Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue3.2001:
NICOTINE MECHANISMS
IN
ALZHEIMER’S DISEASE
Overview of Nicotinic Receptors and Their Roles in the
Central Nervous System
John A. Dani
Alzheimer’s disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative
progression is associated with loss within the cholinergic
systems. It should be anticipated that both muscarinic and
nicotinic mechanisms are affected as cholinergic neurons
are lost. This review focuses on the basic roles of neuronal
nicotinic receptors, some subtypes of which decrease
during Alzheimer’s disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels
that play key roles in synaptic transmission throughout the
central nervous system. Neuronal nicotinic receptors,
however, are not a single entity, but rather there are many
different subtypes constructed from a variety of nicotinic
subunit combinations. This structural diversity and the
presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and
preterminal nicotinic receptors enhance neurotransmitter
release, and postsynaptic nicotinic receptors mediate a
small minority of fast excitatory transmission. In addition,
some nicotinic receptor subtypes have roles in synaptic
plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at
more than one location, and the broad, but sparse,
cholinergic innervation throughout the brain ensures that
nicotinic acetylcholine receptors are important modulators of neuronal excitability. Biol Psychiatry 2001;49:
166 –174 © 2001 Society of Biological Psychiatry
Key Words: Acetylcholine, nicotine, Alzheimer’s disease, tobacco, addiction, plasticity
Introduction
N
icotinic acetylcholine receptors (nAChRs) belong to
the superfamily of ligand-gated ion channels that
includes g-aminobutyric acid A (GABAA), glycine, and
serotonin 3 (5-HT3) receptors (Albuquerque et al 1997;
Dani 2000; Dani and Heinemann 1996; Dani and Mayer
1995; Jones et al 1999; Lena and Changeux 1998; Lindstrom 1997; Lindstrom et al 1996; Luetje et al 1990;
McGehee and Role 1995; Role and Berg 1996; Sargent
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
1993; Wonnacott 1997). Agonists, such as endogenous
acetylcholine or exogenous nicotine, stabilize the open
conformation of the nAChR channel, which transiently
permeates cations before closing back to a resting state or
to a desensitized state that is unresponsive to agonists.
Multiple Subunits Produce Nicotinic
Receptor Diversity
The structure of the nicotinic receptor– channel complex
arises from five polypeptide subunits assembled like
staves of a barrel around a central water-filled pore
(Cooper et al 1991). Although various subunit combinations can produce many different nAChR subtypes, the
nicotinic receptor/channel family can be separated into
three general functional classes that are consistent with
their evolutionary development and their pharmacologic
and physiologic properties: muscle subunits (a1, b1, d, e,
g), which are not discussed here; standard neuronal
subunits (a2–a6 and b2–b4) that form nAChRs in ab
combinations; and subunits (a7–a9) capable of forming
homomeric nAChRs that are inhibited by a-bungarotoxin
(Colquhoun and Patrick 1997; Le Nove`re and Changeux
1995; McGehee and Role 1995). In the third classification,
only the a7 subunit (not a8 or a9) is widely distributed in
the mammalian central nervous system (CNS). There is
evidence that subunits from the separate classes may
combine to form nAChRs, possibly making these groupings less than perfectly distinct (Girod et al 1999; Yu and
Role 1998; Zoli et al 1998).
Heterologous expression systems have been used to
determine possible combinations of nAChR subunits capable of forming active ion channels (McGehee and Role
1995; Patrick et al 1993). Those studies indicated groupings of nAChRs that are easily formed in the Xenopus
oocyte expression system: a7 homomeric receptors, heterodimeric ab nAChRs formed by a combination of a
subunits (a2, a3, or a4) and b subunits (either b2 or b4),
and complex receptors that include more than one type of
a or b subunit (e.g., a4b2b4). This third group of
complex combinations also includes nAChRs containing
subunits such as a5 and b3 that do not form channels
when they are expressed alone or in combination with any
other single a or b subunit (e.g., a4a5b2) (Conroy and
Berg 1995; Conroy et al 1992; Ramirez-Latorre et al
0006-3223/01/$20.00
PII S0006-3223(00)01011-8
Nicotine Receptors in the CNS
1996). a6 can rarely form an ab receptor, and it also
participates in more complex combinations (Gerzanich et
al 1997). Evidence indicates that the a7 subunit can also
form more complex combinations (Girod et al 1999; Yu
and Role 1998; Zoli et al 1998). The basic conclusion
drawn from expression systems is that a limited number of
subunit combinations are favored, but more rare combinations are possible. There is tremendous potential for
nAChR diversity within the CNS.
There are some general rules, and these can be applied
when trying to simplify the influence of particular subunits. For example, a7 homomeric nAChRs have high
calcium permeability and rapid activation and desensitization kinetics, and they are specifically inhibited by a-bungarotoxin and methyllycaconitine (Alkondon et al 1992;
Castro and Albuquerque 1995; Gray et al 1996). Nicotinic
AChRs with similar properties are found in the hippocampus and other neuronal regions, consistent with the hypothesis that a-bungarotoxin binding sites represent a7containing nAChRs (Albuquerque et al 1997; Alkondon
and Albuquerque 1993; Lindstrom 1997; Lindstrom et al
1996; Samuel et al 1997; Zarei et al 1999). Supporting that
hypothesis, a-bungarotoxin binding sites were not detected in a7-knockout mice (Orr-Urtreger et al 1997). The
high-affinity [3H]nicotine binding sites, however, were
still present. Most high-affinity [3H]nicotine sites appear
to contain a4 and b2 subunits, and possibly some also
contain additional subunits. These high-affinity sites are
lost after knockout of the b2 subunit (Zoli et al 1998). In
mice lacking the b2 subunit, other lower affinity nicotine
binding sites are revealed, and these sites are likely to
contain the a3 subunit.
Expression of nAChRs in the CNS
Most nAChRs in the mammalian brain contain either
a4b2 or a7 (Charpantier et al 1998; Cimino et al 1992;
Clarke et al 1985; Schoepfer et al 1990; Se´gue´la et al
1993; Wada et al 1989, 1990). Although many of the
nAChRs contain a4 and b2 subunits, agonist and antagonist profiles differ for cells derived from different nuclei.
For example, both medial habenula and locus coeruleus
neurons express functional nAChRs with a pharmacologic
profile that is consistent with a3 and b4 subunits in those
regions (Mulle et al 1991). Studies indicate that there are
few b2 subunits contributing to medial habenular nAChRs
(Quick et al 1999). Another example is that a7-containing
nAChRs mediate the predominant nicotinic current in
hippocampal neurons, but other nAChR responses may be
attributable to a4b2-containing, a3b4-containing, and
other nAChRs (Albuquerque et al 1997; Alkondon and
Albuquerque 1993; Zarei et al 1999; Zoli et al 1998).
