thus, calcium currentsmediated by nAChRs can have a different voltage depen-dence than is seen for other calcium-permeable ion chan-nels. Also, incoming calcium has a different spatial distri-bution that depends on the location of nAChRs on the cellsurface.

The most basic conformational states of nAChRs arethe closed state at rest, the open state, and the desensitizedstate. The rate at which the nicotinic receptor proceedsthrough the various conformational states and the

Nicotine Receptors in the CNS 167BIOL PSYCHIATRY2001;49:166–174

selectivity with which it conducts cations in the open statedepend on many factors, including the subunit composi-tion. Therefore, the extensive nAChR diversity has thepotential to produce many different responses to endoge-nous or exogenous agonists. The speed of activation, theintensity of the membrane depolarization, the size of theionic signal, the rates of desensitization and recovery fromdesensitization, the pharmacology, and the regulatorycontrols of the ACh response will all depend on thesubunit composition of nAChRs as well as other localfactors. To add further complexity, the three basic confor-mational states (rest, open, and desensitized) do notaccount for the actual kinetic properties of nicotinicreceptors. Rather, there are multiple conformations in-volved in the gating. Desensitization, in particular, canencompass many time constants (Dani et al 2000; Fensteret al 1999b). Thus, there may be short- and long-lived

states of desensitization. Long exposures to low concen-trations of agonist will favor deeper levels of desensitiza-tion, and this situation is often the case for smokers, whomaintain low concentrations of nicotine throughout theday (Benowitz et al 1989; Benwell et al 1995; Clarke1990, 1991; Dani and Heinemann 1996; Ochoa et al 1990;Reitstetter et al 1999; Russell 1989; Wonnacott 1990).

In progressing through this section, our view of thenAChR has grown from an on-off switch regulatingcationic conductance to a sophisticated allosteric macro-molecule (Lena and Changeux 1993, 1998). Figure 1represents sites on a nAChR that can alter function.Competitive antagonists and partial agonists can occupythe agonist binding sites. Open channel blockers, such asphencyclidine, can bind within the pore, and there aremultiple sites for other noncompetitive inhibitors andmodulators. In addition, nAChRs are regulated by several

Figure 1. A representation of the allosteric sites on a nicotinicacetylcholine receptor (nAChR), a cut-away view showing threeof the five subunits that form the pentameric receptor–channelcomplex.

Figure 2. A representation of presynaptic nicotinic acetylcholinereceptors (nAChRs). The nAChRs are positioned so they caninfluence the release of another neurotransmitter, which isreleased by the presynaptic terminal (Pre) onto the postsynapticbouton (Postsynaptic). Evidence indicates that nAChRs initiatean increase of calcium in the presynaptic terminal. The calciumthen enhances the release of the neurotransmitter.

Figure 3. A representation of preterminal or axonal nicotinicacetylcholine receptors (nAChRs). The nAChRs are located in aposition along the axon arbor to indicate they could more easilyinfluence some presynaptic terminals while not affecting others.

Figure 4. A representation of fast nicotinic synaptic transmis-sion. Only nicotinic acetylcholine receptors (nAChRs) are rep-resented on the postsynaptic bouton in this simplified picture.Two presynaptic nAChRs are also shown.

168 J.A. DaniBIOL PSYCHIATRY2001;49:166–174

other factors, including peptide transmitters, various pro-tein kinases, the cytoskeleton, and calcium. Althoughcalcium modulation can act intracellularly (as is usuallythe case), nAChRs can also be allosterically modulated byextracellular calcium, leading to dramatic changes in thechannel opening probability (Adams and Nutter 1992;Amador and Dani 1995; Mulle et al 1992; Vernino et al1992). This modulation occurs over the physiologic con-centration range of external calcium. Therefore, highlevels of neuronal activity that can diminish extracellularcalcium (Heinemann et al 1990; Wiest et al 2000) couldcause a negative feedback that lowers the opening proba-bility of nAChRs.

Calcium modulation is well documented, but there isgreat potential for nAChR modulation by other allostericeffectors. This potential offers points of entry for thera-peutic drugs, such as those that can enhance nAChRactivity to assist Alzheimer’s disease (AD) patients. Pres-ently, cholinergic activity can be enhanced in patients withAD by antiacetylcholinesterase drugs that prolong the timethat ACh is present before being broken down. There isevidence, however, that some antiacetylcholinesterasedrugs (such as physostigmine and galantamine) can allo-sterically potentiate nAChRs (Maelicke and Albuquerque2000). Drugs that could act specifically to enhance theactivity of the required nAChR subtype, while also pro-longing the action of ACh, could be vital in combating thedebilitating effects of AD.

