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The Journal of Neuroscience, May 1, 2002, 22(9):3338-3341
MINI REVIEW
Neuronal Systems Underlying Behaviors Related to Nicotine
Addiction: Neural Circuits and Molecular Genetics
Marina R.
Picciotto1 and
William A.
Corrigall2
1 Department of Psychiatry, Yale University School of
Medicine, New Haven, Connecticut 06508, and 2 Smoking and
Nicotine Dependence Research, Centre for Addiction and Mental
Health and Department of Physiology, University of Toronto, Toronto,
Ontario M5S 2S1, Canada
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ABSTRACT |
Nicotine addiction is a complex behavioral phenomenon
comprising effects on several neural systems. Recent studies have
expanded initial observations that the actions of nicotine on
dopaminergic systems increase dopaminergic activity and release,
leading to nicotine-induced reinforcement. Indeed, the actions of
nicotine on many systems, including brainstem cholinergic, GABAergic,
noradrenergic, and serotonergic nuclei, may help to
mediate nicotine effects related to addiction. Furthermore,
studies of mice lacking nicotinic acetylcholine receptor subunits or
expressing supersensitive forms of these subunits have begun to tie
together the molecular, neurochemical, and behavioral effects of
nicotine. The use of multiple techniques by many laboratories provides
optimism that the field is advancing toward elucidating the basic
mechanisms of nicotine dependence.
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ARTICLE |
The mesolimbic dopamine (DA)
projection from the ventral tegmental area (VTA) to the nucleus
accumbens (NAc) is a central element in drug-reinforced behaviors and
associated conditioned phenomena (Robinson and Berridge, 1993 ).
Nicotine is not an exception (Di Chiara, 2000); however, recent
evidence suggests that several other neurochemical systems also mediate
the addiction-related behaviors of nicotine (Watkins et al., 2000). In
parallel, contemporary molecular genetics, specifically the
availability of lines of knock-out (KO) mice lacking specific subunits
of the nicotinic acetylcholine receptors (nAChRs) and knock-in (KI)
mice with mutations in these subunits, has allowed investigation of the
physiological and behavioral actions of nicotine and determination of
the nAChR subtypes responsible for its various effects. These domains,
which inform our understanding of nicotine addiction, are reviewed here.
Novel anatomical targets and circuits
One brain region receiving recent attention is the brainstem
pedunculopontine tegmental nucleus (PPTg), which has been implicated in
the acquisition of drug-taking, conditioned behaviors, and brain
stimulation reward (Olmstead et al., 1998; Yeomans et al., 2000).
However, interest in PPTg with respect to nicotine self-administration derives primarily from the observation that this behavior is reduced by
microinfusion of the high-affinity nAChR antagonist
dihydro-  erythroidine (DHE) into the VTA (Corrigall et al.,
1994). Consistent with dialysis studies, this observation suggests that
the VTA is a "unified" target for the behavioral and neurochemical
effects of nicotine on midbrain DA. Logically, these observations
question the role of the cholinergic input to VTA nAChRs, which arises from the PPTg and the adjacent laterodorsal tegmental nucleus (LDTg)
(Fig. 1) (Oakman et al., 1995).
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Figure 1.
This schematic represents the rat brain in
sagittal section, showing the anterior-posterior locations for the
pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental
nucleus (LDTg). The cholinergic input to substantia nigra arises from
neurons in the rostral PPTg (gray circles),
whereas the input to the VTA comes from the LDTg (open
circles), with a component from the caudal PPTg
(filled circles). GABA- and glutamate-containing
neurons also found in PPTg and LDTg may synapse locally as well as
project to other brain regions.
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Lesions that reduce the number of PPTg cholinergic neurons and
intra-PPTg microinfusion of DHE both reduce nicotine
self-administration (Lança et al., 2000a). Fos-immunoreactive
neuronal nuclei are readily observed in PPTg and LDTg after
experimenter-administered nicotine (Lança et al., 2000b) and are
located not in the cholinergic neurons but almost exclusively in
identified GABA and glutamate neurons (W. A. Corrigall, A. J. Lança, and D. J. Martens, unpublished observations).
