It is not ‘‘either/or’’: Activation and desensitization of nicotinic
acetylcholine receptors both contribute to behaviors related to nicotine
addiction and mood
Marina R. Picciotto*, Nii A. Addy, Yann S. Mineur, Darlene H. Brunzell
Department of Psychiatry, Yale University School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT 06508, USA
Received 15 August 2007; received in revised form 19 November 2007; accepted 18 December 2007
Nicotine can both activate and desensitize/inactivate nicotinic acetylcholine receptors (nAChRs). An ongoing controversy in the field is towhat
extent the behavioral effects of nicotine result from activation of nAChRs, and to what extent receptor desensitization is involved in these
behavioral processes. Recent electrophysiological studies have shown that both nAChR activation and desensitization contribute to the effects of
nicotine in the brain, and these experiments have provided cellular mechanisms that could underlie the contribution of both these processes to
nicotine-mediated behaviors. For instance, desensitization of nAChRs may contribute to the salience of environmental cues associated with
smoking behaviorand activation and desensitization of nAChRs may contributeto both primary and conditioned drug reward. Similarly, studies of
the antidepressant-like effects of nicotinic agents have revealed a balance between activation and desensitization of nAChRs. This review will
examine the evidence for the contribution of these two very different consequences of nicotine administration to behaviors related to nicotine
addiction, including processes related to drug reinforcement and affective modulation. We conclude that there are effects of nAChR activation and
desensitization on drug reinforcement and affective behavior, and that both processes are important in the behavioral consequences of nicotine in
# 2007 Elsevier Ltd. All rights reserved.
Keywords: Nicotinic acetylcholine receptors; Desensitization; Animal models; Knockout mice; Depression; Mood
1.Activation and desensitization of nicotinic acetylcholine receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.Functional properties of nAChRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.Desensitization of nAChRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4.Upregulation of nAChRs following chronic nicotine exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5.Continued activation as well as desensitization of nAChRs following chronic exposure to nicotine . . . . . . . . . . . . . . . .
Nicotine reinforcement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.nAChR subtypes that contribute to nicotine reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.Desensitization of nAChRs may contribute to salience of environmental cues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.nAChR activation and desensitization contribute to primary and conditioned reward . . . . . . . . . . . . . . . . . . . . . . . . . .
Antidepressant action of nicotinic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Progress in Neurobiology 84 (2008) 329–342
Abbreviations: nAChR, nicotinic acetylcholine receptor; ACh, acetylcholine; a7*; b2*; etc., * denotes other subunits that may not have been identified; PET,
positron emission tomography; VTA, ventral tegmental area; NAc, nucleus accumbens; DA, dopamine; 5-HT, serotonin; KO, knockout mouse; MLA, methylly-
caconitine; DHbE, dihydro-beta-erythroidine; Glu, glutamate; GABA, gamma-aminobutyric acid.
* Corresponding author. Tel.: +1 203 737 2041; fax: +1 203 737 2043.
E-mail address: firstname.lastname@example.org (M.R. Picciotto).
0301-0082/$ – see front matter # 2007 Elsevier Ltd. All rights reserved.
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The cholinergic hypothesis of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Smoking and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Paradoxical effects of nicotinic agents in depression: balance between activation and desensitization . . . . . . . . . . . . . . .
Classical antidepressants can block nAChRs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Activation/desensitization of nAChR subtypes in depression-like behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Anatomical loci underlying nicotinic effects in depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Activation and desensitization of nicotinic
Whereas it is intuitive that activation of nicotinic acetylcho-
line receptors (nAChRs) by nicotine can result in behavioral
consequences, it is also the case that desensitization of
nAChRs, by interrupting the transmission of endogenous
acetylcholine, can also alter neuronal function and result in
behavioral changes. Emerging evidence for electrophysiologi-
cal consequences of both nAChR activation and desensitization
has provided mechanisms that are consistent with the
contribution of both of these processes to nicotine-mediated
behaviors. This review will examine the evidence for the
contribution of these two very different consequences of
nicotine administration to behaviors related to nicotine
addiction, including processes related to drug reinforcement
and affective modulation.
1.2. Functional properties of nAChRs
Nicotine that enters the central nervous system acts at
nAChRs that are located throughout the brain on various
neuronal populations and are found at the soma as well as on
pre- and post-synaptic terminals (McGehee et al., 1995;
Wonnacott, 1997). These receptors function as pentameric
structures composed of either five alpha subunits (homomeric
receptors) or a combination of alpha and beta subunits
(heteromeric receptors) (Cooper et al., 1991; Sargent, 1993).
The identified receptor subunits in the brain include a2 through
a7 subunits as well as b2, b3 and b4 subunits (Boulter et al.,
1987; Couturier et al., 1990a,b; Duvoisin et al., 1989; Sargent,
1993; Wada et al., 1988). The two nAChR subtypes expressed
most widely in the brain are the a7* nAChRs (where asterisk
(*) denotes other nAChR subunits that may not have been
identified) and the a4/b2* nAChRs (Picciotto et al., 1998). The
b2* nAChRs are thought to have the highest affinity for
nicotine and other nicotinic agonists (Lippiello et al., 1987;
McGehee and Role, 1995; Picciotto et al., 1995) while a7*
nAChRs are thought tohave a lower affinity fornicotineinvitro
(Papke and Thinschmidt, 1998; Wonnacott, 1986).
binds at the interface between an alpha and a neighboring alpha
or beta subunit, causing a conformational change and opening
of the channel pore (Galzi and Changeux, 1995; Miyazawa
et al., 2003) to allow influx of sodium and calcium (Le ´na and
Changeux, 1997; Letz et al., 1997; Rogers et al., 1997). A
fundamental property of nAChRs is their susceptibility to
desensitization and inactivation following, and indeed in some
cases independent of, channel opening (Giniatullin et al.,
2005). The equilibrium between channel opening, desensitiza-
tion and inactivation was originally described by Changeux and
colleagues who proposed an allosteric model of nAChR states,
and has been refined for different nAChR subtypes using
experimental measurements of the rate constants for the
transitions between these states (Changeux and Edelstein,
2005; Changeux et al., 1984; Quick and Lester, 2002).