In addition to loss of nicotinic mechanisms, as seen inAD (Nordberg 1994; Paterson and Nordberg 2000; Perryet al 1995), there are other physiologic forms of regulationthat may become disrupted during pathologic conditions(Dani, in press; Dani and Heinemann 1996; Lena andChangeux 1998; Lindstrom 1997; Perry et al 1995; Stein-lein et al 1995). For example, during chronic tobacco use,low concentrations of nicotine cause certain neuronalnAChRs to increase in number and to accumulate in deepstates of desensitization (Fenster et al 1999c; Peng et al1994, 1997). Chronic desensitization may uncouple regu-latory mechanisms important for proper nAChR function-ing and promote incorrect recycling of receptors, therebyleading to an increase in the number of receptors. Inap-propriate changes in the expression of nAChRs may beimportant in the process of tobacco addiction.

Competing Processes of nAChR Activationand Desensitization

At a cholinergic synapse, approximately 1 mmol/L ACh israpidly released into the cleft, immediately activating thenicotinic receptors. In a few milliseconds, the ACh ishydrolyzed by acetylcholinesterase and/or diffuses away.The delivery and removal of ACh is very rapid, and

therefore desensitization is usually not thought to beimportant even though the desensitization process is com-plex. As neuronal nicotinic receptors are diverse andneuronal synapses are anatomically and compositionallyvaried, the role of desensitization in the brain is not wellunderstood and remains a difficult problem. Repeatedlyexposing a synapse to about 1 mmol/L ACh mightnormally produce little desensitization. If the synapticstimulation is extremely high, however, even though therates of recovery from desensitization are fast they maynot allow complete recovery (Dilger and Liu 1992; Fensteret al 1999b; Franke et al 1992). Furthermore, the break-down of ACh releases choline, which could reach locallyhigh concentrations. Higher concentrations of cholinecould desensitize a7-containing nicotinic receptors(Alkondon et al 1997b; Papke et al 1996).

The physiologic role of desensitization may becomeespecially important when considering the desensitizinglevels of nicotine that bathe the brains of smokers (Clarke1991; Dani and Heinemann 1996; Ochoa et al 1990) orwhen considering the effects of drugs that inhibit acetyl-cholinesterase (e.g., to treat patients with AD). Underthose two conditions, some nAChRs are likely to desen-sitize, but not in a uniform manner. At extremely activecholinergic synapses, nAChRs are more susceptible to thedesensitizing influence of the endogenous agonist (ACh).When high rates of cholinergic activity are occurring inconjunction with antiacetylcholinesterase or long expo-sures to nicotine, then the synaptic nAChRs are moresusceptible to desensitization. Evidence indicates thatlonger exposures to agonist allow slower rates of desen-sitization to come into play, such that some nicotinicreceptors can enter longer lasting desensitization (Lesterand Dani 1994; Reitstetter et al 1999).

If desensitization comes into play (normally, pathologi-cally, or owing to drugs), then the rate of synaptic firing willbe an important determinant of how much current enters thesynapse via nicotinic receptors per unit time. The highestsynaptic firing rates would not necessarily produce the mosteffective nicotinic signal because the nAChR would desen-sitize more at the highest rates (Dani et al 2000). Kineticparameters including desensitization depend on the subunitcomposition, and modulatory processes, such as proteinkinases, influence the nAChRs subtypes differently andselectively (Fenster et al 1999a; Paradiso and Brehm 1998).Depending on dynamic modulatory influences, differentnAChR subtypes might become particularly susceptible todesensitization, and the modulatory processes can vary fromsynapse to synapse. Thus, modulatory processes acting uponnAChRs could provide a continually varying, powerful,computational mechanism for manipulating how informationis processed at synapses.

The diversity of nAChRs and their distribution are

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important parameters of the nicotinic cholinergic systems.Creating drugs that discriminate nAChRs based on theirsubtype or location would be important for combatingspecific problems—for example, AD (Wang et al 2000) orforms of epilepsy (Dani 2000; Steinlein et al 1995).

