Nicotinic Receptor Subtypes and Cognitive Function

Edward D. Levin
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center,
Neurobehavioral Research Laboratory, Box 3412, Durham, North Carolina 27710

Received 5 June 2002; accepted 12 July 2002

ABSTRACT: Nicotinic receptor systems are in- ventral hippocampus and basolateral amygdala are in-
volved in a wide variety of behavioral functions includ- volved in working memory function. Working memory
ing cognitive function. Nicotinic medications may pro- impairments were caused by local infusion of either
vide beneficial treatment for cognitive dysfunction such ␣4␤2 or ␣7 antagonists. Ventral hippocampal ␣4␤2
as Alzheimer’s disease, schizophrenia, and attention def- blockade-induced working memory deficits are reversed
icit hyperactivity disorder (ADHD). Nicotine has been by chronic systemic nicotine treatment, while ventral
shown to improve attentional performance in all of these hippocampal ␣7 blockade-induced working memory
disorders. Better efficacy with fewer side effects might deficits were not found to be reversed by the same
be achieved with novel nicotinic ligands selective for nicotine regimen. Interestingly, ␣4␤2 and ␣7 induced
particular nicotinic subtypes. To develop these novel deficits were not found to be additive in either the ven-
selective nicotinic ligands it is important to use animal tral hippocampus or the basolateral amygdala. In fact,
models to determine the critical neurobehavioral bases in the amygdala, ␣7 antagonist cotreatment actually
for nicotinic involvement in cognitive function. Nicotine- reversed the working memory impairment caused by
induced cognitive improvement in rats is most consis- ␣4␤2 antagonist administration. These studies of the
tently seen in working memory tasks. We have found neural nicotinic mechanisms underlying cognitive func-
that both acute and chronic nicotine administration sig- tion are key for opening avenues for development of safe
nificantly improves working memory performance of and effective nicotinic treatments for cognitive dysfunc-
rats in the radial-arm maze. The pharmacologic and tion. © 2002 Wiley Periodicals, Inc. J Neurobiol 53: 633– 640, 2002
anatomic mechanisms for this effect have been examined Keywords: nicotine; nicotinic; ␣4␤2 receptors; ␣7 recep-
in our laboratory in a series of local drug infusion tors; hippocampus; amygdala; working memory; radial-
studies. Both ␣4␤2 and ␣7 nicotinic receptors in the arm maze

INTRODUCTION ceptor deficits have been shown to be key in the

cognitive impairments of Alzheimer’s disease (Nord-
Nicotine has been shown to improve cognitive func- berg and Winblad, 1986; Shimohama et al., 1986;
tion including memory and attention in humans and Whitehouse et al., 1988; Giacobini et al., 1989; Lon-
experimental animals (Newhouse et al., 1997; Levin don et al., 1989; Kellar and Wonnacott, 1990; Rinne
and Simon, 1998; Rusted et al., 2000). Nicotinic re- et al., 1991; Perry et al., 1995) and schizophrenia
(Durany et al., 2000; Leonard et al., 2000). Nicotine
delivered through means other than smoking such as
Correspondence to: E. D. Levin ( edlevin@duke.edu). transdermal patches may prove to be a safe and ef-
Contract grant sponsor: National Institute on Drug Abuse; con-
tract grant number: DA 11943. fective treatment for cognitive impairment seen in
Contact grant sponsor: National Institute of Mental Health; Alzheimer’s disease, schizophrenia and attention def-
contract grant number: MH 64494.
icit hyperactivity disorder (ADHD) and other types of
© 2002 Wiley Periodicals, Inc.
Published online in Wiley InterScience (www.interscience.wiley.com). cognitive dysfunction (Wilson et al., 1995; Levin et
DOI 10.1002/neu.10151 al., 1996b; Levin et al., 1996d; Newhouse et al., 1997;
633
634 Levin