These electrophysiology results are consistent with in situ
BIOL PSYCHIATRY
2001;49:166 –174
167
hybridization studies that indicated high expression of a7
and b2 throughout the rat hippocampus and weaker
expression of a3, a4, a5, and b4 (Se´gue´la et al 1993;
Wada et al 1989, 1990; Zoli et al 1998).
Radiolabeled nicotinic ligands and in situ hybridization
for nAChR messenger RNA indicate a wide, nonuniform
distribution of various subunits, and nuclei often contain
subgroups of nAChR subunits (Charpantier et al 1998;
Cimino et al 1992; Clarke et al 1985; Lena et al 1999; Le
Nove`re et al 1996; Schoepfer et al 1990; Se´gue´la et al
1993; Sihver et al 1998; Wada et al 1989, 1990). Although
one class of nAChRs often predominates within a region,
more than one class or subclass of nAChRs is often
present (e.g., Pidoplichko et al 1997). In addition, individual neurons often express multiple classes of nAChRs, and
even related neighboring neurons can express nicotinic
responses that are significantly different (Dani et al 2000).
Basic Functions of Nicotinic Receptors
Upon binding ACh, the nAChR ion channel is stabilized in
the open conformation for several milliseconds. Then the
open pore of the receptor/channel closes to a resting state
or closes to a desensitized state that is unresponsive to
ACh or other agonists for many milliseconds or more.
While open, nAChRs conduct cations, which can cause a
local depolarization of the membrane and produce an
intracellular ionic signal.
Although sodium and potassium carry most of the
nAChR current, calcium can also make a significant
contribution (Castro and Albuquerque 1995; Decker and
Dani 1990; Dani and Mayer 1995; Se´gue´la et al 1993;
Vernino et al 1992, 1994). Calcium entry through nAChRs
can be biologically important and is different from calcium influx mediated by voltage-gated calcium channels
or by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Both voltage-gated calcium channels and
NMDA receptors require membrane depolarization to pass
current freely. At hyperpolarized (negative) potentials,
voltage-gated calcium channels generally do not open and
NMDA receptors are blocked by extracellular magnesium
ions. Nicotinic nAChRs do open and pass current freely at
negative potentials that provide a strong voltage force
driving cations into the cell. Thus, calcium currents
mediated by nAChRs can have a different voltage dependence than is seen for other calcium-permeable ion channels. Also, incoming calcium has a different spatial distribution that depends on the location of nAChRs on the cell
surface.
The most basic conformational states of nAChRs are
the closed state at rest, the open state, and the desensitized
state. The rate at which the nicotinic receptor proceeds
through the various conformational states and the
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BIOL PSYCHIATRY
2001;49:166 –174
Figure 1. A representation of the allosteric sites on a nicotinic
acetylcholine receptor (nAChR), a cut-away view showing three
of the five subunits that form the pentameric receptor– channel
complex.
selectivity with which it conducts cations in the open state
depend on many factors, including the subunit composition. Therefore, the extensive nAChR diversity has the
potential to produce many different responses to endogenous or exogenous agonists. The speed of activation, the
intensity of the membrane depolarization, the size of the
ionic signal, the rates of desensitization and recovery from
desensitization, the pharmacology, and the regulatory
controls of the ACh response will all depend on the
subunit composition of nAChRs as well as other local
factors. To add further complexity, the three basic conformational states (rest, open, and desensitized) do not
account for the actual kinetic properties of nicotinic
receptors. Rather, there are multiple conformations involved in the gating. Desensitization, in particular, can
encompass many time constants (Dani et al 2000; Fenster
et al 1999b). Thus, there may be short- and long-lived
Figure 2. A representation of presynaptic nicotinic acetylcholine
receptors (nAChRs). The nAChRs are positioned so they can
influence the release of another neurotransmitter, which is
released by the presynaptic terminal (Pre) onto the postsynaptic
bouton (Postsynaptic). Evidence indicates that nAChRs initiate
an increase of calcium in the presynaptic terminal. The calcium
then enhances the release of the neurotransmitter.
J.A. Dani
Figure 3. A representation of preterminal or axonal nicotinic
acetylcholine receptors (nAChRs). The nAChRs are located in a
position along the axon arbor to indicate they could more easily
influence some presynaptic terminals while not affecting others.
states of desensitization. Long exposures to low concentrations of agonist will favor deeper levels of desensitization, and this situation is often the case for smokers, who
maintain low concentrations of nicotine throughout the
day (Benowitz et al 1989; Benwell et al 1995; Clarke
1990, 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 the
nAChR has grown from an on-off switch regulating
cationic conductance to a sophisticated allosteric macromolecule (Lena and Changeux 1993, 1998). Figure 1
represents sites on a nAChR that can alter function.
Competitive antagonists and partial agonists can occupy
the agonist binding sites. Open channel blockers, such as
phencyclidine, can bind within the pore, and there are
multiple sites for other noncompetitive inhibitors and
modulators. In addition, nAChRs are regulated by several
Figure 4. A representation of fast nicotinic synaptic transmission. Only nicotinic acetylcholine receptors (nAChRs) are represented on the postsynaptic bouton in this simplified picture.
Two presynaptic nAChRs are also shown.
Nicotine Receptors in the CNS
other factors, including peptide transmitters, various protein kinases, the cytoskeleton, and calcium. Although
calcium modulation can act intracellularly (as is usually
the case), nAChRs can also be allosterically modulated by
extracellular calcium, leading to dramatic changes in the
channel opening probability (Adams and Nutter 1992;
Amador and Dani 1995; Mulle et al 1992; Vernino et al
1992). This modulation occurs over the physiologic concentration range of external calcium. Therefore, high
levels of neuronal activity that can diminish extracellular
calcium (Heinemann et al 1990; Wiest et al 2000) could
cause a negative feedback that lowers the opening probability of nAChRs.
Calcium modulation is well documented, but there is
great potential for nAChR modulation by other allosteric
effectors. This potential offers points of entry for therapeutic drugs, such as those that can enhance nAChR
activity to assist Alzheimer’s disease (AD) patients. Presently, cholinergic activity can be enhanced in patients with
AD by antiacetylcholinesterase drugs that prolong the time
that ACh is present before being broken down. There is
evidence, however, that some antiacetylcholinesterase
drugs (such as physostigmine and galantamine) can allosterically potentiate nAChRs (Maelicke and Albuquerque
2000). Drugs that could act specifically to enhance the
activity of the required nAChR subtype, while also prolonging the action of ACh, could be vital in combating the
debilitating effects of AD.