Intracranial self-stimulation also induces Fos expression in GABAergic
neurons of the mesopontine tegmentum (Nakahara et al., 2001). GABA
mechanisms are implicated in nicotine self-administration as well. Of
several agents microinfused into the PPTg, only GABA agonists reduce
nicotine self-administration selectively, compared with cocaine
(Corrigall et al., 2001, 2002). Although glutamate mechanisms remain to
be tested, these observations suggest that GABA systems in PPTg may be
a key element in nicotine-rewarded behavior.
Nicotine action in the PPTg may not regulate VTA DA, however. PPTg and
LDTg cholinergic projections to midbrain DA are topographic; VTA input
arises mainly from the LDTg and caudal PPTg (Oakman et al., 1995).
Function appears to follow anatomy. VTA DA neurons and DA release in
the NAc are influenced by LDTg cholinergic cells (Forster and Blaha,
2000). Presumed nAChR-bearing neurons in PPTg, the GABA and glutamate
cells, might project independently. Establishing DA dependence or
independence of PPTg mechanisms will be an important next step in
elucidating its role in nicotine addiction.
Other observations suggest additional targets for nicotine dependence,
but in general have received less attention. For example, although they
have not been a major focus in drug abuse, norepinephrine (NE)
mechanisms may be relevant because they are able to modulate midbrain
DA function (Linnér et al., 2001). Moreover, nicotine releases NE
in various CNS regions (Summers and Giacobini, 1995; Fu et al., 1997)
by action at distinct sites and through several nAChR subtypes (Fu et
al., 1998; Léna et al., 1999). Recent evidence on two fronts
implicates NE more directly in nicotine reinforcement. First, the NE
reuptake inhibitor reboxetine attenuates nicotine self-administration
(Bardo et al., 2001), an observation with added interest given that the
smoking cessation treatment bupropion has an NE component to its
action. Second, NE secretion in the hypothalamic paraventricular
nucleus (PVN), measured with microdialysis, has been shown to increase
during continuous nicotine self-administration (Fu et al., 2001);
nAChRs in the nucleus tractus solitarius may be the locus for this
effect (Fu et al., 1997). These observations suggest an important NE
target for investigation. Perhaps the links among hypothalamic
function, stress responses, and nicotine self-administration may be
profitably explored in the future.
Serotonin (5HT) too might be expected to influence nicotine reward:
nicotine alters 5HT release and neuronal activity (Li et al., 1998),
reward-related nicotine effects are modified by 5HT manipulations
[e.g., behavioral sensitization (Olausson et al., 2001)], and DA
neurons are influenced by 5HT processes (Kalivas, 1993). Yet there is
no direct evidence for distinct 5HT circuitry in nicotine
reinforcement. It may be that 5HT processes underlie the co-morbidity
of nicotine dependence and psychiatric disorders (Balfour and Ridley,
2000). For instance, the overlap of 5HT mechanisms in the
anxiolytic/anxiogenic effects of nicotine (Cheeta et al., 2001) and the
presence of such effects during nicotine self-administration (Irvine et
al., 2001) is an avenue for future exploration.
In overview we can say that PPTg mechanisms of yet-to-be-determined
nature, as well as NE mechanisms, appear to be directly involved in
nicotine reinforcement. Systems such as 5HT and others not discussed
here could also be implicated. In consequence, the most compelling
commentary about these studies is that they implicate previously
unexplored CNS processes in nicotine addiction. As these processes are
plumbed in the future, they will no doubt expand our knowledge of how
drugs gain control of behavior.
Studies of nicotine-modulated systems in KO mice
Recent developments in molecular genetics have also contributed
greatly to the understanding of systems underlying nicotine reinforcement and related behaviors. The nAChR subtypes responsible for
nicotine-mediated stimulation of the DA system have been identified, in
part, in studies using KO mice. Nicotine increases the firing rate of
DA neurons (Grenhoff et al., 1986; Pidoplichko et al., 1997) and
increases DA release from synaptic terminals (Rowell et al., 1987).
Mice lacking the 2 subunit lack all high-affinity binding sites for
nicotine in the VTA and SN (Picciotto et al., 1998), whereas most of
these sites are absent in  4 subunit KO mice (Marubio et al.,
1999).
An elegant study combining RT-PCR and patch-clamp physiology in
wild-type (WT) mice and mice lacking the 4, 2, or 7 subunits showed that most DA neurons in the midbrain express two nAChR subtypes
(Klink et al., 2001). Both types are sensitive to DHE, and the
second subtype is also sensitive to low concentrations of -conotoxin
MII and methyllycaconitine (MLA), although neither subtype contains the
7 subunit. These two classes of nAChRs are thought to be made up of
the 4/5/2 and the 4/5/6/2 subunits, respectively.