White and Levin, 1999). Novel nicotinic agonists that ment in cognitive function. Thus, the onset and sub-
are selective for particular nicotinic receptor subtypes sequent adaptation to decreased receptor action can be
may provide more specific therapeutic benefits for studied much in the same way it can be studied with
treating cognitive dysfunction with fewer adverse side local infusion pharmacologic methods. There may be
effects. Different types of cognitive dysfunctions the drawback of being unable to de-induce the con-
seem to involve different types of nicotinic receptor ditional knockout to study the reexpression of the
subtypes. For example, ␣4-containing receptors seem nicotinic receptor system after compensation has
to be particularly decreased in Alzheimer’s disease taken place. This is relatively straightforward with
(Martin-Ruiz et al., 1999), while ␣4␤2 and ␣7 recep- pharmacologic methods with the cessation of chronic
tors both seem to be decreased in schizophrenia (Du- local infusion. However, there remains the distinct
rany et al., 2000; Leonard et al., 2000). The key to the advantage of the selectivity of the knockout method-
development of safe and effective novel nicotinic ology in contrast to the invariable multimodal actions
agonists for different types of cognitive dysfunction is of drug probes. Any drug has a variety of actions.
better understanding of the differential role nicotinic Greater specificity can be achieved with lower doses
receptor subtypes play in cognitive function. Animal of drug administration, but even at low doses multiple
models of cognitive function and dysfunction are es- actions cannot be completely avoided.
sential in the development of novel nicotinic medica- Pharmacologic and molecular approaches have
tions. Not only do animal models provide a test for the complementary advantages. Combined approaches
functional effects of new nicotinic ligands; they can may be useful (Ohno et al., 2001). When both kinds of
also help determine the critical neurobehavioral studies are conducted the field can use the converging
mechanisms underlying nicotinic-induced cognitive evidence to more accurately determine the mecha-
improvement. nisms by which nicotinic receptors influence cogni-
tive function.

PHARMACOLOGICAL AND GENETIC

APPROACHES TO RECEPTOR SYSTEMIC NICOTINE EFFECTS
SUBTYPE ANALYSIS ON MEMORY

Great advances have been made in recent years using We have used the pharmacologic approach to help
molecular approaches to the study of receptor func- determine the involvement of nicotinic systems in
tion. As described in other articles in this issue, very cognitive function as well as testing nicotinic treat-
specific manipulations can be made using genetic ment in models of cognitive dysfunction. In rat (for
methods to eliminate one type of nicotinic receptor reviews see Brioni et al., 1997; Levin and Simon,
subunit. However, data from genetic knockouts of 1998) and monkey (for review see Buccafusco et al.,
individual nicotinic receptors can be difficult to inter- 1996) models of nicotine-induced cognitive improve-
pret. The absence of these receptors from the zygote ment is more clearly seen in terms of effects on
stage onward can cause a variety of cascading effects. memory performance than attention, although atten-
Nicotinic receptors play important roles in the control tional performance has been documented to be im-
of neurodevelopment (Levin and Slotkin, 1998; proved by nicotine in some studies (Mirza and Stol-
Broide and Leslie, 1999). Eliminating select popula- erman, 1998; McGaughy et al., 1999; Stolerman et al.,
tions of nicotinic receptors can have effects on neu- 2000). These animal models are vital for the determi-
rodevelopment that last a lifetime. It would be diffi- nation of the mechanisms of nicotinic-induced cogni-
cult to differentiate the persisting effects of these tive improvement.
neurodevelopmental alterations from the effects of Importantly, for possible clinical use we have
lacking a particular nicotinic receptor subtype in found that the efficacy of nicotine improvement of
adulthood. Among the effects on neurodevelopment memory does not diminish with chronic administra-
may be compensatory changes to “wire around” the tion. Rats were pretrained on the eight-arm radial
missing receptor system, such that function is rela- maze with a food reinforcement at the end of each
tively preserved. These developmental problems can arm. They learned to avoid entering an arm more than
be sidestepped with the use of inducible knockouts. once because each arm was only baited once. After
Inducible knockout techniques can also make use of they reached asymptotic levels of performance (they
local infusion of the inducing agent so that regional improved to their best level and maintained that
selectivity can be used to determine the anatomic level), nicotinic drug treatments were started. The
definition of the nicotinic receptor subtype involve- choice accuracy used in the eight-arm maze where all
 Nicotinic Receptors and Memory 635