In addition to loss of nicotinic mechanisms, as seen in
AD (Nordberg 1994; Paterson and Nordberg 2000; Perry
et al 1995), there are other physiologic forms of regulation
that may become disrupted during pathologic conditions
(Dani, in press; Dani and Heinemann 1996; Lena and
Changeux 1998; Lindstrom 1997; Perry et al 1995; Steinlein et al 1995). For example, during chronic tobacco use,
low concentrations of nicotine cause certain neuronal
nAChRs to increase in number and to accumulate in deep
states of desensitization (Fenster et al 1999c; Peng et al
1994, 1997). Chronic desensitization may uncouple regulatory mechanisms important for proper nAChR functioning and promote incorrect recycling of receptors, thereby
leading to an increase in the number of receptors. Inappropriate changes in the expression of nAChRs may be
important in the process of tobacco addiction.
Competing Processes of nAChR Activation
and Desensitization
At a cholinergic synapse, approximately 1 mmol/L ACh is
rapidly released into the cleft, immediately activating the
nicotinic receptors. In a few milliseconds, the ACh is
hydrolyzed by acetylcholinesterase and/or diffuses away.
The delivery and removal of ACh is very rapid, and
BIOL PSYCHIATRY
2001;49:166 –174
169
therefore desensitization is usually not thought to be
important even though the desensitization process is complex. As neuronal nicotinic receptors are diverse and
neuronal synapses are anatomically and compositionally
varied, the role of desensitization in the brain is not well
understood and remains a difficult problem. Repeatedly
exposing a synapse to about 1 mmol/L ACh might
normally produce little desensitization. If the synaptic
stimulation is extremely high, however, even though the
rates of recovery from desensitization are fast they may
not allow complete recovery (Dilger and Liu 1992; Fenster
et al 1999b; Franke et al 1992). Furthermore, the breakdown of ACh releases choline, which could reach locally
high concentrations. Higher concentrations of choline
could desensitize a7-containing nicotinic receptors
(Alkondon et al 1997b; Papke et al 1996).
The physiologic role of desensitization may become
especially important when considering the desensitizing
levels of nicotine that bathe the brains of smokers (Clarke
1991; Dani and Heinemann 1996; Ochoa et al 1990) or
when considering the effects of drugs that inhibit acetylcholinesterase (e.g., to treat patients with AD). Under
those two conditions, some nAChRs are likely to desensitize, but not in a uniform manner. At extremely active
cholinergic synapses, nAChRs are more susceptible to the
desensitizing influence of the endogenous agonist (ACh).
When high rates of cholinergic activity are occurring in
conjunction with antiacetylcholinesterase or long exposures to nicotine, then the synaptic nAChRs are more
susceptible to desensitization. Evidence indicates that
longer exposures to agonist allow slower rates of desensitization to come into play, such that some nicotinic
receptors can enter longer lasting desensitization (Lester
and Dani 1994; Reitstetter et al 1999).
If desensitization comes into play (normally, pathologically, or owing to drugs), then the rate of synaptic firing will
be an important determinant of how much current enters the
synapse via nicotinic receptors per unit time. The highest
synaptic firing rates would not necessarily produce the most
effective nicotinic signal because the nAChR would desensitize more at the highest rates (Dani et al 2000). Kinetic
parameters including desensitization depend on the subunit
composition, and modulatory processes, such as protein
kinases, influence the nAChRs subtypes differently and
selectively (Fenster et al 1999a; Paradiso and Brehm 1998).
Depending on dynamic modulatory influences, different
nAChR subtypes might become particularly susceptible to
desensitization, and the modulatory processes can vary from
synapse to synapse. Thus, modulatory processes acting upon
nAChRs could provide a continually varying, powerful,
computational mechanism for manipulating how information
is processed at synapses.
The diversity of nAChRs and their distribution are
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BIOL PSYCHIATRY
2001;49:166 –174
important parameters of the nicotinic cholinergic systems.
Creating drugs that discriminate nAChRs based on their
subtype or location would be important for combating
specific problems—for example, AD (Wang et al 2000) or
forms of epilepsy (Dani 2000; Steinlein et al 1995).
Main Cholinergic Projections
Before looking further into the roles of nAChRs, we need
to consider some of the basic properties of the cholinergic
innervation. Cholinergic systems provide diffuse innervation to practically all of the brain, but a relatively small
number of cholinergic neurons innervate each neural area
(Kasa 1986; Woolf 1991). Despite the sparse innervation,
cholinergic activity drives or modulates a wide variety of
behaviors. By initially acting on nAChRs, nicotine or
nicotinic innervation can increase arousal, heighten attention, influence rapid eye movement sleep, produce states
of euphoria, decrease fatigue, decrease anxiety, act centrally as an analgesic, transiently normalize sensory gating
in schizophrenic patients, and influence a number of
cognitive functions (Adler et al 1999; Everitt and Robbins
1997; Levin 1992; Marubio et al 1999; Rose and Levin
1991). It is thought that cholinergic systems particularly
affect discriminatory processes by increasing the signalto-noise ratio and by helping to evaluate the significance
and relevance of stimuli.
Although cholinergic neurons are distributed along the
axis from the spinal cord and brain stem to the basal
telencephalon, there are two major cholinergic project
subsystems that can be identified. One cholinergic system
arises from neurons in the pedunculopontine tegmentum
and the laterodorsal pontine tegmentum, providing widespread innervation mainly to the thalamus and midbrain
areas and also descending innervation that reaches to the
brain stem. The second major cholinergic system arises in
the basal forebrain and makes broad projections mainly
throughout the cortex and hippocampus. In general, a
relatively few cholinergic neurons make spare projections
that reach broad areas. Thus, the activity of a rather small
number of cholinergic neurons can influence relatively
large neuronal structures.
Nicotinic Mechanisms in the CNS
The most widely observed synaptic role of nAChRs in the
CNS is to influence neurotransmitter release. Figure 2
depicts presynaptic nAChRs, which have been found to
increase the release of nearly every neurotransmitter that
has been examined (Albuquerque et al 1997; Alkondon et
al 1997a; Gray et al 1996; Guo et al 1998; Jones et al
1999; Li et al 1998; McGehee et al 1995; McGehee and
Role 1995; Radcliffe and Dani 1998; Radcliffe et al 1999;
J.A. Dani
Role and Berg 1996; Wonnacott 1997). Exogenous application of nicotinic agonists can enhance and nicotinic
antagonists can often diminish the release of ACh, dopamine, norepinephrine, and serotonin as well as glutamate
and GABA. In many cases, the a7-containing nAChRs,
which are highly calcium permeable, mediate the increased release of neurotransmitter, but in other cases
different nAChR subtypes are involved. In rat hippocampal slices and cultures, presynaptic a7-containing nAChRs
were shown to initiate a calcium influx that, consequently,
enhances glutamate release from presynaptic terminals
(Albuquerque et al 1997; Gray et al 1996). Intense
nicotinic stimulation was able to enhance glutamate release on multiple time scales, extending from seconds to a
few minutes (Radcliffe and Dani 1998). Similar enhancements of release were obtained with a higher probability at
GABAergic presynaptic terminals (Radcliffe et al 1999).
