Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol49.Issue3.2001:

Is There Nicotinic Modulation of Nerve Growth
Factor? Implications for Cholinergic Therapies in
Alzheimer’s Disease
Marcus Rattray
Studies on the neurobiology of nerve growth factor (NGF)
reveal a diverse range of actions. Through alterations in
gene expression, NGF is important in maintaining and
regulating the phenotype of neurons that express the
high-affinity receptor, trkA. Nerve growth factor also has
a rapid action, revealed by its role in pain signaling in
bladder and in skin. In the central nervous system (CNS),
NGF has an intimate relationship with the cholinergic
system. It promotes cholinergic neuron survival after
experimental injury but also maintains and regulates the
phenotype of uninjured cholinergic neurons. In addition to
these effects mediated by gene expression, NGF has a
rapid neurotransmitter-like action to regulate cholinergic
neurotransmission and neuronal excitability. Consistent
with its actions on the cholinergic system, NGF can
enhance function in animals with cholinergic lesions and
has been proposed to be useful in humans with Alzheimer’s disease (AD); however, the problems of CNS delivery and of side effects (particularly pain) limit the clinical

efficacy of NGF. Drug treatment strategies to enhance
production of NGF in the CNS may be useful in the
treatment of AD. Nicotine is one such agent, which, when
administered directly to the hippocampus in rats, produces
long-lasting elevation of NGF production. Biol Psychiatry 2001;49:185–193 © 2001 Society of Biological
Psychiatry
Key Words: Neurotrophin, hippocampus, acetylcholine,
glutamate, NGF, trkA

Introduction

N

erve growth factor (NGF) is the prototypic neurotrophic factor. In humans and other mammals, the
neurotrophins comprise a family of four similar proteins
named NGF, brain-derived neurotrophic factor (BDNF),

From the Biochemical Neuropharmacology Group, Centre for Neuroscience Research, GKT School of Biomedical Sciences, King’s College London, London,
United Kingdom.
Address reprint requests to Marcus Rattray, GKT School of Biomedical Sciences,

King’s College London, Centre for Neuroscience Research, Hodgkin Building,
Guy’s Hospital Campus, London SE1 1UL, UK.
Received May 23, 2000; revised August 14, 2000; accepted August 22, 2000.

© 2001 Society of Biological Psychiatry

neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5)
(Lindsay et al 1994). The first member of this family to be
characterized was NGF, and it remains the best studied.
This molecule exists as a dimer of two identical polypeptide chains, each of 118 amino acid residues (McDonald
and Blundell 1991). All neurotrophins have a similar
overall structure, with a small number of amino acid
differences between the neurotrophins determining the
specificity of receptor binding.
The best understood neurotrophin receptors are the
family of proteins known as tyrosine receptor kinase (trk).
Within this family are three distinct but closely related
receptors known as trkA (p140trk), trkB, and trkC. Each trk
receptor subunit crosses the cell membrane a single time.
The extracellular portion of each trk forms the neurotrophin-binding site, with differences in amino acid residues

determining binding selectivity. NGF binds to trkA,
BDNF, and NT-4/5 bind to trkB. Neurotrophin-3 binds
relatively selectively to trkC but also can bind to trkA and
trkB (Ultrech et al 1999). The intracellular portion of the
receptor contains a tyrosine kinase (TK) domain and
various sites that can dock with other proteins.
Binding of NGF to trkA causes receptor dimerization,
enabling an active complex of two trk receptor subunits
with the neurotrophin molecules to be formed. This
change of shape results in phosphorylation of three tyrosine residues on each subunit within the TK domains.
The activated TK domains catalyze the phosphorylation of
several adjacent tyrosine residues within the intracellular
regions of each receptor subunit. These phosphorylated
regions are then able to dock with, and activate by
phosphorylation, a number of enzymes and proteins in the
nerve ending (Figure 1A). Docked proteins bind to additional proteins and activate them (Figure 1A). Thus, a
large number of signaling proteins become recruited and
activated as a consequence of NGF binding to the trk
receptor. These include phospholipase C gamma, which
mediates phospholipid hydrolysis, and a number of protein

kinases (including PI3 kinase, S6 kinase, protein kinase C,
and mitogen-activated protein [MAP] kinase), which are
capable of phosphorylating a wide range of target proteins.
0006-3223/01/$20.00
PII S0006-3223(00)01047-7