1.3. Desensitization of nAChRs
Studies of nAChR subunits expressed in Xenopus oocytes,
as well as native currents in brain slices, originally suggested
that a7* nAChRs were particularly susceptible to inactivation,
making a7-dependent currents difficult to measure unless
agonists were delivered very rapidly, whereas b2* and b4*
nAChRs exhibited desensitization in response to nicotine
these in vitro preparations (Couturier et al., 1990a; Giniatullin
et al., 2005; Pidoplichko et al., 1997). More recent studies have
shown that presynaptic effects of lower concentrations of
nicotine, that are blocked by nicotinic agents thought to be
selective for a7* nAChRs, persist in the continued presence of
nicotinein rat(Mansvelder etal., 2002) andmouse(Wooltorton
et al., 2003) brain slices, whereas presynaptic effects that are
blocked with agents thought to be selective for b2* nAChRs
desensitize during continued nicotine application in the brain
slice (Mansvelder et al., 2002; Mansvelder and McGehee,
2000). One question that has not yet been answered is whether
the pre- and post-synaptic nAChR subtypes differ in their
susceptibility to desensitization, and whether nAChRs in
different neuronal populations are differentially sensitive to
desensitization. One possibility is that accessory proteins
strongly influence the likelihood that nAChRs will undergo
desensitization. For example, the Lynx1 protein can accelerate
the desensitization of various nAChR subtypes, whereas
knockout of Lynx1 in mice results in increased nAChR
activation that ultimately causes neuronal degeneration (Miwa
et al., 2006, 1999). Thus, it would be interesting to determine
the relative susceptibility of a7* and b2* nAChRs to
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 330
desensitization in pre- and post-synaptic responses of nicotine
in mice lacking Lynx1.
Despite the decreased response of nAChRs to agonists in the
desensitized state, desensitized nAChRs have a higher affinity
for ACh and other ligands than those in the ‘‘activatable’’ state
(Heidmann et al., 1983; Quick and Lester, 2002); thus
equilibrium binding experiments, particularly those using
concentrations of nicotine near the Kd for the desensitized
state, are likely to measure nAChRs in the high affinity
(desensitized) state predominantly. Increased nicotine binding
in the brain after chronic nicotine exposure measured in living
human subjects using very low concentrations of radiolabeled
nicotinic compounds (Staley et al., 2006) may therefore reflect,
in part, an increased pool of nAChRs in the desensitized state.
Furthermore, as will be discussed throughout this review, the
balance between nicotine-mediated activation and desensitiza-
tion of specific subtypes of nAChRs can influence the
functional and behavioral responses to nicotine exposure.
The likelihood that chronic nicotine exposure results in both
peaks of activation and long-term desensitization of nAChRs
suggests that functional responses associated with chronic
nicotine exposure due to smoking are due, at least in part, to
nAChR desensitization. For instance, it has been suggested that
maintained nAChR desensitization may be important for
relieving nicotine withdrawal in human smokers (Brody et al.,
2006) as is discussed below.
In human subjects, profound effects that are likely due to
nAChR activation and desensitization have been observed after
just 1 cigarette. Nicotine levels in the blood, which reach the
brain within 8–10 s (Matta et al., 2007), typically peak shortly
after cigarette smoking, ?50 ng/ml (300 nM) 5 min after 1
cigarette (Henningfield et al., 1993), and then show a steady
decline in the subsequent 20 min after smoking (Benowitz
et al., 1989). Nicotine levels in chronic smokers measured
during the day, however, reveal blood nicotine concentrations
ranging from 10 to 50 ng/ml (60–300 nM) (Benowitz et al.,
1989); thus, the sustained elevated nicotine levels experienced
by chronic smokers throughout the day could result in cycles of
both nAChR activation and desensitization. The desensitiza-
tion, in particular, may be related to receptor occupancy given
reports suggest that nAChR occupancy is nearly complete after
1 cigarette (Brody et al., 2006). In a recent positron emission
tomography (PET) imaging study, b2* occupancy was ?88%
percent after just 1 cigarette, with corresponding plasma levels
that have been shown to lead to 50% desensitization of a4b2
nAChRs (Brody et al., 2006). Since venous plasma levels in
chronic smokers after multiple cigarettes are higher than those
obtained with a single cigarette, the authors suggest that
smoking in these individuals may lead to nearly complete high
affinity nAChR occupancy and desensitization and that
smoking maintains this desensitization (Brody et al., 2006).
It should be noted, however, that this PET ligand may only
reveal the highest affinity subclass of nAChRs, which are likely
to be in the desensitized state (Changeux et al., 1984). Thus,
nAChRs in the activatable state may not be measured using this
1.4. Upregulation of nAChRs following chronic nicotine
While chronic nicotine exposure leads to receptor desensi-
tization, it also leads to compensatory changes such as
upregulation of nicotine binding sites. Chronic nicotine
exposure has been shown to lead to robust nAChR upregulation
in both human smokers and in animal models. For instance, in
post-mortem brains, increased high affinity nAChR binding has
been observed in several regions including the cortex and
hippocampus (Benwell et al., 1988; Perry et al., 1999). In
addition to these post-mortem observations, upregulation of
b2* nAChRs in the cortex and striatum have been observed
using SPECT imaging of human smokers even after the 7 days
of smoking abstinence required to clear nicotine from the brain
(Staley et al., 2006). Thus, it appears that both chronic nicotine
administration and early withdrawal are sufficient to drive
nAChR upregulation. This observation is supported by animal
studies, which also show nAChR upregulation after chronic
nicotine administration. Both a7* and b2* nAChR upregula-
tion have been observed in various brain regions after chronic
nicotine administration ranging from 8 to 21 days of exposure,
although b2* nAChRs appear to be more consistently
upregulated across multiple studies (Marks et al., 1983;
Schwartz and Kellar, 1985). Indeed, b2 nAChR subunit
knockout mice do not show upregulation of nicotine binding
sites (McCallum et al., 2006a). While it is clear that a4/b2*
nAChRs are upregulated following chronic nicotine exposure,
data on upregulation of a6/b2* nAChRs has been more
variable. Studies of a6/b2* nAChRs after nicotine exposure
have reported upregulation (Parker et al., 2004), down-
regulation (Lai et al., 2005) and no change (McCallum
et al., 2006b) in this nAChR subtype. Further studies will be
required to clarify this issue, but it seems likely that a4/b2*
nAChRs are more reliably upregulated by nicotine exposure
than a6/b2* nAChRs.