The forms of enhancement lasting several minutes or more
require that the incoming calcium acts as a second messenger to modify glutamatergic synaptic transmission
indirectly. Properly localized calcium influx mediated by
nAChRs initiates enzymatic activity (such as protein
kinases and phosphatases) that is known to modify glutamatergic synapses.
Figure 3 depicts nAChRs at a preterminal location,
where they can also alter the release of various neurotransmitters. Particularly at GABAergic synapses, activation of
preterminal nAChRs has been found to depolarize the
membrane locally, leading to activation of voltage-dependent channels that directly mediate the synaptic calcium
influx underlying enhanced GABA release (Alkondon et
al 1997a; Lena et al 1993). The agonist-induced effect
mediated by preterminal nAChRs was inhibited by tetrodotoxin, which blocks sodium channels and, thereby,
prevents the regenerative voltage activation of calcium
channels in the presynaptic terminal. Axonal nAChRs may
also modulate transmitter release and local excitability in
another way. As represented in Figure 3, strategically
located nAChRs might enable an action potential to invade
only a portion of the axonal arbor. By directly exciting or
by shunting the progress of an action potential at a
bifurcation, axonal nAChRs could initiate or alter the
spread of neuronal excitation.
Figure 4 depicts direct, fast nicotinic synaptic transmission. Fast nicotinic transmission has been detected as a
small excitatory input at several neuronal areas. In the
hippocampus, fast nicotinic transmission onto GABAergic
interneurons has been reported (Alkondon et al 1998;
Frazier et al 1998; Hefft et al 1999). In developing visual
cortex, nicotinic transmission can be evoked onto both
glutamatergic pyramidal cells and GABAergic interneurons (Roerig et al 1997). Because nicotinic synapses have
a low density, they are difficult to detect experimentally in
Nicotine Receptors in the CNS
brain slice preparations. Where it has been reported, fast
nicotinic transmission is a minor component of the excitatory input, which is overwhelmingly glutamatergic. It is
likely that nicotinic transmission is present at low densities
in more neuronal areas than the few that have been
presently reported. Although direct nicotinic excitation of
a neuron usually does not predominate, it could influence
the excitability of a group of neurons owing to the broad
cholinergic projections into an area. Thus, beyond their
specific roles at discrete synapses, nAChRs also modulate
neuronal circuits in a broader sense.
An example of nicotinic modulation of circuit excitability was seen in the hippocampal slice (Ji and Dani 2000).
While recording from CA1 pyramidal neurons, local
application of nicotinic agonist onto interneurons caused
both inhibition and disinhibition. Activating nAChRs on
interneurons that directly innervated pyramidal neurons
caused inhibition of the pyramidal neuron, and activating
interneurons that innervated mainly other interneurons
caused disinhibition. The disinhibition probably occurred
because the nicotinic agonist activated interneurons that
then inhibited other interneurons (Alkondon et al 1999).
Consequently, GABAergic inhibitory activity decreased in
the area; thus, some pyramidal neurons were temporarily
released from their inhibitory inputs (i.e., disinhibition).
The results in the hippocampus indicate that, owing to
the broad projections by cholinergic neurons, nicotinic
activity can influence not just synaptic events but also the
excitability of neuronal areas (Dani 2000; Ji and Dani
2000). By influencing circuits, nAChRs may modulate the
rhythmic activity in the hippocampus or in other regions.
A property of hippocampal circuits is that they enter into
different rhythmic oscillations. For example, theta
rhythms and gamma rhythms often occur during paradoxical sleep or while awake rats explore their environments
(Vanderwolf 1969). The periods of circuit activity that
accompany these rhythms provide opportunities for synaptic plasticity that underlies learning and memory
(Huerta and Lisman 1993). Because interneurons are
important determinants of the rhythmic oscillations and
they receive cholinergic afferents that can modulate the
rhythms (Csicsvari et al 1999; Dragoi et al 1999), it seems
likely that nAChRs influence the patterns of activity in the
hippocampus and elsewhere.
Nicotinic AChRs also have roles during development
and neuronal plasticity (Broide and Leslie 1999; Role and
Berg 1996). The density of nAChRs varies during the
course of development, and nAChRs can contribute to
activity-dependent calcium signals. For example, presynaptic a7-containing nAChRs increased the release of
glutamate preferentially onto postsynaptic NMDA receptors in the developing rat auditory cortex, but not in the
mature cortex (Aramakis and Metherate 1998). By en-
BIOL PSYCHIATRY
2001;49:166 –174
171
hancing glutamate release particularly at the locations of
NMDA receptors, nAChRs might help to modulate activity-dependent synaptic plasticity that is often initiated by
postsynaptic NMDA receptors (Malenka and Nicoll 1999).
Nicotinic regulatory, plasticity, and developmental influences are particularly important when considering the
etiology of disease. Biological changes that inappropriately alter nicotinic mechanisms could immediately influence the release of many neurotransmitters and alter
circuit excitability. However, nicotinic dysfunction could
have long-term developmental consequences that are expressed later in life.
In summary, the tremendous diversity of nAChRs
provides the flexibility necessary for them to play multiple, varied roles. Broad, sparse cholinergic projects ensure
that nicotinic mechanisms modulate the neuronal excitability of relatively wide circuits. Although fast nicotinic
transmission is not the predominant driving force, it can
contribute excitatory input to many synapses at one time.
Presynaptic and preterminal nAChRs modulate the release
of all the major neurotransmitters that have been tested.
During the progression of AD, cholinergic inputs degenerate and the number of nAChRs in some areas decreases
(Nordberg 1994; Perry et al 1995). Loss of nicotinic
mechanisms, which modulate the gain and fidelity of
synapses and modulate the excitability of circuits, are
likely to contribute to the overall cognitive deficits associated with AD.
Work from this laboratory is supported by National Institutes of Health
grants from the National Institute on Drug Abuse (Nos. DA09411 and
DA12661) and from the National Institute of Neurological Disorders and
Stroke (No. NS21229).
Aspects of the work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajarko,
Puerto Rico. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaceutica LP.