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M. Rattray

Figure 1. Nerve growth factor (NGF) signaling at the synapse. (A) At the nerve terminal, NGF binds to the trkA receptor. Activation
of the receptor complex stimulates docking of a number of proteins; shown here are phosphatidyl inositol 3 kinase (PI3K), ShC, and
phospholipase C g (PLCg). ShC activates the SOS/Grb complex to activate the small GTPase, Ras, and MAP kinase (MAPK). Other
protein kinases, including protein kinase C (PKC) and P70-S6 kinase (P70 S6K), are activated. A signaling complex is formed that is
retrogradely transported along the axon to the cell body, where it can cause the phosphorylation of transcription factors and cause
changes in gene expression (Friedman et al 1999). (B) Current evidence suggests that NGF can cause short-term regulation of neurons
independent of retrograde transport of the signaling complex and gene expression. Binding of NGF to trk causes enhanced

neurotransmitter release (i) and may activate various receptors (ii) and ion channels (iii) to enhance neuronal electrical activity.

The complex cascade of intracellular signaling events
underlies the biological effects of the neurotrophins
(Friedman and Greene 1999).
The complex of NGF/trkA with docked proteins, including phospholipase C gamma, is endocytosed at the
synapse to form signaling complexes that are retrogradely
transported along the axon to the cell body (Grimes et al
1996). When the signaling complex reaches the neuronal
cell body, it will phosphorylate transcription factors,
including cAMP response element-binding protein
(CREB), which can then enter the nucleus (Riccio et al
1997). In this manner, trk receptor activation is directly
linked to alteration of gene expression. Alterations in the
pattern of gene expression underlie the maintenance,
survival, and plasticity effects of NGF and other neurotrophins on their target neurons. In addition to these
events, which would be predicted to occur hours to days
after neurotrophin binding to trk receptors, there is an
increased awareness that NGF and other neurotrophins can
exert more rapid effects on neurotransmitter synthesis,

release, and the electrical activity of neurons by altering
the activity of proteins involved in synaptic transmission
(Figure 1B).

Another neurotrophin receptor exists, named p75NTR, a
member of the TNF receptor/Fas/CD40 superfamily.
p75NTR, binds to NGF and other neurotrophins with
approximately equal affinity (Chao 1994). Receptor activation stimulates several intracellular events that are quite
distinct to those mediated by trk receptors. The p75NTR
receptor does not contain tyrosine kinase activity but
instead mediates several distinct biochemical effects including sphingolipid hydrolysis and activation of the c-Jun
amino terminal protein kinase (JNK) signaling pathway
(Friedman and Greene 1999).
Current evidence suggests that for cells that express
p75NTR but not a trk receptor, the dominant effect of
neurotrophin-mediated p75NTR signaling is cell death.
Neurotrophin signaling through p75NTR plays an important role in programmed cell death during the development
of the nervous system (Friedman and Greene 1999). In
some cholinergic neurons of the central nervous system
(CNS), and in all neurotrophin-sensitive sensory and

sympathetic neurons in the peripheral nervous system,
p75NTR is coexpressed with one or more trk receptors. For
these neurons, the death signals from p75NTR activation
are suppressed by interactions with trk or signals from trk.

Nicotine and NGF

In this case, cell death does not occur in response to
neurotrophins; instead p75NTR signaling somehow modulates the effect of trk receptor activation to suppress the
death signal.