A number of recent studies have examined the mechanisms
underlying nAChR upregulation, and a number of different
pathways have been implicated in this process. For example,
nicotine can potentiate nAChR assembly in the endoplasmic
reticulum followed by transport of the receptor to the cell
surface (Corringer et al., 2006; Darsow et al., 2005; Sallette
et al., 2005; Vallejo et al., 2005). One question that is still a
point of controversy is whether the increase in nicotine binding
in functional, activatable nAChRs, or whether increased
binding simply reflects an increase in desensitized nAChRs.
It appears that the increased surface expression of nAChRs
following chronic nicotine can indeed result in increased
activation of nAChRs (Vallejo et al., 2005; Wonnacott, 1990),
although the discrepancy between studies suggests that there is
a dynamic equilibrium between activation and desensitization
of nAChRs following chronic nicotine exposure. For instance,
nicotine-mediated neurotransmitter release can occur after
nicotine exposure that desensitizes nAChRs (Benwell and
Balfour, 1992; Iyaniwura et al., 2001). Furthermore, as will be
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 331
described in the next section, nicotine exposure can lead to
simultaneous activation and desensitization of different nAChR
1.5. Continued activation as well as desensitization of
nAChRs following chronic exposure to nicotine
Despite compelling evidence that chronic nicotine exposure,
for example in human smokers, results in profound nAChR
desensitization, examination of the different rates of activation
and desensitization between a7 and b2* nAChRs suggests that
not all nAChRs are desensitized under these conditions. In the
ventral tegmental area (VTA), b2* nAChRs are found on the
soma of DA neurons (Klink et al., 2001) as well as on
GABAergic terminals (Mansvelder et al., 2002), whereas a7*
nAChRs can be found at lower levels on DA neurons, but are
also expressed on glutamatergic terminals (Mansvelder et al.,
2002; Mansvelder and McGehee, 2000). Activation of b2*
nAChRs on the soma of DA neurons stimulates the firing of
these neurons, as well as acute DA release (Picciotto et al.,
1998). As mentioned earlier, at nicotine concentrations of
500 nM or higher, electrophysiological studies in combination
with pharmacological agents to isolate individual nAChR-
mediated currents have shown that a7* nAChR activation is
characterized by fast currents that desensitize on a millisecond
timescale while b2* nAChRs desensitize more slowly on a
second timescale (Couturier et al., 1990a; Giniatullin et al.,
2005; Pidoplichko et al., 1997). However, at lower nicotine
concentrations, which may be more similar to those observed at
steady state in a smoker’s brain (250 nM), b2* nAChRs also
desensitize rapidly (Mansvelder et al., 2002; Mansvelder and
McGehee, 2000). Furthermore, when even lower nicotine
concentrations (20–80 nM) were examined in an attempt to
model the low levels experienced by chronic smokers over long
time periods, robust b2* desensitization was observed without
any a7 desensitization (Wooltorton et al., 2003). This b2*
desensitization may be due to a process known as high-affinity
desensitization that is observed with low concentration of the
agonist, whereby desensitization can occur without activation
of the receptor (Giniatullin et al., 2005). This type of
desensitization without movement through the open state is
predicted by the allosteric model of transitions between closed,
activated and desensitized states, and is based on stabilization
of the highest affinity, desensitized state of the receptors by
continued presence of low levels of the ligand (Changeux et al.,
1984). Thus, these subtype specific effects illustrate how
nAChR activation and desensitization can occur simulta-
neously in response to nicotine administration.
Simultaneous activation and desensitization of specific
nAChR subtypes can influence functional responses to nicotine
in part on GABAergic terminals (Mansvelder et al., 2002) and
glutamatergic terminals (Mansvelder et al., 2002; Mansvelder
and McGehee, 2000). The low level nicotine concentrations
experienced by smokers over long periods are suggested to
preferentially desensitize a4b2 nAChRs on GABAergic
terminals and not a7 nAChRs on glutamatergic terminals in
the VTA, thus shifting the presynaptic effects of nicotine from a
mixed inhibition and excitation of DA neurons, toward the
glutamatergic response to nicotine (Mansvelder et al., 2002;
Mansvelder and McGehee, 2000). This shift in the functional
output in the VTA also has implications for nicotine-mediated
behaviors, as will be further discussed throughout this review.
Another functional output that is influenced by rates of
nAChR activation and desensitization is nicotine-mediated
administration leads to increased release of dopamine that
persists, and indeed shows a sensitized response (increased
dopamine (DA) release in response to challenge with the same
nicotine dose), despite any nAChR desensitization that is likely
to have occurred (Benwell and Balfour, 1992; Iyaniwura et al.,
2001). This appears to be due in part to adaptations in the
glutamatergic system downstream of nAChRs (Ferrari et al.,
2002). Thus, even when nicotine results in desensitization of
nAChRs, increased downstream responses may result in
increased behavioral responses to nicotine challenge (Fig. 1).
mediated dopamine responses, particularly after nAChR
desensitization, are more likely to occur if the dopaminergic
neurons projecting from the VTA to the nucleus accumbens
(NAc) are stimulated and firing in burst mode (Rice and Cragg,
shownthat application ofboth nicotine andan antagonistofb2*
nAChRs to dopaminergic terminals decreases DA release when
the DA neurons are firing tonically, but permits ongoing DA
release when DA neurons are in a phasic state (Rice and Cragg,
2004; Zhang and Sulzer, 2004). These data suggest that
desensitization of nAChRs on DA terminals increases the
exposure shifts the balance toward glutamate-mediated excita-
tion of DA neurons (Mansvelder et al., 2002; Wooltorton et al.,
VTA and increased filtering in the striatum/nucleus accumbens
suggests that chronic nicotine exposure would greatly increase
responsetoenvironmental stimulithatincreaseDA neuron burst
firing, and would greatly decrease DA responses under
conditions when these neurons were firing tonically (Rice and
Cragg, 2004; Zhang and Sulzer, 2004).
Studies in systems involving neurotransmitters other than
DA have also demonstrated instances where nicotinic agonists
and antagonists have resulted in the same neurochemical effect.