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IN
ALZHEIMER’S DISEASE
Overview of Nicotinic Receptors and Their Roles in the
Central Nervous System
John A. Dani
Alzheimer’s disease is a complex disorder affecting multiple neurotransmitters. In particular, the degenerative
progression is associated with loss within the cholinergic
systems. It should be anticipated that both muscarinic and
nicotinic mechanisms are affected as cholinergic neurons
are lost. This review focuses on the basic roles of neuronal
nicotinic receptors, some subtypes of which decrease
during Alzheimer’s disease. Nicotinic acetylcholine receptors belong to a superfamily of ligand-gated ion channels
that play key roles in synaptic transmission throughout the
central nervous system. Neuronal nicotinic receptors,
however, are not a single entity, but rather there are many
different subtypes constructed from a variety of nicotinic
subunit combinations. This structural diversity and the
presynaptic, axonal, and postsynaptic locations of nicotinic receptors contribute to the varied roles these receptors play in the central nervous system. Presynaptic and
preterminal nicotinic receptors enhance neurotransmitter
release, and postsynaptic nicotinic receptors mediate a
small minority of fast excitatory transmission. In addition,
some nicotinic receptor subtypes have roles in synaptic
plasticity and development. Nicotinic receptors are distributed to influence many neurotransmitter systems at
more than one location, and the broad, but sparse,
cholinergic innervation throughout the brain ensures that
nicotinic acetylcholine receptors are important modulators of neuronal excitability. Biol Psychiatry 2001;49:
166 –174 © 2001 Society of Biological Psychiatry
Key Words: Acetylcholine, nicotine, Alzheimer’s disease, tobacco, addiction, plasticity
Introduction
N
icotinic acetylcholine receptors (nAChRs) belong to
the superfamily of ligand-gated ion channels that
includes g-aminobutyric acid A (GABAA), glycine, and
serotonin 3 (5-HT3) receptors (Albuquerque et al 1997;
Dani 2000; Dani and Heinemann 1996; Dani and Mayer
1995; Jones et al 1999; Lena and Changeux 1998; Lindstrom 1997; Lindstrom et al 1996; Luetje et al 1990;
McGehee and Role 1995; Role and Berg 1996; Sargent
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
1993; Wonnacott 1997). Agonists, such as endogenous
acetylcholine or exogenous nicotine, stabilize the open
conformation of the nAChR channel, which transiently
permeates cations before closing back to a resting state or
to a desensitized state that is unresponsive to agonists.
Multiple Subunits Produce Nicotinic
Receptor Diversity
The structure of the nicotinic receptor– channel complex
arises from five polypeptide subunits assembled like
staves of a barrel around a central water-filled pore
(Cooper et al 1991). Although various subunit combinations can produce many different nAChR subtypes, the
nicotinic receptor/channel family can be separated into
three general functional classes that are consistent with
their evolutionary development and their pharmacologic
and physiologic properties: muscle subunits (a1, b1, d, e,
g), which are not discussed here; standard neuronal
subunits (a2–a6 and b2–b4) that form nAChRs in ab
combinations; and subunits (a7–a9) capable of forming
homomeric nAChRs that are inhibited by a-bungarotoxin
(Colquhoun and Patrick 1997; Le Nove`re and Changeux
1995; McGehee and Role 1995). In the third classification,
only the a7 subunit (not a8 or a9) is widely distributed in
the mammalian central nervous system (CNS). There is
evidence that subunits from the separate classes may
combine to form nAChRs, possibly making these groupings less than perfectly distinct (Girod et al 1999; Yu and
Role 1998; Zoli et al 1998).
Heterologous expression systems have been used to
determine possible combinations of nAChR subunits capable of forming active ion channels (McGehee and Role
1995; Patrick et al 1993). Those studies indicated groupings of nAChRs that are easily formed in the Xenopus
oocyte expression system: a7 homomeric receptors, heterodimeric ab nAChRs formed by a combination of a
subunits (a2, a3, or a4) and b subunits (either b2 or b4),
and complex receptors that include more than one type of
a or b subunit (e.g., a4b2b4). This third group of
complex combinations also includes nAChRs containing
subunits such as a5 and b3 that do not form channels
when they are expressed alone or in combination with any
other single a or b subunit (e.g., a4a5b2) (Conroy and
Berg 1995; Conroy et al 1992; Ramirez-Latorre et al
0006-3223/01/$20.00
PII S0006-3223(00)01011-8
Nicotine Receptors in the CNS
1996). a6 can rarely form an ab receptor, and it also
participates in more complex combinations (Gerzanich et
al 1997). Evidence indicates that the a7 subunit can also
form more complex combinations (Girod et al 1999; Yu
and Role 1998; Zoli et al 1998). The basic conclusion
drawn from expression systems is that a limited number of
subunit combinations are favored, but more rare combinations are possible. There is tremendous potential for
nAChR diversity within the CNS.
There are some general rules, and these can be applied
when trying to simplify the influence of particular subunits. For example, a7 homomeric nAChRs have high
calcium permeability and rapid activation and desensitization kinetics, and they are specifically inhibited by a-bungarotoxin and methyllycaconitine (Alkondon et al 1992;
Castro and Albuquerque 1995; Gray et al 1996). Nicotinic
AChRs with similar properties are found in the hippocampus and other neuronal regions, consistent with the hypothesis that a-bungarotoxin binding sites represent a7containing nAChRs (Albuquerque et al 1997; Alkondon
and Albuquerque 1993; Lindstrom 1997; Lindstrom et al
1996; Samuel et al 1997; Zarei et al 1999). Supporting that
hypothesis, a-bungarotoxin binding sites were not detected in a7-knockout mice (Orr-Urtreger et al 1997). The
high-affinity [3H]nicotine binding sites, however, were
still present. Most high-affinity [3H]nicotine sites appear
to contain a4 and b2 subunits, and possibly some also
contain additional subunits. These high-affinity sites are
lost after knockout of the b2 subunit (Zoli et al 1998). In
mice lacking the b2 subunit, other lower affinity nicotine
binding sites are revealed, and these sites are likely to
contain the a3 subunit.
Expression of nAChRs in the CNS
Most nAChRs in the mammalian brain contain either
a4b2 or a7 (Charpantier et al 1998; Cimino et al 1992;
Clarke et al 1985; Schoepfer et al 1990; Se´gue´la et al
1993; Wada et al 1989, 1990). Although many of the
nAChRs contain a4 and b2 subunits, agonist and antagonist profiles differ for cells derived from different nuclei.
For example, both medial habenula and locus coeruleus
neurons express functional nAChRs with a pharmacologic
profile that is consistent with a3 and b4 subunits in those
regions (Mulle et al 1991). Studies indicate that there are
few b2 subunits contributing to medial habenular nAChRs
(Quick et al 1999). Another example is that a7-containing
nAChRs mediate the predominant nicotinic current in
hippocampal neurons, but other nAChR responses may be
attributable to a4b2-containing, a3b4-containing, and
other nAChRs (Albuquerque et al 1997; Alkondon and
Albuquerque 1993; Zarei et al 1999; Zoli et al 1998).