Main Cholinergic Projections

Before looking further into the roles of nAChRs, we needto consider some of the basic properties of the cholinergicinnervation. Cholinergic systems provide diffuse innerva-tion to practically all of the brain, but a relatively smallnumber of cholinergic neurons innervate each neural area(Kasa 1986; Woolf 1991). Despite the sparse innervation,cholinergic activity drives or modulates a wide variety ofbehaviors. By initially acting on nAChRs, nicotine ornicotinic innervation can increase arousal, heighten atten-tion, influence rapid eye movement sleep, produce statesof euphoria, decrease fatigue, decrease anxiety, act cen-trally as an analgesic, transiently normalize sensory gatingin schizophrenic patients, and influence a number ofcognitive functions (Adler et al 1999; Everitt and Robbins1997; Levin 1992; Marubio et al 1999; Rose and Levin1991). It is thought that cholinergic systems particularlyaffect discriminatory processes by increasing the signal-to-noise ratio and by helping to evaluate the significanceand relevance of stimuli.

Although cholinergic neurons are distributed along theaxis from the spinal cord and brain stem to the basaltelencephalon, there are two major cholinergic projectsubsystems that can be identified. One cholinergic systemarises from neurons in the pedunculopontine tegmentumand the laterodorsal pontine tegmentum, providing wide-spread innervation mainly to the thalamus and midbrainareas and also descending innervation that reaches to thebrain stem. The second major cholinergic system arises inthe basal forebrain and makes broad projections mainlythroughout the cortex and hippocampus. In general, arelatively few cholinergic neurons make spare projectionsthat reach broad areas. Thus, the activity of a rather smallnumber of cholinergic neurons can influence relativelylarge neuronal structures.

Nicotinic Mechanisms in the CNS

The most widely observed synaptic role of nAChRs in theCNS is to influence neurotransmitter release. Figure 2depicts presynaptic nAChRs, which have been found toincrease the release of nearly every neurotransmitter thathas been examined (Albuquerque et al 1997; Alkondon etal 1997a; Gray et al 1996; Guo et al 1998; Jones et al1999; Li et al 1998; McGehee et al 1995; McGehee andRole 1995; Radcliffe and Dani 1998; Radcliffe et al 1999;

Role and Berg 1996; Wonnacott 1997). Exogenous appli-cation of nicotinic agonists can enhance and nicotinicantagonists can often diminish the release of ACh, dopa-mine, norepinephrine, and serotonin as well as glutamateand GABA. In many cases, thea7-containing nAChRs,which are highly calcium permeable, mediate the in-creased release of neurotransmitter, but in other casesdifferent nAChR subtypes are involved. In rat hippocam-pal slices and cultures, presynaptica7-containing nAChRswere shown to initiate a calcium influx that, consequently,enhances glutamate release from presynaptic terminals(Albuquerque et al 1997; Gray et al 1996). Intensenicotinic stimulation was able to enhance glutamate re-lease on multiple time scales, extending from seconds to afew minutes (Radcliffe and Dani 1998). Similar enhance-ments of release were obtained with a higher probability atGABAergic presynaptic terminals (Radcliffe et al 1999).The forms of enhancement lasting several minutes or morerequire that the incoming calcium acts as a second mes-senger to modify glutamatergic synaptic transmissionindirectly. Properly localized calcium influx mediated bynAChRs initiates enzymatic activity (such as proteinkinases and phosphatases) that is known to modify gluta-matergic synapses.

Figure 3 depicts nAChRs at a preterminal location,where they can also alter the release of various neurotrans-mitters. Particularly at GABAergic synapses, activation ofpreterminal nAChRs has been found to depolarize themembrane locally, leading to activation of voltage-depen-dent channels that directly mediate the synaptic calciuminflux underlying enhanced GABA release (Alkondon etal 1997a; Lena et al 1993). The agonist-induced effectmediated by preterminal nAChRs was inhibited by tetro-dotoxin, which blocks sodium channels and, thereby,prevents the regenerative voltage activation of calciumchannels in the presynaptic terminal. Axonal nAChRs mayalso modulate transmitter release and local excitability inanother way. As represented in Figure 3, strategicallylocated nAChRs might enable an action potential to invadeonly a portion of the axonal arbor. By directly exciting orby shunting the progress of an action potential at abifurcation, axonal nAChRs could initiate or alter thespread of neuronal excitation.