Models for NGF Effects: Lessons from the
Peripheral Nervous System
Until recently, our knowledge of the functions of NGF and
the other neurotrophins has arisen from studies of the
developing nervous system. The neurotrophic concept
states that the tissue to be innervated by a particular group
of neurons produces a limiting amount of a trophic factor
that, during a critical stage in target innervation, binds to
receptors, is internalized, and retrogradely transported to

the cell bodies of these neurons. This supply of neurotrophin is critical to the development of an appropriate
phenotype and connectivity of the target neuron. For
developing neurons at least, a supply of the appropriate
neurotrophins is essential for cell survival. These concepts
have been extensively tested and refined, particularly in
the peripheral nervous system.
In the adult, neurotrophin expression continues to be
widespread, suggesting a role of these factors beyond that
of neuronal development. For example, NGF is produced
by many peripheral tissues, in particular, the skin and
other tissues that receive a rich sensory or sympathetic
innervation. Many sympathetic neurons in the adult express trkA (and p75NTR) receptors, as do a class of primary
sensory neurons that are particularly important in acute
and inflammatory pain (McMahon 1996; Snider and McMahon 1998). Although it is clear that subgroups of
sensory neurons retain their sensitivity to neurotrophins, it
is also clear that a supply of neurotrophins is not necessary
for the survival of these responsive neurons. Therefore, a
new appreciation of the roles of these factors is emerging
that does not fit with the classical neurotrophic concept:
NGF is now known to play a role in cell survival after

injury, regeneration, collateral sprouting, neuronal size
and complexity, expression of transmitters, and neuronal
sensitivity (McMahon et al 1995; McMahon 1996; Woolf
1996).
In the context of the adult nervous system, NGF is the
best studied of the neurotrophins. Numerous studies have
tested in vivo the effects of either administering exogenous NGF or sequestering naturally produced NGF. These
experiments show that it can alter neuronal gene expression in sensory neurons (e.g., Michael et al 1997; Woolf
1996). Inflammatory injuries cause increased levels of
NGF in peripheral tissues and therefore increase the
exposure of sensory neurons to NGF (McMahon et al
1995; Woolf et al 1994; Woolf 1996). Under these
conditions, NGF-dependent changes occur in the excitabil-

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187

ity and in the responsiveness of neurons to stimuli.

Underlying these effects are alterations in neurotransmitter
and neuropeptide release and in the sensitivity of neurons
by alterations in neurotransmitter receptors and ion channels (e.g.; Fjell et al 1999; Malcangio et al 1997; McMahon 1996; Woolf et al 1996). Furthermore, NGF can
induce morphologic changes, such as sprouting and outgrowth in responsive sensory or sympathetic axons, particularly after injury (e.g., Ramer et al 2000). These effects
are all consistent with increased retrograde transport of
trkA signaling complexes that alter gene expression in the
NGF-responsive neurons.
One of the unexpected discoveries from these experiments was that NGF could produce changes in neuronal
excitability and behaviors that are inconsistent with the
time course of receptor internalization, retrograde transport, and gene expression. One example of this phenomenon comes from a model of chemical inflammation of the
rat bladder. About 30 min after exposure of the bladder to
an irritant, there is a behavioral and electrophysiologic
response corresponding to pain. This rapid response,
analogous to pain in humans, is dependent on NGF,
confined to the population of sensory nerve fibers that
express trkA, and involves the rapid induction of NGF
mRNA and protein in the inflamed tissue (Dmitrieva et al
1997; Oddiah et al 1998). These results strongly suggest
that NGF has direct and rapid actions on neuronal excitability and that these effects occur too quickly to be
mediated by retrograde transport of signaling complexes.

NGF and the Basal Forebrain
Cholinergic System
In contrast to the periphery, NGF expression in the central
nervous system is much more restricted; NGF mRNA and
protein are expressed in a number of brain regions, with
the hippocampus providing the single largest source of
NGF in the entire CNS (Korsching et al 1985). In the
hippocampus, NGF messenger RNA and protein is expressed by the principal excitatory (glutamate) neurons in
the hippocampus, as well as by a subset of g-aminobutyric
acid– containing inhibitory neurons (Rocamora et al
1996). These hippocampal target cells receive rich innervation from ascending neurons with their cell bodies in the
basal forebrain.
Numerous studies have demonstrated that cholinergic
neurons are responsive to NGF. All cholinergic neurons
express trkA (Holtzman et al 1995). The distribution of
p75NTR is more restricted than trkA, being expressed by
subsets of cholinergic cells, notably the cholinergic neurons of the basal forebrain (Batchelor et al 1989). Cholinergic neurons account for nearly all of the NGF-responsive
neurons in the CNS, although there are groups of noncho-