These electrophysiology results are consistent with in situ
BIOL PSYCHIATRY
2001;49:166 –174
167
hybridization studies that indicated high expression of a7
and b2 throughout the rat hippocampus and weaker
expression of a3, a4, a5, and b4 (Se´gue´la et al 1993;
Wada et al 1989, 1990; Zoli et al 1998).
Radiolabeled nicotinic ligands and in situ hybridization
for nAChR messenger RNA indicate a wide, nonuniform
distribution of various subunits, and nuclei often contain
subgroups of nAChR subunits (Charpantier et al 1998;
Cimino et al 1992; Clarke et al 1985; Lena et al 1999; Le
Nove`re et al 1996; Schoepfer et al 1990; Se´gue´la et al
1993; Sihver et al 1998; Wada et al 1989, 1990). Although
one class of nAChRs often predominates within a region,
more than one class or subclass of nAChRs is often
present (e.g., Pidoplichko et al 1997). In addition, individual neurons often express multiple classes of nAChRs, and
even related neighboring neurons can express nicotinic
responses that are significantly different (Dani et al 2000).
Basic Functions of Nicotinic Receptors
Upon binding ACh, the nAChR ion channel is stabilized in
the open conformation for several milliseconds. Then the
open pore of the receptor/channel closes to a resting state
or closes to a desensitized state that is unresponsive to
ACh or other agonists for many milliseconds or more.
While open, nAChRs conduct cations, which can cause a
local depolarization of the membrane and produce an
intracellular ionic signal.
Although sodium and potassium carry most of the
nAChR current, calcium can also make a significant
contribution (Castro and Albuquerque 1995; Decker and
Dani 1990; Dani and Mayer 1995; Se´gue´la et al 1993;
Vernino et al 1992, 1994). Calcium entry through nAChRs
can be biologically important and is different from calcium influx mediated by voltage-gated calcium channels
or by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. Both voltage-gated calcium channels and
NMDA receptors require membrane depolarization to pass
current freely. At hyperpolarized (negative) potentials,
voltage-gated calcium channels generally do not open and
NMDA receptors are blocked by extracellular magnesium
ions. Nicotinic nAChRs do open and pass current freely at
negative potentials that provide a strong voltage force
driving cations into the cell. Thus, calcium currents
mediated by nAChRs can have a different voltage dependence than is seen for other calcium-permeable ion channels. Also, incoming calcium has a different spatial distribution that depends on the location of nAChRs on the cell
surface.
The most basic conformational states of nAChRs are
the closed state at rest, the open state, and the desensitized
state. The rate at which the nicotinic receptor proceeds
through the various conformational states and the
168
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2001;49:166 –174
Figure 1. A representation of the allosteric sites on a nicotinic
acetylcholine receptor (nAChR), a cut-away view showing three
of the five subunits that form the pentameric receptor– channel
complex.
selectivity with which it conducts cations in the open state
depend on many factors, including the subunit composition. Therefore, the extensive nAChR diversity has the
potential to produce many different responses to endogenous or exogenous agonists. The speed of activation, the
intensity of the membrane depolarization, the size of the
ionic signal, the rates of desensitization and recovery from
desensitization, the pharmacology, and the regulatory
controls of the ACh response will all depend on the
subunit composition of nAChRs as well as other local
factors. To add further complexity, the three basic conformational states (rest, open, and desensitized) do not
account for the actual kinetic properties of nicotinic
receptors. Rather, there are multiple conformations involved in the gating. Desensitization, in particular, can
encompass many time constants (Dani et al 2000; Fenster
et al 1999b). Thus, there may be short- and long-lived
Figure 2. A representation of presynaptic nicotinic acetylcholine
receptors (nAChRs). The nAChRs are positioned so they can
influence the release of another neurotransmitter, which is
released by the presynaptic terminal (Pre) onto the postsynaptic
bouton (Postsynaptic). Evidence indicates that nAChRs initiate
an increase of calcium in the presynaptic terminal. The calcium
then enhances the release of the neurotransmitter.
J.A. Dani
Figure 3. A representation of preterminal or axonal nicotinic
acetylcholine receptors (nAChRs). The nAChRs are located in a
position along the axon arbor to indicate they could more easily
influence some presynaptic terminals while not affecting others.
states of desensitization. Long exposures to low concentrations of agonist will favor deeper levels of desensitization, and this situation is often the case for smokers, who
maintain low concentrations of nicotine throughout the
day (Benowitz et al 1989; Benwell et al 1995; Clarke
1990, 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 the
nAChR has grown from an on-off switch regulating
cationic conductance to a sophisticated allosteric macromolecule (Lena and Changeux 1993, 1998). Figure 1
represents sites on a nAChR that can alter function.
Competitive antagonists and partial agonists can occupy
the agonist binding sites. Open channel blockers, such as
phencyclidine, can bind within the pore, and there are
multiple sites for other noncompetitive inhibitors and
modulators. In addition, nAChRs are regulated by several
Figure 4. A representation of fast nicotinic synaptic transmission. Only nicotinic acetylcholine receptors (nAChRs) are represented on the postsynaptic bouton in this simplified picture.
Two presynaptic nAChRs are also shown.
Nicotine Receptors in the CNS
other factors, including peptide transmitters, various protein kinases, the cytoskeleton, and calcium. Although
calcium modulation can act intracellularly (as is usually
the case), nAChRs can also be allosterically modulated by
extracellular calcium, leading to dramatic changes in the
channel opening probability (Adams and Nutter 1992;
Amador and Dani 1995; Mulle et al 1992; Vernino et al
1992). This modulation occurs over the physiologic concentration range of external calcium. Therefore, high
levels of neuronal activity that can diminish extracellular
calcium (Heinemann et al 1990; Wiest et al 2000) could
cause a negative feedback that lowers the opening probability of nAChRs.
Calcium modulation is well documented, but there is
great potential for nAChR modulation by other allosteric
effectors. This potential offers points of entry for therapeutic drugs, such as those that can enhance nAChR
activity to assist Alzheimer’s disease (AD) patients. Presently, cholinergic activity can be enhanced in patients with
AD by antiacetylcholinesterase drugs that prolong the time
that ACh is present before being broken down. There is
evidence, however, that some antiacetylcholinesterase
drugs (such as physostigmine and galantamine) can allosterically potentiate nAChRs (Maelicke and Albuquerque
2000). Drugs that could act specifically to enhance the
activity of the required nAChR subtype, while also prolonging the action of ACh, could be vital in combating the
debilitating effects of AD.