memory, while four were never baited to test refer-

ence memory. Those four unbaited arms were kept
constant for each rat. Chronic nicotine treatment spe-
cifically improved working memory performance in
the 16-arm radial maze, but had no discernible effect
on reference memory (Levin et al., 1996a). This se-
lective improvement of working memory is similar to
the effect seen with acute nicotine injection (Levin et
al., 1997).
More than one nicotinic receptor subtype seems to
be involved in cognitive function. Nicotinic receptor
subtype selective drugs are being developed to pro-
vide cognitive improvement with fewer side effects.
Both ␣4␤2 and ␣7 nicotinic agonists are effective.
Anabaseine-related analogs that are selective ␣7 ago-
nists significantly improved working memory in
younger and aged rats (Meyer et al., 1994; Arendash
et al., 1995; Meyer et al., 1997). Systemic adminis-
Figure 1 Chronic nicotine (5 or 12 mg/kg/day) effects on tration of another type of ␣7 agonist ARR 17779
rats’ eight-arm radial maze choice accuracy s measured by significantly improved learning on the radial-arm
entries to repeat (the number of correct entries before the
maze and reversed the working memory impairment
first repeated entry) (Levin et al., 1990; Levin and Rose,
caused by fimbria-fornix sections (Levin et al.,
1990; Levin et al., 1993a, 1993b; Levin and Rose, Levin et
al., 1995; Levin et al., 1996c; Levin and Torry, 1996). PRE 1999a). ABT-418, an ␣4␤2 agonist, improved mem-
⫽ pretreatment baseline performance; NW1, NW2 and ory in monkeys (Buccafusco et al., 1995) and reversed
NW3 ⫽ Weeks 1 through 3 of chronic nicotine treatment; the memory impairment caused by septal lesions
WW1 and WW2 ⫽ Weeks 1 and 2 after withdrawal from (Decker et al., 1994). Another ␣4␤2 agonist RJR
chronic nicotine treatment. The choice accuracy measure is 2403 significantly improved working memory (Levin
entries to repeat (the number of correct entries before an and Christopher, 2002), an effect that persisted for at
error occurs). Both chronic nicotine continuous infusion least 6 h after a single subcutaneous injection. Both
doses caused improvement during the period of administra- ␣7 and ␣4␤2 nicotinic agonists have been found to
tion. Only the 12 mg/kg/day dose caused persisting im- improve memory function. However, this does not
provement after withdrawal.
mean that other nicotinic receptor subtypes may not
be involved as well. Filling in that blank part of the
the arms are baited with a reinforcer is entries to map will depend on the development of more differ-
repeat which is the number of correct entries the rat entially selective nicotinic agonists and antagonists so
makes before it repeats a choice. We have found in 20 that more complete information concerning the in-
years of research that entries to repeat is a sensitive volvement of a broader diversity of nicotinic receptor
and reliable measure of choice accuracy in the eight- subtypes on memory can be determined.
arm radial maze when all arms are baited. As shown
in Figure 1, we have found that chronic infusion of
either 5 or 12 mg/kg/day of nicotine significantly HIPPOCAMPAL INVOLVEMENT IN
improves memory performance on the eight-arm NICOTINIC ACTIONS ON MEMORY
maze over 3– 4 weeks of treatment (Levin et al., 1990;
Levin and Rose, 1990; Levin et al., 1993a, 1993b; For local infusion studies, antagonists offer the ad-
Levin and Rose, Levin et al., 1995; Levin et al., vantage of having a unidirectional effect of blocking
1996c; Levin and Torry, 1996). Chronic coadminis- nicotinic receptors. In contrast, agonists often have a
tration of mecamylamine with chronic nicotine infu- bidirectional effect of stimulation and desensitization.
sion blocked the nicotine-induced memory improve- This can be especially problematic for interpretation
ment (Levin et al., 1993a). Further testing was of local infusion studies in which there is a spatial
conducted with other sets of rats using a 16-arm maze concentration gradient to consider. Close to the local
to differentiate working memory (session-specific infusion site, high doses of agonist may have a more
changing memory) from reference memory (invariant pronounced desensitizing effect than further from the
across session memory). Twelve of the arms were infusion site where net stimulation of nicotinic recep-
baited at the beginning of each session to test working tors may be more preserved with lower concentrations
636 Levin