Figure 4 depicts direct, fast nicotinic synaptic transmis-sion. Fast nicotinic transmission has been detected as asmall excitatory input at several neuronal areas. In thehippocampus, fast nicotinic transmission onto GABAergicinterneurons has been reported (Alkondon et al 1998;Frazier et al 1998; Hefft et al 1999). In developing visualcortex, nicotinic transmission can be evoked onto bothglutamatergic pyramidal cells and GABAergic interneu-rons (Roerig et al 1997). Because nicotinic synapses havea low density, they are difficult to detect experimentally in

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brain slice preparations. Where it has been reported, fastnicotinic transmission is a minor component of the exci-tatory input, which is overwhelmingly glutamatergic. It islikely that nicotinic transmission is present at low densitiesin more neuronal areas than the few that have beenpresently reported. Although direct nicotinic excitation ofa neuron usually does not predominate, it could influencethe excitability of a group of neurons owing to the broadcholinergic projections into an area. Thus, beyond theirspecific roles at discrete synapses, nAChRs also modulateneuronal circuits in a broader sense.

An example of nicotinic modulation of circuit excitabil-ity was seen in the hippocampal slice (Ji and Dani 2000).While recording from CA1 pyramidal neurons, localapplication of nicotinic agonist onto interneurons causedboth inhibition and disinhibition. Activating nAChRs oninterneurons that directly innervated pyramidal neuronscaused inhibition of the pyramidal neuron, and activatinginterneurons that innervated mainly other interneuronscaused disinhibition. The disinhibition probably occurredbecause the nicotinic agonist activated interneurons thatthen inhibited other interneurons (Alkondon et al 1999).Consequently, GABAergic inhibitory activity decreased inthe area; thus, some pyramidal neurons were temporarilyreleased from their inhibitory inputs (i.e., disinhibition).

The results in the hippocampus indicate that, owing tothe broad projections by cholinergic neurons, nicotinicactivity can influence not just synaptic events but also theexcitability of neuronal areas (Dani 2000; Ji and Dani2000). By influencing circuits, nAChRs may modulate therhythmic activity in the hippocampus or in other regions.A property of hippocampal circuits is that they enter intodifferent rhythmic oscillations. For example, thetarhythms and gamma rhythms often occur during paradox-ical sleep or while awake rats explore their environments(Vanderwolf 1969). The periods of circuit activity thataccompany these rhythms provide opportunities for syn-aptic plasticity that underlies learning and memory(Huerta and Lisman 1993). Because interneurons areimportant determinants of the rhythmic oscillations andthey receive cholinergic afferents that can modulate therhythms (Csicsvari et al 1999; Dragoi et al 1999), it seemslikely that nAChRs influence the patterns of activity in thehippocampus and elsewhere.

Nicotinic AChRs also have roles during developmentand neuronal plasticity (Broide and Leslie 1999; Role andBerg 1996). The density of nAChRs varies during thecourse of development, and nAChRs can contribute toactivity-dependent calcium signals. For example, presyn-aptic a7-containing nAChRs increased the release ofglutamate preferentially onto postsynaptic NMDA recep-tors in the developing rat auditory cortex, but not in themature cortex (Aramakis and Metherate 1998). By en-

hancing glutamate release particularly at the locations ofNMDA receptors, nAChRs might help to modulate activ-ity-dependent synaptic plasticity that is often initiated bypostsynaptic NMDA receptors (Malenka and Nicoll 1999).Nicotinic regulatory, plasticity, and developmental influ-ences are particularly important when considering theetiology of disease. Biological changes that inappropri-ately alter nicotinic mechanisms could immediately influ-ence the release of many neurotransmitters and altercircuit excitability. However, nicotinic dysfunction couldhave long-term developmental consequences that are ex-pressed later in life.

In summary, the tremendous diversity of nAChRsprovides the flexibility necessary for them to play multi-ple, varied roles. Broad, sparse cholinergic projects ensurethat nicotinic mechanisms modulate the neuronal excit-ability of relatively wide circuits. Although fast nicotinictransmission is not the predominant driving force, it cancontribute excitatory input to many synapses at one time.Presynaptic and preterminal nAChRs modulate the releaseof all the major neurotransmitters that have been tested.During the progression of AD, cholinergic inputs degen-erate and the number of nAChRs in some areas decreases(Nordberg 1994; Perry et al 1995). Loss of nicotinicmechanisms, which modulate the gain and fidelity ofsynapses and modulate the excitability of circuits, arelikely to contribute to the overall cognitive deficits asso-ciated with AD.

Work from this laboratory is supported by National Institutes of Healthgrants from the National Institute on Drug Abuse (Nos. DA09411 andDA12661) and from the National Institute of Neurological Disorders andStroke (No. NS21229).

Aspects of the work were presented at the symposium “NicotineMechanisms in Alzheimer’s Disease,” March 16–18, 2000, Fajarko,Puerto Rico. The conference was sponsored by the Society of BiologicalPsychiatry through an unrestricted educational grant provided by JanssenPharmaceutica LP.

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