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linergic neurons that express trkA, including some of the
principal cells of the hippocampus (Cellerino 1996; Holtzman et al 1995). There are no noncholinergic neurons
known to express p75NTR, but this receptor is expressed by
some hippocampal astrocytes (Dougherty and Milner
1999). The distribution of NGF and its receptors suggests
an intimate and precise interrelationship between cholinergic neurons and their NGF-producing targets.
Given that NGF is expressed in the targets for cholinergic
neurons and that cholinergic neurons are responsive to NGF,
it may be expected that NGF would have a classic neurotrophic role to mediate cholinergic cell survival during development; however, studies using transgenic mice deficient in
NGF or trkA suggest that in prenatal and early postnatal
periods there is little, if any, cholinergic cell loss in the CNS
(Chen et al 1997; Crowley et al 1994; Fagan et al 1997;
Ruberti et al 2000). This absence of central cholinergic
deficits contrasts with the notable absence of sensory neurons
observed in the NGF knockout transgenic animals prenatally
and postnatally (Crowley et al 1994). These results clearly
show that NGF is not critical for basal forebrain cholinergic
neuron survival during development. Although basal forebrain cholinergic neurons are responsive to NGF during their
development, other trophic factors are required for their
survival. The actual survival factors are unknown, but it is
clear that developing cholinergic neurons are responsive to a
number of trophic factors, particularly BDNF (Ward and
Hagg 2000) and maintain this responsiveness in adult life
(Koliatsos et al 1994).
To what extent NGF is necessary as a survival factor for
adult cholinergic neurons remains controversial. It promotes the survival of cholinergic neurons after axotomy
(Hefti 1986; Kromer 1987; Williams et al 1986). Measuring the effects of reduced availability of NGF to undamaged cholinergic neurons has been technically difficult.
Partial removal in vivo of the NGF supply to cholinergic
neurons in transgenic animals or near-complete removal
by ablation of the hippocampus causes severe cholinergic
neuronal atrophy, with little or no neuronal death (Chen et
al 1997; Sofroniew et al 1993). These studies have been
interpreted to mean that NGF is not a survival factor for
cholinergic neurons in the adult; however, a more recent
study using a transgenic mouse that lacks NGF and
survives to adulthood suggests that a complete lack of
NGF in vivo in the adult does cause cholinergic cell loss
in the basal forebrain (Ruberti et al 2000).
As outlined above, reduction in the NGF supply to basal
forebrain cholinergic neurons causes atrophy in cholinergic neurons. These changes are reminiscent of the
cholinergic neuronal changes in Alzheimer’s disease
(AD). In AD, however, there is no evidence that it is NGF
deficiency that causes cholinergic cell loss. In fact, measurements in postmortem brains from AD patients show