For instance, while nicotine increases serotonin (5-HT) release
in hippocampal slices, the nAChR antagonist mecamylamine
also increases 5-HT levels similar to nicotine (Kenny et al.,
2000). This could result from similar physiological mechan-
isms to those described above that have been studied in the
VTA. A number of studies in knockout (KO) mice lacking the
b2 subunit of the nAChR have shown that both functional
deletion in KO mice and nicotine administration in wild-type
mice can lead to the same cellular or behavioral effects,
suggesting that nicotine administration may normally desensi-
tize b2* nAChRs in these paradigms and that desensitization
then contributes to these cellular or behavioral responses
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 332
(Brunzell et al., 2006; Cohen et al., 2005; Mechawar et al.,
2004; Picciotto et al., 1995). As will be discussed in the next
section, the behavioral consequences of nicotine exposure
related to nicotine reinforcement may thus result from a
combination of nAChR activation and desensitization.
Finally, while there is much less data available, it is
important to note that a number of nAChR subtypes are
expressed on non-neuronal cell types in brain (Gahring et al.,
2004a,b) that could potentially modulate the response to
nicotine. For instance, nicotine can increase intracellular free
calcium and promote calcium waves in astrocytes through
activation of nAChRs (Oikawa et al., 2005; Sharma and
Vijayaraghavan, 2001). More data are requiredto determine the
effects that these nAChRs could have on nicotine-induced
behavioral and neuronal modulation related to reward and
mood and to determine whether there is equivalent desensitiza-
tion of nAChRs in non-neuronal cells following nicotine
exposure as has been seen in neurons.
2. Nicotine reinforcement
Tobacco dependence is a complex behavioral phenomenon.
Although initiation of tobacco use is likely to involve the
primary reinforcing effects of nicotine, those initiating
smoking, and particularly habitual smokers, also derive
pleasure from the sensory cues associated with smoking
(Perkins et al., 2001; Rose, 2006; Rose et al., 1985). External
cues greatly enhance nicotine self-administration in rodents
(Stein et al., 1998), smoking-associated cues activate the VTA
and DA projection areas including the nucleus accumbens,
cingulate cortex and amygdala (Due et al., 2002). As noted in
Section 1,it isclear that acuteactivationof nAChRs by nicotine
can stimulate the firing of DA neurons (Grenhoff et al., 1986;
Klink et al., 2001; Picciotto et al., 1998; Svensson et al., 1990).
Studies in striatal synaptosomes, however, show that lower
doses of nicotine, consistent with those in the blood of human
smokers, result in desensitization rather than activation of
nAChRs as measured by nicotine-dependent dopamine release
(Grady et al., 1992, 1994; Rowell and Duggan, 1998; Rowell
and Hillebrand, 1994). In addition, electrophysiological studies
showthat steadystates of nicotine that would be achievedin the
bloodstream of a regular smoker can desensitize midbrain
nAChRs with a time course of recovery that requires several
may explain why the first cigarette of the day is often reported
as the most pleasurable (Russell, 1989), but it does not explain
why people continue to smoke throughout the day. This section
will review the evidence suggesting that nAChRs in both the
activatable and the desensitized state might drive both primary
and conditioned reward associated with tobacco smoking.
2.2. nAChR subtypes that contribute to nicotine reward
The primary rewarding effects of nicotine are likely
regulated by a combination of events that include the activation
and desensitization of various nAChR subtypes. An accumula-
tion of data suggests that both the b2* and a7 nAChR subtypes
contribute to nicotine-associated increases in DA release and
associated nicotine-dependent behaviors (Corrigall et al., 1994;
Epping-Jordan et al., 1999; Laviolette and van der Kooy, 2003;
Mansvelder et al., 2002; Picciotto et al., 1998; Pidoplichko
et al., 2004; Shoaib and Stolerman, 1994). Pretreatment with
methyllycaconitine (MLA), an a7 nAChR antagonist, can
Fig. 1. Activation and desensitization contribute to physiological effects of
nicotine in the mesolimbic circuitry. (A) Baseline: in the absence of nicotine,
the endogenous neurotransmitter acetylcholine (ACh) is released in the ventral
tegmental area (VTA) from terminals of cholinergic brainstem nuclei including
the pedunculopontine tegmental area (Lanc ¸a et al., 2000). The mixed choli-
nergic stimulationof glutamatergic (Glu)and GABAergic (GABA) terminalsin
the VTA supports both tonic and phasic activity of dopaminergic (DA) neurons
(Grenhoff and Svensson, 1992). In addition, cholinergic interneurons release
ACh onto the terminals of dopaminergic neurons (DA) in the nucleus accum-
bens (NAc) (Zhou et al., 2001). At baseline, ACh in the striatum allows tonic
firing of DA neurons to result in significant DA release (Rice and Cragg, 2004;
Zhang and Sulzer, 2004). (B) Extended nicotine exposure: the effect of nicotine
in the VTA is initially to increase the firing rate of DA neurons (Grenhoff et al.,
glutamate release (Grillner and Svensson, 2000; Schilstrom et al., 1998), and
the nicotine-mediated increase in glutamate release does not desensitize during
continuous administration of nicotine (Mansvelder et al., 2002; Wooltorton
et al., 2003). By contrast,the ability of nicotineto increaseGABA release in the
VTA undergoes rapid desensitization (Mansvelder et al., 2002; Wooltorton
et al., 2003). In the NAc, nicotine initially increases release of DA from
terminals, but these nAChRs undergo rapid desensitization (Grady et al.,
1994; Rowell and Hillebrand, 1994). Desensitization of these nAChRs
decreases the ability of tonic firing to release DA in the NAc, but maintains
the effect of phasic firing on DA release, thereby acting as a filter for events
increasing phasic firing (Rice and Cragg, 2004; Zhang and Sulzer, 2004). Thus,
nicotineacts in the VTA to increasephasic firing, and in the NAc to increase the
salience of that increase in phasic firing.
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 333
attenuate nicotine self-administration suggesting a potential
role for VTA a7* receptors in nicotine reward (Markou and
Paterson, 2001); but at doses necessary to penetrate the blood
brain barrier, MLA has significant affinity for a6/b2* nAChRs
(Mogg et al., 2002) suggesting a potential role of these receptor
subtypes in nicotine self-administration. At the DA terminals,
however, b2* nAChRs (a4/b2, a6/b3/b2, a4/a6/b3/b2, a4/
a5/b2) and not a7* nAChRs, support nicotine-stimulated DA
release (Salminen et al., 2004, Champtiaux and Changeux,
Activation of b2* nAChRs in the VTA appears to be critical
for the primary reinforcing effects of nicotine. Local and
systemic administration of a selective b2* nAChR antagonist,
dihydro-beta-erythroidine (DHbE), blocks nicotine
administration in rodents (Corrigall et al., 1992; Grottick
et al., 2000). Studies in b2* nAChR null mutant mice further
show that b2* nAChRs are necessary for nicotine self-
administration, DA-dependent locomotor activation, nicotine-
associated enhancement of NAc DA release, and nicotine-
associated enhancement of conditioned reinforcement (Brun-
zell et al., 2006; King et al., 2004; Marubio et al., 2003;
Picciotto et al., 1998). While several subtypes of b2* nAChRs
are found in the VTA, a number of pieces of evidence suggest
that a4/b2* nAChRs are critical mediators of nicotine reward.