In addition to loss of nicotinic mechanisms, as seen in
AD (Nordberg 1994; Paterson and Nordberg 2000; Perry
et al 1995), there are other physiologic forms of regulation
that may become disrupted during pathologic conditions
(Dani, in press; Dani and Heinemann 1996; Lena and
Changeux 1998; Lindstrom 1997; Perry et al 1995; Steinlein et al 1995). For example, during chronic tobacco use,
low concentrations of nicotine cause certain neuronal
nAChRs to increase in number and to accumulate in deep
states of desensitization (Fenster et al 1999c; Peng et al
1994, 1997). Chronic desensitization may uncouple regulatory mechanisms important for proper nAChR functioning and promote incorrect recycling of receptors, thereby
leading to an increase in the number of receptors. Inappropriate changes in the expression of nAChRs may be
important in the process of tobacco addiction.
Competing Processes of nAChR Activation
and Desensitization
At a cholinergic synapse, approximately 1 mmol/L ACh is
rapidly released into the cleft, immediately activating the
nicotinic receptors. In a few milliseconds, the ACh is
hydrolyzed by acetylcholinesterase and/or diffuses away.
The delivery and removal of ACh is very rapid, and
BIOL PSYCHIATRY
2001;49:166 –174
169
therefore desensitization is usually not thought to be
important even though the desensitization process is complex. As neuronal nicotinic receptors are diverse and
neuronal synapses are anatomically and compositionally
varied, the role of desensitization in the brain is not well
understood and remains a difficult problem. Repeatedly
exposing a synapse to about 1 mmol/L ACh might
normally produce little desensitization. If the synaptic
stimulation is extremely high, however, even though the
rates of recovery from desensitization are fast they may
not allow complete recovery (Dilger and Liu 1992; Fenster
et al 1999b; Franke et al 1992). Furthermore, the breakdown of ACh releases choline, which could reach locally
high concentrations. Higher concentrations of choline
could desensitize a7-containing nicotinic receptors
(Alkondon et al 1997b; Papke et al 1996).
The physiologic role of desensitization may become
especially important when considering the desensitizing
levels of nicotine that bathe the brains of smokers (Clarke
1991; Dani and Heinemann 1996; Ochoa et al 1990) or
when considering the effects of drugs that inhibit acetylcholinesterase (e.g., to treat patients with AD). Under
those two conditions, some nAChRs are likely to desensitize, but not in a uniform manner. At extremely active
cholinergic synapses, nAChRs are more susceptible to the
desensitizing influence of the endogenous agonist (ACh).
When high rates of cholinergic activity are occurring in
conjunction with antiacetylcholinesterase or long exposures to nicotine, then the synaptic nAChRs are more
susceptible to desensitization. Evidence indicates that
longer exposures to agonist allow slower rates of desensitization to come into play, such that some nicotinic
receptors can enter longer lasting desensitization (Lester
and Dani 1994; Reitstetter et al 1999).
If desensitization comes into play (normally, pathologically, or owing to drugs), then the rate of synaptic firing will
be an important determinant of how much current enters the
synapse via nicotinic receptors per unit time. The highest
synaptic firing rates would not necessarily produce the most
effective nicotinic signal because the nAChR would desensitize more at the highest rates (Dani et al 2000). Kinetic
parameters including desensitization depend on the subunit
composition, and modulatory processes, such as protein
kinases, influence the nAChRs subtypes differently and
selectively (Fenster et al 1999a; Paradiso and Brehm 1998).
Depending on dynamic modulatory influences, different
nAChR subtypes might become particularly susceptible to
desensitization, and the modulatory processes can vary from
synapse to synapse. Thus, modulatory processes acting upon
nAChRs could provide a continually varying, powerful,
computational mechanism for manipulating how information
is processed at synapses.
The diversity of nAChRs and their distribution are
170
BIOL PSYCHIATRY
2001;49:166 –174
important parameters of the nicotinic cholinergic systems.
Creating drugs that discriminate nAChRs based on their
subtype or location would be important for combating
specific problems—for example, AD (Wang et al 2000) or
forms of epilepsy (Dani 2000; Steinlein et al 1995).
Main Cholinergic Projections
Before looking further into the roles of nAChRs, we need
to consider some of the basic properties of the cholinergic
innervation. Cholinergic systems provide diffuse innervation to practically all of the brain, but a relatively small
number of cholinergic neurons innervate each neural area
(Kasa 1986; Woolf 1991). Despite the sparse innervation,
cholinergic activity drives or modulates a wide variety of
behaviors. By initially acting on nAChRs, nicotine or
nicotinic innervation can increase arousal, heighten attention, influence rapid eye movement sleep, produce states
of euphoria, decrease fatigue, decrease anxiety, act centrally as an analgesic, transiently normalize sensory gating
in schizophrenic patients, and influence a number of
cognitive functions (Adler et al 1999; Everitt and Robbins
1997; Levin 1992; Marubio et al 1999; Rose and Levin
1991). It is thought that cholinergic systems particularly
affect discriminatory processes by increasing the signalto-noise ratio and by helping to evaluate the significance
and relevance of stimuli.
Although cholinergic neurons are distributed along the
axis from the spinal cord and brain stem to the basal
telencephalon, there are two major cholinergic project
subsystems that can be identified. One cholinergic system
arises from neurons in the pedunculopontine tegmentum
and the laterodorsal pontine tegmentum, providing widespread innervation mainly to the thalamus and midbrain
areas and also descending innervation that reaches to the
brain stem. The second major cholinergic system arises in
the basal forebrain and makes broad projections mainly
throughout the cortex and hippocampus. In general, a
relatively few cholinergic neurons make spare projections
that reach broad areas. Thus, the activity of a rather small
number of cholinergic neurons can influence relatively
large neuronal structures.
Nicotinic Mechanisms in the CNS
The most widely observed synaptic role of nAChRs in the
CNS is to influence neurotransmitter release. Figure 2
depicts presynaptic nAChRs, which have been found to
increase the release of nearly every neurotransmitter that
has been examined (Albuquerque et al 1997; Alkondon et
al 1997a; Gray et al 1996; Guo et al 1998; Jones et al
1999; Li et al 1998; McGehee et al 1995; McGehee and
Role 1995; Radcliffe and Dani 1998; Radcliffe et al 1999;
J.A. Dani
Role and Berg 1996; Wonnacott 1997). Exogenous application of nicotinic agonists can enhance and nicotinic
antagonists can often diminish the release of ACh, dopamine, norepinephrine, and serotonin as well as glutamate
and GABA. In many cases, the a7-containing nAChRs,
which are highly calcium permeable, mediate the increased release of neurotransmitter, but in other cases
different nAChR subtypes are involved. In rat hippocampal slices and cultures, presynaptic a7-containing nAChRs
were shown to initiate a calcium influx that, consequently,
enhances glutamate release from presynaptic terminals
(Albuquerque et al 1997; Gray et al 1996). Intense
nicotinic stimulation was able to enhance glutamate release on multiple time scales, extending from seconds to a
few minutes (Radcliffe and Dani 1998). Similar enhancements of release were obtained with a higher probability at
GABAergic presynaptic terminals (Radcliffe et al 1999).