M. Rattray

that there is no change in the capacity of the CNS to
produce NGF (mRNA levels) with increased levels of
NGF protein in the cortex and hippocampus (Fahnestock
et al 1996; Hock et al 1998; Jette et al 1994; Scott et al
1995). Increased NGF levels are thought to reflect a
decreased ability of cholinergic neurons to retrogradely
transport NGF.
In the adult, NGF influences the messenger RNA levels,
structural plasticity, response to injury, and maintenance of
basal forebrain cholinergic neurons. Administration of NGF
to the uninjured CNS causes a number of effects on cholinergic neurons, including hypertrophy, sprouting, upregulation
of NGF receptors, increased levels of choline acetyltransferase (ChAT), and increased choline uptake (Heisenberg et
al 1994; Higgins et al 1989; Lapchak et al 1992; Mobley et
al 1985). These results are all consistent with a role of NGF
to maintain the cholinergic phenotype through retrograde
transport of the NGF/trkA signaling complex from cholinergic nerve terminals in the hippocampus to the cell bodies in
the basal forebrain (Seiler et al 1984).
There are also rapid actions of NGF on cholinergic
neurons. It can rapidly increase acetylcholine release and
choline uptake in synaptosomes (Knipper et al 1994), an
effect that cannot include effects via gene expression because
the cell bodies are not present in these preparations. Similarly, in cultured septal neurons, NGF has been shown to
produce rapid increases in intracellular calcium levels, a
stimulus known to enhance neurotransmitter release (Nonner
et al 2000). It has been shown to cause rapid increases in the
firing rate of cholinergic neurons (Albeck et al 1999). In other
types of neurons, NGF can cause rapid activation of calciumdependent potassium channels (Holm et al 1997) and voltage-sensitive calcium channels (Jia et al 1999), actions that
may underlie NGF effects on cholinergic neuronal excitability and acetylcholine release. These findings fit well with the
emerging evidence that neurotrophins can behave as neurotransmitter-like molecules. In fact, in a similar manner to a
neurotransmitter, NGF can be released by neurons upon
depolarization (Blöchl and Thoenen 1995).
Altogether, these studies suggest that NGF does not have
a classic neurotrophic role in cholinergic cell survival. Instead, it is an important regulator of cholinergic neuron
morphology and function and would be predicted to maintain, or even improve, cholinergic function in AD in three
ways. First, increases of NGF levels in appropriate regions of
the CNS would be predicted to promote the survival of
degenerating or damaged cholinergic neurons. Second, such
increases would be predicted to promote sprouting and
enhance neurotransmitter synthesis in uninjured cholinergic
neurons. Third, they would be predicted to enhance cholinergic neuronal firing and transmitter release through actions
independent of retrograde signaling and gene expression.

Nicotine and NGF

Nerve Growth Factor, Cognition, and
Alzheimer’s Disease
On the basis of the data described above, NGF, through its
effects on the cholinergic system, may be predicted to
improve cognitive functions in AD. Animal studies
strongly support this notion and have shown that NGF can
enhance performance in behavioral cognitive tasks
(Gustilo et al 1999; Pellymounter et al 1996) and slow
cognitive decline in aged rats (Martinez-Serrano and
Bjorklund 1998). It has been shown to have a role in
physiologic correlates of memory acquisition in the hippocampus (Bergado et al 1998). Conversely, reduction of
NGF levels appears to have a detrimental effect on
learning and cognitive behaviors. Animals with reduced
levels of NGF (anti-NGF antibodies, transgenic animals)
show impaired spatial learning (Chen et al 1997; Van der
Zee et al 1995).
From the evidence outlined above, it is likely that
increased exposure of NGF to cholinergic neurons will be
beneficial in AD. Because NGF does not cross the
blood– brain barrier, and there are no small molecule
agonists available, at present NGF must be delivered
directly to the central nervous system. Experimental methods include gene transfer, cell grafts, or direct administration of NGF through intracerebroventricular infusion (Eagle et al 1995; Gustilo et al 1999; Hefti 1986; Kromer
1987; Martinez-Serrano and Bjorklund 1998; Williams et
al 1986; Winkler et al 2000; Wyman et al 1999). In
general, in animals with deafferentation lesions and impaired cognitive function, these approaches have been
shown to enhance cholinergic neuron integrity and restore
some behavioral functions.
In AD patients, there is limited evidence at present that
NGF may be beneficial. Treatment with NGF was tested in
three patients, with no clear improvement in cognitive
function (Eriksdotter Jonhagen et al 1998). In this study,
the potential therapeutic benefits of NGF infusion were
offset by severe pain. Large quantities of NGF administered over long periods are likely to diffuse to affect the
peripheral nervous system and cause pain. These peripheral side effects at present limit the therapeutic use of
intracerebroventricular NGF. In addition to the painful
side effects in humans, recent animal studies document a
number of adverse behavioral effects and Schwann cell
proliferation after high doses of NGF administered by the
intracerebroventricular route (Winkler et al 2000). On this
basis, alternative means of delivering NGF to the CNS
must be considered. In the future, gene therapy and
transplantation techniques may prove successful, but these
strategies are confined to the laboratory at present.
It may be possible to use pharmacologic approaches to
increase the production of NGF within the CNS. The