Mice with a genetic knockout of the a4 nAChR subunit fail to
show nicotine-dependent enhancements of DA release (Mar-
ubio et al., 2003), and a single nucleotide mutation that renders
the a4* nAChRs hypersensitive to nicotine stimulation
promotes conditioned place preference at otherwise sub-
optimal doses of nicotine (Tapper et al., 2004). Interestingly,
a4* nAChR knockout mice show an increase in basal DA
release in the NAc (Marubio et al., 2003), suggesting that
inactivation of a4b2* nAChRs may enhance baseline
dopaminergic tone. In addition to a4/b2* nAChRs, a6/b2*
nAChRs are highly expressed in DA neurons. Unfortunately,
studies using knockout mice have not yet elucidated the role of
these nAChRs in nicotine-related phenotypes, likely because
the a4 subunit can substitute for the a6 subunit in animals
2002). Thus, pharmacological or conditional knockdown
approaches will be necessary to identify the distinct roles of
a6b2* nAChRs in nicotine reinforcement.
2.3. Desensitization of nAChRs may contribute to
salience of environmental cues
Electrochemical cyclic voltammetry studies suggest that
nAChRs integrate the activity state of DA neurons to adjust
dopaminergic tone (Rice and Cragg, 2004; Zhang and Sulzer,
2004). As noted in Section 1, nicotine and nicotinic antagonists
result in similar effects on this tuning process, suggesting that
desensitization of nAChRs regulates this integrative process
(Rice and Cragg, 2004; Zhang and Sulzer, 2004) (Fig. 1). Both
nicotine and DHbE decrease DA release when the DA neurons
are firing tonically, but enhance DA release when DA neurons
are in a phasic state (Rice and Cragg, 2004), as one would
expect during the presentation of a reward (Schultz, 2002). As
environmental cues gain more control over behavior following
repeated presentation of cues with a primary reinforcer, there is
a transition from phasic activity of DA neurons in response to
the primary reinforcer, to phasic activity in response to the
conditioned stimulus (cue) (Schultz, 2002). Electrochemical
cyclic voltammetry studies show that DA release also shifts
contingency from the primary reinforcer to the cue after
Pavlovian pairing of primary and conditioned stimuli (Day
et al., 2007).
Paradoxically, although nicotine administration enhances
subunit also elevates conditioned reinforcement at baseline
(Brunzell et al., 2006). DA release in the NAc shell is necessary
potential mechanism for the elevated conditioned reinforcement
Desensitizationofb2* nAChRs onGABA terminals inthe VTA
following nicotine exposure results in increased activity of DA
neurons (Mansvelder et al., 2002; Wooltorton et al., 2003), and
may thereforeregulate conditionedreinforcementbydecreasing
an inhibitory effect of the endogenous neurotransmitter
acetylcholine on dopaminergic tone. Together, these data
suggest that desensitization of high affinity b2* nAChRs could
potentially enhance the response to environmental cues paired
with smoking and make them more salient.
2.4. nAChR activation and desensitization contribute to
primary and conditioned reward
As has been suggested for other drugs of abuse, sensitization
of the DA system might regulate nicotine-associated condi-
tioned reward (Robbins and Everitt, 2002; Robinson and
Berridge,1993; TaylorandRobbins,1984).Acute,chronic, and
prior chronic nicotine exposure all enhance conditioned
reinforcement (Brunzell et al., 2006; Olausson et al., 2003,
2004a,b). Unlike conditioned reinforcement at baseline, which
seems to be enhanced by nAChR inactivation, nicotine-
associated enhancement of conditioned reward appears to
require activation of nAChRs. The non-selective nAChR
antagonist mecamylamine blocks the ability of nicotine to
enhance conditioned reinforcement (Olausson et al., 2004a),
and b2* nAChR null mutant mice fail to show nicotine-
associated enhancement of conditioned reinforcement (Brun-
zell et al., 2006). These data suggest that activation of b2*
nAChRs on DA soma, and potentially activation of a7*
nAChRs, may contribute to nicotine-associated elevations in
As noted in Section 1, in human smokers, studies using a
PET ligand recognizing b2* nAChRs, have shown that very
low levels of nicotine are sufficient to displace the majority of
nAChR binding in human brain (Brody et al., 2006) and one
smoking episode is sufficient to occupy most of the brain’s high
affinity b2* nAChRs for up to 5 h after a period of abstinence
(Staley et al., 2006). The increased availability of nAChRs
following overnight abstinence ought to activate a surplus of
high affinity nAChRs, making the first cigarette highly
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342334
reinforcing to smokers. In support of this theory, smokers show
elevated nicotine-associated DA release compared to non-
smokers (Brody et al., 2004). The subsequent desensitization of
the high affinity b2* nAChRs that occurs prior to finishing the
first cigarette could also enhance the conditioned reinforcing
properties of cues associated with smoking as discussed earlier
in this section, by increasing DA release from neurons firing
phasically. Throughout the remainder of the day, cigarette-
associated cues and pleasurable events such as eating would be
expected to shift dopamine neurons into a phasic state, during
which time smoking a cigarette might enhance DA release via
desensitization of b2* nAChRs. Hence, it is possible that
smokers ingest nicotine to both activate and desensitize
nAChRs in the brain.
3. Antidepressant action of nicotinic agents
A number of studies have suggested that at least a subset of
smokers continue smoking to manage mood symptoms. Thus,
in addition to the primary and secondary reinforcing effects of
nicotine, the ability of nicotine to alter affective states is also
likely to be important for ongoing smoking. Interestingly,
antidepressants can also aid in smoking cessation. For instance,
high doses of fluoxetine or other classes of antidepressants can
increase quit rates, and these effects are reversed once the
treatment is stopped (Hall et al., 1998; Hughes et al., 2000;
Kotlyar et al., 2001). The most striking connection between
smoking and depression is the norepinephrine–dopamine
reuptake inhibitor bupropion, which is prescribed as both an
antidepressant and as an aid to smoking cessation (Dwoskin
et al., 2006; Hayford et al., 1999). This suggests that depression
and nicotine dependence may share some common neuronal
substrates. This section will therefore discuss the data on
activation and desensitization of nAChRs in behaviors related
to mood and depression.