of the agonist. These concentric spheres of nicotinic

receptor desensitization and activation could make
interpretation of local infusion of nicotinic receptor
agonists quite confusing. Local nicotinic receptor an-
tagonist infusion has in our series of studies demon-
strated the importance of nicotinic receptors in the
limbic system and the midbrain for spatial working
memory function.
The hippocampus was the initial region we inves-
tigated. A plethora of studies had demonstrated the
importance of the hippocampus for working memory
function. In particular, cholinergic innervation of the
hippocampus by neurons in the medial septal area was
shown to be critical for optimal memory performance.
Muscarinic ACh receptors in the hippocampus were
the focus of much of the early work in this area.
Certainly, hippocampal muscarinic receptors are im-
portant. Local hippocampal scopolamine infusion has
been shown in our studies and others to significantly
impair working memory performance (Kim and
Levin, 1996). Septohippocampal cholinergic innerva-
tion uses not only muscarinic but also nicotinic recep-
tors. Autoradiographic studies have demonstrated the
presence of ␣7 (Whiteaker et al., 1999; Fabian-Fine et
al., 2001) and ␣4 (Didier et al., 1995) containing
nicotinic receptors in the hippocampus. We have
found the hippocampus to be important for chronic
nicotine effects on memory function. Small hip-
pocampal ibotenic acid lesions, which did not signif-
icantly impair working memory performance, blocked Figure 2 Acute infusion of the nonspecific nicotinic an-
the chronic nicotine-induced memory improvement tagonist mecamylamine into the ventral tegmental area,
substantia nigra, ventral hippocampus and nucleus accum-
(Levin et al., 1999b). The critical site of action for
bens on eight-arm radial maze choice accuracy (entries to
chronic nicotine in the hippocampus appears to be repeat, mean ⫾ S.E.M.) (Levin et al., 1994; Kim and Levin,
postsynaptic to the septohippocampal projection. 1996). Impairments seen with mecamylamine infusions into
Chronic nicotine-induced memory improvement was the ventral tegmental area, substantia nigra and ventral
not attenuated by knife-cut lesions of this fiber bundle hippocampus, but not with the same doses infused into the
(Levin et al., 1993b). nucleus accumbens.
Ohno and coworkers initially demonstrated that
local infusion of the nonspecific nicotinic receptor
antagonist mecamylamine into the hippocampus effect after infusion into the nucleus accumbens (Fig.
caused working memory but not reference memory 2) (Kim and Levin, 1996).
impairment in rats in a three spatial choice maze task Subsequent studies with more specific nicotinic
(Ohno et al., 1993). We subsequently replicated their receptor antagonists in the ventral hippocampus
finding. As shown in Figure 2, the same dose range of showed the involvement of both ␣7 and ␣4␤2 nico-
mecamylamine significantly impaired choice accu- tinic receptors with working memory function. As
racy in the eight-arm radial maze after infusion into shown in Figure 3, significant dose-effect induced
the ventral hippocampus (Kim and Levin, 1996). This radial-arm maze working memory deficits were seen
effect was not specific to the hippocampus. The same after acute ventral hippocampal infusion of either the
dose range of mecamylamine in the midbrain dopa- ␣7 antagonist MLA or the ␣4␤2 antagonist DH␤E
mine nuclei (ventral tegmental area and substantia (Felix and Levin, 1997). One caveat of this experi-
nigra) also caused significant working memory im- ment is that at the high end of the dose range tested,
pairments (Fig. 2) (Levin et al., 1994). Interestingly, these drugs may have had lessened specificity.
the specificity of this dose range of mecamylamine To determine if lower, more specific doses of MLA
was seen in its locus of action with no discernable and DH␤E would affect memory performance, their
 Nicotinic Receptors and Memory 637

Figure 3 Acute nicotinic antagonist infusion the ␣4␤2

nicotinic antagonist DH␤E and the ␣7 nicotinic antagonist
MLA into the ventral hippocampus and eight-arm radial
maze choice accuracy (mean ⫾ S.E.M.) (Felix and Levin,
1997). Both antagonists caused working memory impair-
ments in the eight-arm maze, albeit at high doses.

effects were tested in animals trained on the more

difficult 16-arm radial maze (Levin et al., 2002). As Figure 5 Chronic systemic nicotine infusion (5 mg/kg/
shown in Figure 4, both MLA and DH␤E significantly day) and low-dose acute nicotinic antagonist infusion the
impaired working memory at lower doses in the more ␣4␤2 nicotinic antagonist DH␤E and the ␣7 nicotinic an-
difficult 16-arm maze. Reference memory was only tagonist MLA into the ventral hippocampus and eight-arm
very slightly affected (data not shown). Interestingly, radial maze choice accuracy (mean ⫾ S.E.M.) (Bancroft
the two nicotinic receptor antagonists did not have and Levin, 2000; Bettany and Levin, 2001). Both DH␤E
additive effects when administered together. This was and MLA caused working memory impairments. Chronic
not due to a ceiling in the number of errors possible on systemic nicotine infusion reversed the DH␤E-induced im-
pairment but not the MLA-induced impairment.
this maze. We have seen substantially more errors in
response to other drug manipulations such as NMDA
receptor blockade with dizocilpine (Levin et al., 1998). The nonadditivity of simultaneous ␣7 and
␣4␤2 blockade in the ventral hippocampus may be
due to some mechanistic interaction that limits their
total common effect, such as convergence on hip-
pocampal GABA interneurons (Alkondon and Albu-
querque, 2001).
Both acute DH␤E and MLA infusion into the
ventral hippocampus caused significant working
memory impairment but they respond to systemic
nicotine in different ways. Figure 5 shows two exper-
iments in which equimolar doses of these antagonists
were infused into the ventral hippocampus (Bancroft
and Levin, 2000; Bettany and Levin, 2001). They had
similar effects impairing working memory accuracy
in the eight-arm radial maze. However, chronic sys-
temic nicotine infusion (5 mg/kg/day) had a differen-
Figure 4 Low-dose acute nicotinic antagonist infusion of
tial effect on the impairments caused by these two
the ␣4␤2 nicotinic antagonist DH␤E and the ␣7 nicotinic
drugs. The DH␤E-induced memory deficit was elim-
antagonist MLA into the ventral hippocampus and 16-arm
radial maze choice accuracy (mean ⫾ S.E.M.) (Levin et al., inated by chronic systemic nicotine while the MLA-
2002). Both antagonists caused working memory impair- induced deficit was not.
ments in the 16-arm maze at lower doses than in the eight- Both ␣4␤2 and ␣7 nicotinic receptor subtypes in
arm maze. The impairments caused by DH␤E and MLA the hippocampus are important for working memory
were not additive. function. As shown in Figure 3, memory in the radial-
638 Levin