An 7 subunit-containing nAChR is also expressed in somewhat less
than half of the DA neurons. The continued presence of a slow,
MLA-sensitive current in DA neurons in 7 subunit KO mice, and its
absence in 2 subunit KO mice (Klink et al., 2001), suggests that
MLA-sensitive nAChRs on VTA neurons that are stimulated by low
concentrations of nicotine (Pidoplichko et al., 1997) may not contain
the 7 subunit. In slices through the SN and VTA, Ca2+ influx could be evoked with either
nicotine or choline, suggesting that both 2 and 7
subunit-containing nAChRs contribute to this effect (Tsuneki et al.,
2000).
The 6 and 3 subunits have been shown to combine with the 2
subunit in vitro, with or without the 4 subunit, to form
functional nAChRs (Kuryatov et al., 2000), suggesting that these
subunits may contribute to the observed nicotine-sensitive currents in DA neurons (Klink et al., 2001). The 2 subunit is critical not only
for currents in DA cell bodies but also for nicotine-induced DA release
from synaptosomes or as measured by microdialysis, both of which are
abolished in 2 subunit KO mice (Picciotto et al., 1998; Grady et
al., 2001). Cyclic voltammetric studies also confirm that nicotine- and
ACh-evoked DA release are abolished in 2 subunit KO mice (Zhou et
al., 2001).
Importantly, nicotine can enhance synaptic plasticity in glutamatergic
inputs to VTA neurons via an MLA-sensitive nAChR (Mansvelder and
McGehee, 2000). This effect could underlie plastic changes in the DA
system that lead to the development of addiction. The ability of
nicotine to affect synaptic strength in both excitatory and inhibitory
inputs to the DA cell bodies is one of the critical areas for future
research on the physiological basis of nicotine addiction.
Behavioral phenotypes in mice with mutations in nAChR subunits
Mutations in nAChR subunits that contribute to nicotine-induced DA
release, including the 4, 6, 7, 2, and 3 subunits, might
be expected to affect nicotine self-administration. WT mice trained to
self-administer cocaine and then switched to nicotine continue to
self-administer nicotine, whereas 2 subunit KO mice do not
self-administer nicotine and extinguish their response as if they had
been given saline (Picciotto et al., 1998), suggesting that this
subunit may be involved in nicotine reinforcement. The 2 subunit of
the nAChR also modulates the reinforcing effects of cocaine in the
conditioned place preference (CPP) paradigm. KO mice lacking the 2
subunit show reduced CPP to a threshold dose of cocaine, do not show
the alterations in DA turnover in the striatum seen in WT mice after
administration of cocaine, and show attenuated induction of the chronic
fos-related antigens after cocaine treatment (Zachariou et al., 2001).
These results suggest that nicotine can modulate cocaine reinforcement
by increasing DA tone and support the idea that endogenous ACh, acting
through nAChRs containing the 2 subunit, modulates DA neurotransmission.
Drug-induced locomotor activation also may contribute to
psychostimulant-induced reinforcement. Nicotine increases locomotion, via activation of DA pathways (Clarke et al., 1988), in a familiar environment. 2 subunit KO mice show reduced locomotion in a familiar environment (Picciotto et al., 1998), whereas KI mice expressing a low
level of a super-sensitive 4 subunit show increased locomotion in a
novel environment (Labarca et al., 2001). This suggests that 4/2-containing nAChRs are important for spontaneous locomotor activity. One line of 4 subunit KO mice shows reduced habituation to
a novel environment (Ross et al., 2000), whereas a second line of 4
subunit KO mice showed no differences in locomotor activity in a novel
environment (Marubio et al., 1999), suggesting that different genetic
backgrounds or different methods of measuring locomotor activity may
contribute to phenotypic heterogeneity. Infusion of 6 antisense
oligonucleotides could also attenuate the locomotor-activating effects
of nicotine in rats (Le Novère et al., 1999). Taken together,
these results suggest that the 4, 6, and 2 subunits are
involved in the ability of nicotine to stimulate both the DA system and
locomotor activity.