3.2. The cholinergic hypothesis of depression
The involvement of the cholinergic system in the etiology of
depression, while not as prominent in the literature as the
monoamine hypothesis, was put forward several decades ago.
a fine balance exists between cholinergic and noradrenergic
systems, and that over-activation of the cholinergic component
would lead to depression (Janowsky et al., 1972). This
hypothesis stems from clinical observations showing that
physostigmine, a potent inhibitor of acetylcholinesterase that
increasesAChconcentration, could exacerbatemood disorders.
Following treatment with physostigmine, non-depressed sub-
jects had heightened anxiety, aggression and irritability,
whereas depressed patients exhibited prolonged and more
severe symptoms (Janowsky et al., 1974) and a majority of
bipolar patients exhibited signs of depression (Oppenheim
et al., 1979). Cholinergic sensitivity was also suggested as a
marker of genetic predisposition for depression (Janowsky
et al., 1994). In addition, alteration of central acetylcholine
turnover has been shown in response to prolonged stress-
exposure (Giladet al., 1987), a keyfactor in the development of
depressive behavior (Nemeroff, 2004; Penza et al., 2003).
Finally, imaging studies have demonstrated that depressed
patients have increased central concentrations of choline (the
limiting precursor of ACh) and this is reversed after recovery
(Charles et al., 1994). Another study found elevated levels of
choline in the orbitofrontal cortex of adolescents with mood
disorders (Steingard et al., 2000). One concern is that
Alzheimer’s disease patients treated with acetylcholinesterase
inhibitors might develop greater symptoms of depression;
however, it is difficult to make conclusions about the role of
ACh in mood symptoms in these subjects, since the mood of
Alzheimer’s patients is likely to be affected by numerous
factors unrelated to the direct effects of the cholinesterase
Initially, it was believed that the ability of elevated ACh to
result in depression-like symptoms was mediated primarily
through muscarinic ACh receptors, and it was not clear whether
the effects of heightened cholinergic tone occurred through
peripheral or central mechanisms (Janowsky et al., 1972).
However,studies have since demonstrated that nAChRs are key
in the response to cholinergic stimulation triggered by
cholinergic agents including physostigmine (Rhodes et al.,
2001). Taken together, these data strongly suggest that
heightened cholinergic activity and/or sensivity can contribute
to the development and the exacerbation of symptoms of
depression. By extension, it also suggests that over-activation
ofnAChRs byendogenous AChcouldpotentially be partofthis
complex mechanism. While it is clear that the monoaminergic
systems are critical for the treatment of depression, a role for
the cholinergic system, perhaps through modulation of
monoaminergic signaling, is also likely.
3.3. Smoking and depression
Nicotine dependence shows strong comorbidity with mood
disorders including depression. Clinical studies have demon-
strated a connection between smoking behavior and genetic
susceptibility to depression (Cinciripini et al., 2004; Lerman
et al., 1998) and numerous observations suggest that smoking
and nicotine can regulate mood in humans and animals.
Depressed patients are twice as likely to smoke than thegeneral
population (Diwan et al., 1998; Glassman et al., 1990). Further,
the nicotine patch can alleviate symptoms of depression in non-
smokers (Salin-Pascual et al., 1995) and it is believedthat some
depressed patients initiate smoking as an attempt to self-
medicate depressive symptoms with nicotine (Markou et al.,
1998; Patton et al., 1998). Cigarettes might therefore be used as
an efficient method to self-administer nicotine to a desired
level. Similarly, it is believed that schizophrenic subjects, who
have a very high rate of smoking, may be medicating an
attentional deficit with the nicotine in cigarette smoke. An
interesting set of studies has suggested that these patients are
more likely to smoke because they attribute greater benefits to
smoking than a control population (Spring et al., 2003). Indeed,
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 335
nicotine can reverse some of the neurocognitive impairments
et al., 2005).
It should be noted, however, that the self-medication
hypothesis for smoking alone cannot explain nicotine addiction
in depressed subjects, since a large proportion of depressed
patients do not smoke, and craving for cigarettes is strongly
influenced by other factors including environmental cues
associated with smoking (see Section 2) and developmental
exposure to nicotine through maternal smoking (Ernst et al.,
2001) or during adolescence (Patton et al., 1998).
Smoking cessation can also exacerbate symptoms of
depression (Glassman et al., 1990), although the effects of
acute nicotinewithdrawal on mood may be the result of distinct
mechanisms from the ability of nicotine in tobacco to affect
mood during ongoing smoking.Similarly,while depression and
smoking are correlated and share potential common pathways,
determinants but that a causal relationship does not exist
et al., 2003).
3.4. Paradoxical effects of nicotinic agents in depression:
balance between activation and desensitization
Animal studies have also shown that chronic nicotine
administration can elicit antidepressant-like effects in rats both
in the learned helplessness (Semba et al., 1998) and the forced
swim (Djuric et al., 1999; Tizabi et al., 1999) paradigms.
Further, the nicotinic partial agonist cytisine results in
antidepressant-like effects in several behavioral paradigms in
mice (Mineur et al., 2007).
Because nicotine is a nicotinic receptor agonist, it seems
paradoxical that nicotine administration is antidepressant. If
nicotine can relieve depressive symptoms, then why does
physostigmine, which increases acetylcholine concentration,
increase depressive symptoms? Further, several classes of
nicotinic agonists have antidepressant actions in both human
studies and animal models (Ferguson et al., 2000; Gatto et al.,
2004) but several nicotinic antagonists have shown to have
potent antidepressant effects (Ferguson et al., 2000; Shytle
et al., 2002). These data can be reconciled if the ability of
nicotine to desensitize nAChRs is primarily responsible for its
ability to alleviate depressive symptoms. Thus, nicotine and
other nicotinic agonists and partial agonists may be anti-
depressant because they limit the ability of endogenous ACh to
signal through nAChRs. Similarly, nicotinic antagonists would
exert the same effect on depressive symptoms by decreasing
cholinergic tone on nAChRs.