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189

potential advantages of this strategy are that NGF should
be induced in the correct brain regions. In addition, this
approach is likely to circumvent the peripheral side effects
of NGF and would not require surgical procedures. Nerve
growth factor mRNA expression and protein secretion are
tightly linked and can be regulated by a variety of
compounds in vitro, including known drugs that act on
neurotransmitter receptors (reviewed in Bennett et al
1999). Therefore, numerous agents have the potential to
enhance NGF expression and secretion in the brain.
A number of nonclassic compounds have shown to
increase synthesis of NGF in astrocytes. These drugs
include a phosphodiesterase inhibitor, propentofylline
(Rother et al 1998) and various quinone derivatives, such
as idebenone, pyrroloquinoline quinone, and 1,4-benzoquinone (Takeuchi et al 1990; Yamada et al 1999;
Yamaguchi et al 1993). It is argued that these drugs may
improve cholinergic neuron survival and enhance cognitive performance via increasing astrocyte secretion of
NGF. How these drugs modulate NGF levels is unknown,
and it is not known whether their clinical or preclinical
efficacy in AD (if any) resides specifically in the ability of
these compounds to increase NGF levels.

Cholinergic and Glutamatergic Regulation
of NGF Levels: Prospects for AD Treatment
In AD there is extensive loss of cholinergic and glutamatergic input into the hippocampus (reviewed in Francis et
al 1993, 1999). Loss of nicotinic acetylcholine receptors is
a clear finding in AD (Court 2001; Nordberg 2001),
suggesting that fast cholinergic transmission is particularly
affected in the disease. In the hippocampus, nicotinic
receptors effect multiple neurotransmitter systems, which
may underlie the cognitive enhancing effects of nicotinic
receptor agonists and opposite effects of nicotinic antagonists. In addition to effects on classical neurotransmitter
systems, it is possible that the cholinergic and glutamatergic inputs may be endogenous regulators of NGF in the
hippocampus—and therefore that hippocampal NGF can
be regulated by conventional and novel drugs targeted to
the cholinergic or glutamatergic systems.
Several studies have measured NGF mRNA or protein
levels after deafferentation lesions, using chemical or
surgical procedures to remove the cholinergic or glutamatergic input to the hippocampus (Table 1). Although these
studies show that glutamate and acetylcholine neurons are
regulators of NGF, the results are difficult to interpret.
Selective deafferentation lesions of the cholinergic neurons of the septohippocampal system cause upregulation
of NGF levels in the hippocampus that is most prominent
weeks to months after experimental injury (Table 1);
however, if a more destructive lesion (fimbria fornix

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M. Rattray

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Table 1. Afferent Regulation of Nerve Growth Factor (NGF) Levels in the Hippocampus
Deafferentation lesion

Effect

Reference

AF64A lesion of
septohippocampal cholinergic
neurons

1NGF protein and mRNA 7 weeks
after lesion

Hellweg et al 1997

Ig92 saporin lesion of
septohippocampal cholinergic
neurons

1NGF protein, 3 months after lesion
1NGF protein, 2 weeks after lesion
No change NGF mRNA
1 week–5 months after lesion
Blocks seizure-induced increases in NGF

Gu et al 1998
Roßner et al 1997
Yu et al 1995

2NGF mRNA

1NGF protein 10 d after lesion

da Penha Berzaghi et al 1993
Lapchak et al 1992
Gasser et al 1986
Larkfors et al 1987

1NGF mRNA
1NGF mRNA (rapid)
1NGF protein 3,8 d after lesion

Gwag et al 1994
Forster et al 1997
Conner et al 1994

Fimbria fornix transection
removing cholinergic and other
inputs
Angular bundle transection
and/or entorhinal cortex lesion