The forms of enhancement lasting several minutes or more
require that the incoming calcium acts as a second messenger to modify glutamatergic synaptic transmission
indirectly. Properly localized calcium influx mediated by
nAChRs initiates enzymatic activity (such as protein
kinases and phosphatases) that is known to modify glutamatergic synapses.
Figure 3 depicts nAChRs at a preterminal location,
where they can also alter the release of various neurotransmitters. Particularly at GABAergic synapses, activation of
preterminal nAChRs has been found to depolarize the
membrane locally, leading to activation of voltage-dependent channels that directly mediate the synaptic calcium
influx underlying enhanced GABA release (Alkondon et
al 1997a; Lena et al 1993). The agonist-induced effect
mediated by preterminal nAChRs was inhibited by tetrodotoxin, which blocks sodium channels and, thereby,
prevents the regenerative voltage activation of calcium
channels in the presynaptic terminal. Axonal nAChRs may
also modulate transmitter release and local excitability in
another way. As represented in Figure 3, strategically
located nAChRs might enable an action potential to invade
only a portion of the axonal arbor. By directly exciting or
by shunting the progress of an action potential at a
bifurcation, axonal nAChRs could initiate or alter the
spread of neuronal excitation.
Figure 4 depicts direct, fast nicotinic synaptic transmission. Fast nicotinic transmission has been detected as a
small excitatory input at several neuronal areas. In the
hippocampus, fast nicotinic transmission onto GABAergic
interneurons has been reported (Alkondon et al 1998;
Frazier et al 1998; Hefft et al 1999). In developing visual
cortex, nicotinic transmission can be evoked onto both
glutamatergic pyramidal cells and GABAergic interneurons (Roerig et al 1997). Because nicotinic synapses have
a low density, they are difficult to detect experimentally in
Nicotine Receptors in the CNS
brain slice preparations. Where it has been reported, fast
nicotinic transmission is a minor component of the excitatory input, which is overwhelmingly glutamatergic. It is
likely that nicotinic transmission is present at low densities
in more neuronal areas than the few that have been
presently reported. Although direct nicotinic excitation of
a neuron usually does not predominate, it could influence
the excitability of a group of neurons owing to the broad
cholinergic projections into an area. Thus, beyond their
specific roles at discrete synapses, nAChRs also modulate
neuronal circuits in a broader sense.
An example of nicotinic modulation of circuit excitability was seen in the hippocampal slice (Ji and Dani 2000).
While recording from CA1 pyramidal neurons, local
application of nicotinic agonist onto interneurons caused
both inhibition and disinhibition. Activating nAChRs on
interneurons that directly innervated pyramidal neurons
caused inhibition of the pyramidal neuron, and activating
interneurons that innervated mainly other interneurons
caused disinhibition. The disinhibition probably occurred
because the nicotinic agonist activated interneurons that
then inhibited other interneurons (Alkondon et al 1999).
Consequently, GABAergic inhibitory activity decreased in
the area; thus, some pyramidal neurons were temporarily
released from their inhibitory inputs (i.e., disinhibition).
The results in the hippocampus indicate that, owing to
the broad projections by cholinergic neurons, nicotinic
activity can influence not just synaptic events but also the
excitability of neuronal areas (Dani 2000; Ji and Dani
2000). By influencing circuits, nAChRs may modulate the
rhythmic activity in the hippocampus or in other regions.
A property of hippocampal circuits is that they enter into
different rhythmic oscillations. For example, theta
rhythms and gamma rhythms often occur during paradoxical sleep or while awake rats explore their environments
(Vanderwolf 1969). The periods of circuit activity that
accompany these rhythms provide opportunities for synaptic plasticity that underlies learning and memory
(Huerta and Lisman 1993). Because interneurons are
important determinants of the rhythmic oscillations and
they receive cholinergic afferents that can modulate the
rhythms (Csicsvari et al 1999; Dragoi et al 1999), it seems
likely that nAChRs influence the patterns of activity in the
hippocampus and elsewhere.
Nicotinic AChRs also have roles during development
and neuronal plasticity (Broide and Leslie 1999; Role and
Berg 1996). The density of nAChRs varies during the
course of development, and nAChRs can contribute to
activity-dependent calcium signals. For example, presynaptic a7-containing nAChRs increased the release of
glutamate preferentially onto postsynaptic NMDA receptors in the developing rat auditory cortex, but not in the
mature cortex (Aramakis and Metherate 1998). By en-
BIOL PSYCHIATRY
2001;49:166 –174
171
hancing glutamate release particularly at the locations of
NMDA receptors, nAChRs might help to modulate activity-dependent synaptic plasticity that is often initiated by
postsynaptic NMDA receptors (Malenka and Nicoll 1999).
Nicotinic regulatory, plasticity, and developmental influences are particularly important when considering the
etiology of disease. Biological changes that inappropriately alter nicotinic mechanisms could immediately influence the release of many neurotransmitters and alter
circuit excitability. However, nicotinic dysfunction could
have long-term developmental consequences that are expressed later in life.
In summary, the tremendous diversity of nAChRs
provides the flexibility necessary for them to play multiple, varied roles. Broad, sparse cholinergic projects ensure
that nicotinic mechanisms modulate the neuronal excitability of relatively wide circuits. Although fast nicotinic
transmission is not the predominant driving force, it can
contribute excitatory input to many synapses at one time.
Presynaptic and preterminal nAChRs modulate the release
of all the major neurotransmitters that have been tested.
During the progression of AD, cholinergic inputs degenerate and the number of nAChRs in some areas decreases
(Nordberg 1994; Perry et al 1995). Loss of nicotinic
mechanisms, which modulate the gain and fidelity of
synapses and modulate the excitability of circuits, are
likely to contribute to the overall cognitive deficits associated with AD.
Work from this laboratory is supported by National Institutes of Health
grants from the National Institute on Drug Abuse (Nos. DA09411 and
DA12661) and from the National Institute of Neurological Disorders and
Stroke (No. NS21229).
Aspects of the work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajarko,
Puerto Rico. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaceutica LP.
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