Data in human subjects support the idea that blockade rather
than activationofnAChRs resultsinantidepressant-like effects.
For example, the non-competitive, non-selective nAChR
antagonist mecamylamine as well as the nicotine patch,
decrease symptoms of depression in depressed non-smoking
patients and patients with Tourette’s syndrome (Dursun and
Kutcher, 1999; Mihailescu and Drucker-Colin, 2000; Salin-
Pascual et al., 1995, 1996). Mecamylamine and the competitive
nicotinic antagonist DhbE also have antidepressant-like
properties in mice (Caldarone et al., 2004; Mineur et al.,
2007; Rabenstein et al., 2006).
A number of studies have shown that chronic administration
of nicotinic agonists (including nicotine through regular
smoking or as delivered through the nicotine patch) can
desensitize rather than activate nAChRs (Reitstetter et al.,
1999), leading to functional antagonism (Gentry and Lukas,
2002; Quick and Lester, 2002). Such an effect would be
expected to be antidepressant (Djuric et al., 1999; Kinnunen
et al., 1996; Tizabi et al., 1999). Indeed, this hypothesis
suggests that the increased depressive symptoms observed in
somepatients followingacutecessationfromsmoking might be
explained by the fact that the clearance of nicotine following
smokingcessation coupledwithpersistent nAChRupregulation
(Staley et al., 2006) results in increased ability of ACh to
activate these upregulated nAChRs.
3.5. Classical antidepressants can block nAChRs
Interestingly, a significant body of evidence is accumulating
suggesting that many of the commonly used antidepressants can
(Shytle et al., 2002) for a detailed review). The doses at which
these compounds are able to antagonize nAChRs are in many
cases within the low micro-molar range reached when
antidepressants are administered chronically. Thus, while the
primary targets of classical antidepressants are on monoamine
systems, it is possible that nicotinic antagonism could be one
component that plays a role in antidepressant response.
Animalstudiessupportthe ideathatnAChRs maycontribute
to the antidepressant effects of classical antidepressants. For
example, the tricyclic antidepressant amitriptyline has no effect
in neurochemical and behavioral assays of antidepressant
efficacy in KO mice lacking the b2 nAChR subunit, strongly
suggesting that b2* nAChRs are involved in this antidepressant
response (Caldarone et al., 2004). Further, a subthreshold dose
of the nicotinic antagonist mecamylamine combined with the
tricyclic antidepressant amitriptyline results in antidepressant-
like effects in mice, reinforcing the idea that blockade of
nAChRs yields antidepressant-like effects (Caldarone et al.,
2004); however, it is not yet clear whether this additive effect
suggeststhatnicotiniccompounds andclassical antidepressants
act on similar pathways.
3.6. Activation/desensitization of nAChR subtypes in
Pharmacological studies have demonstrated that non-
selective antagonism of nAChRs with mecamylamine can be
antidepressant,butfurther studieshavetried tofocusontherole
of specific receptor subtypes in this effect. For instance, the a4/
b2* subclass of nAChRs is necessary for the antidepressant-
and using selective pharmacological agents (Gatto et al., 2004;
Mineur et al., 2007; Rabenstein et al., 2006). In addition, at
baseline, KO mice lacking the b2* subunit show decreased
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 336
depression-like behavior in the forced swim and tail suspension
tests at baseline, supporting the possibility that the b2 KO
mimics the effect of nAChR blockade (Caldarone et al., 2004;
Rabenstein et al., 2006). However, other subtypes of nAChR
may also be involved in the effects of nicotinic agents. For
example, like mice lacking the b2 nAChR subunit, KO mice
lacking the a7 subunit do not respond to the broad-spectrum
nAChR antagonist mecamylamine in mouse models of
antidepressant response (Rabenstein et al., 2006). Similarly,
cytisine, a nicotinic partial agonist that blocks a4/b2* nAChRs
but activates a3/b4* and a7* nAChRs (Papke and Porter
Papke, 2002; Picciotto et al., 1995), is also effective in animal
models of antidepressant efficacy (Mineur et al., 2007). Thus, it
is not yet clear whether nAChR antagonism is the only
mechanism underlying the antidepressant effects of nicotine, or
whether antagonism of a4/b2* nAChRs coupled with agonism
of other nAChR subtype(s) may also contribute.
3.7. Anatomical loci underlying nicotinic effects in
The effect of nAChR antagonism appears to be centrally
mediated since unlike the permeant antagonist mecamylamine,
hexamethonium, a nicotinic antagonist that does not cross the
blood–brain barrier, did not result in a significant antidepres-
sant-like response in mice (Rabenstein et al., 2006). The
hippocampus has been a major focus of interest in mood
disorders, essentially because numerous depressed patients
show shrinkage of this brain region (Sheline, 2000), and also
due to the neurotrophic hypothesis of depression (Duman et al.,
1999; Malberg et al., 2000). Both b2* and a7 nAChRs are
found in the hippocampus (Gotti et al., 2006) and KO mice
lacking the b2 nAChR subunit do not show an antidepressant-
induced increase in hippocampal neurogenesis, consistent with
the lack of a behavioral response to amitriptyline treatment
are necessary for the ability of amitriptyline to increase
hippocampal neurogenesis, an effect that has been suggested to
underlie the response to chronic antidepressant treatment
(Malberg et al., 2000; Santarelli et al., 2003).
In addition to the hippocampus, the amygdala is known to
mediate affective behavior and to be the target for classical
antidepressants (Clark et al., 2006; Drevets, 2001). Both
mecamylamine and cytisine, consistent with their antidepres-
sant-like properties, decrease c-fos immunoreactivity in the
basolateral amydgala, indicating a reduction of neuronal
activity in this region (Mineur et al., 2007). This mode of
action would be consistent with observations in patients
showing an increased activity of this structure during
depressive episodes and stress (Drevets, 2001), reversed by
specific antidepressant treatment (Clark et al., 2006). Because
of the correlative nature of the association between nicotinic
effects in the amygdala and antidepressant-like effects, further
studies will be necessary to establish (or refute) a causal link
between decreased activity in basolateral amygdala and the
antidepressant-like properties of nicotinic agents. In addition,
despite the strong comorbidity that exists between mood
disorders and smoking, the overlapping mechanisms/neural
substrates that could explain the link between these two
phenotypes have not yet been identified.