arm maze was impaired by local hippocampal infu-

sion of either DH␤E, the ␣4␤2 antagonist, or MLA,
the ␣7 antagonist (Felix and Levin, 1997; Levin et al.,
2002), as well as the nicotinic receptor channel
blocker mecamylamine (Kim and Levin, 1996).
Chronic systemic nicotine was found to effectively
overcome the working memory deficit caused by hip-
pocampal infusion of the ␣4␤2 antagonist DH␤E
(Bancroft and Levin, 2000). However, the same dose
of chronic systemic nicotine that reversed DH␤E-
induced working memory impairments was ineffec-
tive in attenuating intrahippocampal infusions of
equimolar doses of the ␣7 antagonist MLA (Bettany Figure 6 Low-dose acute nicotinic antagonist infusion the
and Levin, 2001). These data suggest that although ␣4␤2 nicotinic antagonist DH␤E and the ␣7 nicotinic an-
ventral hippocampal ␣7 and ␣4␤2 nicotinic receptors tagonist MLA into the basolateral amygdala and 16-arm
are important for memory function, ␣7 receptors may radial maze choice accuracy (mean ⫾ sem) (Addy et al.,
be more essential for the expression of the actions of 2002). Both antagonists caused working memory impair-
systemic nicotine on working memory function. ments in the 16-arm maze. The impairments caused by
DH␤E and MLA were not additive. In fact, the 6.75 ␮g/side
dose of DH␤E reversed the impairment caused by 6.75
TOPICS FOR FURTHER RESEARCH ␮g/side of MLA.

Certainly, the hippocampus is not the only brain area because of the availability of relatively selective li-
important for nicotinic involvement in memory func- gands for these receptor subtypes. As other nicotinic
tion. As discussed above, our earlier results showed receptor subtype selective agonists and antagonists
that infusions of the nonspecific nicotinic antagonist become available, the other nicotinic receptor sub-
mecamylamine into the ventral tegmental area and types can be more easily studied.
substantia nigra significantly impaired working mem-
ory performance, whereas the same doses infused into
the nucleus accumbens did not significantly affect CONCLUSIONS
memory performance. The amygdala appears to be
important for nicotinic actions on spatial memory. Nicotinic systems are vital in the neural basis of
Amygdalar nicotinic antagonist infusion effects on cognitive function. Nicotinic-based therapeutic treat-
memory have also been examined. In an initial study ments may be useful for the treatment of a variety of
(Addy et al., 2002), we found that as in the ventral cognitive disorders including Alzheimer’s disease,
hippocampus, local infusion of MLA or DH␤E into schizophrenia, and attention deficit hyperactivity dis-
the basolateral amygdala caused significant impair- order (ADHD). Whole animal models are critical for
ments in working memory as measured by 16-arm determining the neurobehavioral mechanisms of the
maze choice accuracy. Also, like with ventral hip- cognitive effects of nicotinic treatments, including
pocampal infusion, the combination of MLA and critical nicotinic receptor subtypes and their anatomic
DH␤E did not cause an additive effect. In fact, with localization and interactions with other neural sys-
basolateral amygdalar infusion coadministration of tems. Mechanistic whole animal studies can help im-
DH␤E with MLA actually significantly reduced the prove the understanding of the neurobiology of mem-
working memory error rate back down to control ory and aid in the development of therapeutic agents
levels (Fig. 6). The basolateral amygdala has been for memory dysfunction.
known to be important for memory of fear condition-
ing (Maren, 1999), but its role in spatial appetitive
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