transection) is used, which cuts the axons of both the
cholinergic and noncholinergic septohippocampal neurons, there is a long-lasting downregulation of NGF
mRNA in the hippocampus (Table 1). Surgery to reduce
glutamate input into the hippocampus produces upregulation of NGF levels (Table 1). These studies broadly
suggest that CNS lesions mimicking the hippocampal
deafferentation in AD lead to upregulation of NGF levels
in targets and that NGF levels are subject to complex
control mechanisms. It is difficult to extrapolate these
findings into AD, where there is little if any change in
NGF mRNA, but rather enhanced levels of protein due to
impaired retrograde transport of NGF.
Because the lesion studies suggest that cholinergic and
glutamatergic afferents regulate NGF production in the
hippocampus, cholinergic drugs, glutamatergic drugs, or
both may be effective inducers of NGF. Nicotinic drugs,
as well as drugs that enhance acetylcholine transmission,
are effective in improving cognitive function in both
normal humans and in AD patients (Francis et al 1999;
Newhouse 2001), and there is the interesting possibility
that they may influence NGF. Perhaps surprisingly, there
are few studies to have looked at this possibility in vivo. A
recent study has tested the effects of local administration
of cholinergic drugs into the hippocampus on neurotrophin
mRNA levels (French et al 1999). Drug doses were
carefully chosen in relation to previous studies, and only
doses that caused no hippocampal neuronal death and did
not cause seizures were used.
Nicotine, when injected into the hippocampus, caused a
persistent increase in NGF mRNA levels in the principal
neurons of the hippocampus that emerged 2 to 4 hours
after drug administration and was still apparent 72 hours
after drug administration, the last time point analyzed in
the study. This contrasted with the muscarinic receptor

Kokaia et al 1996

agonist pilocarpine, which produced a very transient
increase in NGF mRNA levels (French et al 1999). The
effect was also highly selective for NGF, because BDNF
mRNA levels showed a rapid and transient increase after
nicotine administration (French et al 1999). The nicotineinduced increase of NGF mRNA levels was blocked by
N-methyl-D-aspartate and a-amino-3-hydroxy-5-methyl4-isoxazole propionate glutamate receptor antagonists,
consistent with the increase being dependent on nicotineinduced release of glutamate within the hippocampus
(Gray et al 1996). The study strongly suggests that quite
large and long-lasting induction of NGF in appropriate

Figure 2. Nicotinic–nerve growth factor (NGF) interactions in
the hippocampus. Current evidence suggests that local infusions
of nicotine into the hippocampus increases NGF messenger RNA
levels. The results are consistent with the model whereby
acetylcholine (ACh) is released from nerve terminals to activate
nicotinic receptors on glutamatergic neurons. Glutamate is released and via a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA) receptors, or
both, it stimulates NGF production in cells intrinsic to the
hippocampus. Nerve growth factor will activate trkA receptors
on the cholinergic nerve terminals, providing trophic support and
influencing the activity of these neurons to further enhance ACh
release.

Nicotine and NGF

CNS regions can be achieved with drug doses that are
pharmacologically relevant.
These findings suggest a model of reciprocal interaction
between cholinergic afferents and NGF-producing principal neurons in the hippocampus (Figure 2), an idea
developed by other researchers (e.g., Knipper et al 1994;
Yu et al 1995), which provides a testable concept for
future studies. The model shown in Figure 2 defines a
reinforcing loop whereby acetylcholine release elevates
NGF production, and then NGF affects acetylcholine
neurons to provide trophic support and further enhance
acetylcholine synthesis and release. The implications of
this model are that some cholinergic drugs may have
cognitive enhancing effects beyond their primary effects
as cholinesterase inhibitors and receptor agonists. A number of cholinergic drugs, including nicotinic receptor
agonists, are currently in development for use in AD
(Francis et al 1999). It is possible that in addition to having
direct effects on cognition (e.g., Newhouse 2001), this
kind of drug may provide a positive neurotrophic influence to the cholinergic neurons that may help both to
prevent their degeneration in AD and to enhance cholinergic neurotransmission.

Some of the work presented in this article was supported by the
Wellcome Trust and the Medical Research Council of Great Britain.
I gratefully acknowledge my collaborators on these projects: Michael
V. Sofroniew, John V. Priestley, and Stephen B. McMahon.
Aspects of this work were presented at the symposium “Nicotine
Mechanisms in Alzheimer’s Disease,” March 16 –18, 2000, Fajardo,
Puerto Rico. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Janssen
Pharmaeutica LP.

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