While there are many hypotheses, there is as yet no solid
consensus about the neural substrates and brain loci that are
critical for mood disorders. Similarly, while nAChR antagon-
ism can be antidepressant, it is not yet known whether the
nAChRs involved are pre- or post-synaptic, the cell type(s)
involved and whether nicotinic antagonism leads to a net
reduction of neuronal activity (through direct inhibition, for
instance) or to disinhibition of GABAergic targets. The cell
types on which nAChRs are located (and activated/desensi-
induced by nicotinic agents. Thus, nicotinic receptors located
on monoaminergic neurons represent a particularly relevant
the anatomical substrates underlying the antidepressant effects
of nicotinic agents.
An important caveat to the idea that inactivation of nAChRs
is antidepressant is that the nicotinic antagonist mecamylamine
can block the ability of nicotine to be effective in some models
of antidepressant efficacy in selectively bred rats (Tizabi et al.,
2000). This suggests that nAChR activation can have
antidepressant-like effects, and may reflect the fact that a
similar balance of desensitization of a4/b2* nAChRs and
activation of a7* nAChRs that has been shown in the VTA can
also modulate monoamine systems related to mood.
The studies reviewed here show that there is no simple
relationship between smoking and nAChR activation or
desensitization. Rather, coordinated activation and desensitiza-
tion of a number of different nAChRs on different neuronal
subtypes likely occurs in response to nicotine administration
through smoking. Neither desensitization alone nor activation
alone is sufficient to explain the behavioral consequences of
nicotine intake, just as nicotine reward alone is not sufficient to
explain smoking behavior. Instead, activation and desensitiza-
tion of nAChRs contributeto an ensemble of behavioraleffects,
including nicotine reward, conditioned reinforcement and
modulation of mood, that promote ongoing smoking behavior.
The fact that desensitization contributes significantly to
some of the effects of chronic nicotine intake suggests that
some of the effects of nicotine are due to disruption of
endogenous ACh signaling. While this is easiest to describe
with respect to the cholinergic hypothesis of depression, it is
of normal ACh signaling in the VTA and other brain regions.
This is supported by studies showing that nicotinic antagonists
modulate the rewarding effects of drugs of abuse such as
cocaine (Levin et al., 2000; Reid et al., 1999; Zachariou et al.,
2001; Zanetti et al., 2006), suggesting a role for ACh in reward
circuits more generally than just in nicotine reward.
These studies also suggest that there is a role for tonic ACh
signaling in behaviors related to reward and affect. Micro-
dialysis studies using the no-net-flux method have shown that
M.R. Picciotto et al./Progress in Neurobiology 84 (2008) 329–342 337
the baseline level of extracellular ACh is in the range of 4.5 nM
at rest in the mouse hippocampus (Laplante et al., 2004). One
possibility is that nAChRs act as sensors of tonic ACh levels.
The volume transmission hypothesis suggests that basal levels
of neurotransmitters can coordinate the excitability of
ensembles of neurons across a broad distance (Zoli et al.,
1999). The tonic activation and desensitization of nAChRs in
the DA system, the hippocampus or the amygdala could
regulate reward and affect by setting an overall tone for
neuronal activity in these circuits. Thus, the ability of nAChR
antagonists to decrease cfos activity in the amygdala and other
brain areas (Mineur et al., 2007) reflects disruption of
cholinergic tone in those brain regions that is likely to
contribute to the behavioral effects of these nicotinic agents.
The balance between activation and desensitization of
nAChRs has been elegantly explored in a number of studies
of the DA system (Fig. 1). In this system, the temporal sequence
of activation of b2* nAChRs on DA neurons in the VTA,
mediated activation of glutamate release onto DA neurons
(Mansvelder et al., 2002; Wooltorton et al., 2003). Combined
leading to decreased transmission of tonic DA neuronal firing,
but maintained release of DA in responseto phasic DA neuronal
firing (Rice and Cragg, 2004; Zhang and Sulzer, 2004), this
pattern of nAChR activity could result in increased salience of
environmental cues that were paired with nicotine intake.
nAChR activation and desensitization that could occur more
generally throughout the brain. Future studies may reveal a
similar network level of nicotinic regulation in other systems,
such as the hippocampus and amygdala. Future studies using
could clarify the effects of activation and desensitization of
particular nAChR populations on nicotine-related behaviors.
It is interesting that several of the current therapeutics for
smoking cessation have both activating and desensitizing/
patch does deliver nicotine, but it does so with pharmacoki-
netics which favor desensitization of nAChRs (Gries et al.,
1998). Varenicline is a partial agonist of a4/b2* nAChRs (Coe
et al., 2005), butalso activates a7-type nAChRs (Mihalaket al.,
2006). While there are common behavioral effects observed
between smoked nicotine, nicotine patch and varenicline,
neither patch (Jorenby et al., 1995) nor varenicline are
reinforcing (Rollema et al., 2007). The observation that
nicotine patch or mecamylamine can significantly improve
mood in patients affected by Tourette’s syndrome (Silver et al.,
2001) supports the idea that this effect of the patch is likely to
be a result of nAChR desensitization. Finally, bupropion, while
having effects on monoamine transporters, has also been shown
to be a non-competitive antagonist of nAChRs (Dwoskin et al.,
2006). Thus, it appears that partial agonism or blockade of
nAChRs may be particularly useful for aiding smoking
cessation. One potential reason for this possibility is that
interferencewith cholinergictransmission ameliorates negative
mood symptoms. It would therefore be predicted that a subset
of patients taking varenicline may report that their mood
symptoms are decreased by the drug. Further, partial agonism
or blockade of nAChRs may be helpful in decreasing cue-
induced craving by decreasing the firing rate of VTA neurons,
while maintaining the filtering effect on DA terminals that
allows other salient reward signals to induce DA release in the
In summary, both activation and desensitization appear to
contribute to the primary rewarding properties of nicotine and
tosecondary conditioned reinforcement. Further,it appears that
blockade of nAChRs can be antidepressant-like in animals and
human subjects, through either direct blockade of nAChRs or
functional antagonism through desensitization. Thus, agents,
like nicotine itself, and partial agonists of nAChRs, have the
unique ability to regulate network properties of ensembles of
neurons, through differential activation and desensitization of
nAChRs on excitatory and inhibitory neuronal cell bodies and
terminals.This may beawidespread mechanism underlyingthe
effects of nAChRs on a number of different brain systems.
This work was supported by NIH grants MH77681,
DA13334/AA15632, DA14241, DA10455 and DA00436.
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