Conclusions
In spite of, or perhaps because of, the relative newness of these
studies, research into the neuronal systems underlying nicotine dependence has in many ways capitalized on emerging knowledge from
different domains. Perhaps most impressive has been the degree to which
researchers interested in nAChRs have tested the consequences of their
manipulations in behaving animals, using models that have been
developed by behavioral neuroscientists to understand drug-taking
behavior itself and other related phenomena. For its part, behavioral
neuroscience research in the nicotine field has begun to elucidate
novel circuitry in drug reinforcement, an advance that permits analysis
at the molecular level. Even from the still early data described in
this review, we can surmise that nicotine addiction is based on the
action of the drug at several systems. One can extrapolate with hope to
a near future in which the profitability of these efforts is fully
evident in discovering the basic mechanisms of nicotine dependence.
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FOOTNOTES |
This work has been supported by National Institute on Drug
Abuse (NIDA) Grants DA00436, DA10455, and DA84733 (M.R.P.), and NIDA
Grant DA09577 (W.A.C.).
Correspondence should be addressed to Marina Picciotto, Department of
Psychiatry, Yale University School of Medicine, 34 Park Street, Third
Floor Research, New Haven, CT 06508. E-mail:
marina.picciotto{at}yale.edu.
| |
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M. E. Liechti, L. Lhuillier, K. Kaupmann, and A. Markou
Metabotropic Glutamate 2/3 Receptors in the Ventral Tegmental Area and the Nucleus Accumbens Shell Are Involved in Behaviors Relating to Nicotine Dependence
J. Neurosci.,
August 22, 2007;
27(34):
9077 - 9085.
[Abstract]
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Y. F. F. Medel and P. D. Gardner
Transcriptional Repression by a Conserved Intronic Sequence in the Nicotinic Receptor {alpha}3 Subunit Gene
J. Biol. Chem.,
June 29, 2007;
282(26):
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[Abstract]
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S. Agatsuma, M. Lee, H. Zhu, K. Chen, J. C. Shih, I. Seif, and N. Hiroi
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Hum. Mol. Genet.,
September 15, 2006;
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[Abstract]
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[PDF]
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D. Goldman, G. Oroszi, and F. Ducci
The Genetics of Addictions: Uncovering the Genes
Focus,
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[Abstract]
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A. D. Le, Z. Li, D. Funk, M. Shram, T. K. Li, and Y. Shaham
Increased Vulnerability to Nicotine Self-Administration and Relapse in Alcohol-Naive Offspring of Rats Selectively Bred for High Alcohol Intake
J. Neurosci.,
February 8, 2006;
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[Abstract]
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B. S. Gutkin, S. Dehaene, and J.-P. Changeux
A neurocomputational hypothesis for nicotine addiction
PNAS,
January 24, 2006;
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[Abstract]
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S. Ikemoto, M. Qin, and Z.-H. Liu
Primary Reinforcing Effects of Nicotine Are Triggered from Multiple Regions Both Inside and Outside the Ventral Tegmental Area
J. Neurosci.,
January 18, 2006;
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F. Berrendero, V. Mendizabal, P. Robledo, L. Galeote, A. Bilkei-Gorzo, A. Zimmer, and R. Maldonado
Nicotine-Induced Antinociception, Rewarding Effects, and Physical Dependence Are Decreased in Mice Lacking the Preproenkephalin Gene
J. Neurosci.,
February 2, 2005;
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[Abstract]
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A. R. Kosowski and S. Liljequist
The NR2B-Selective N-Methyl-D-aspartate Receptor Antagonist Ro 25-6981 [({+/-})-(R*,S*)-{alpha}-(4-Hydroxyphenyl)-{beta}-methyl-4-(phenylmethyl)-1-piperidine Propanol] Potentiates the Effect of Nicotine on Locomotor Activity and Dopamine Release in the Nucleus Accumbens
J. Pharmacol. Exp. Ther.,
November 1, 2004;
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[Abstract]
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J. Cami and M. Farre
Drug Addiction
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L. H. Wilkins Jr., V. P. Grinevich, J. T. Ayers, P. A. Crooks, and L. P. Dwoskin
N-n-Alkylnicotinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Interaction with alpha 4beta 2* and alpha 7* Neuronal Nicotinic Receptors
J. Pharmacol. Exp. Ther.,
January 1, 2003;
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A. S. Rauhut, S. N. Mullins, L. P. Dwoskin, and M. T. Bardo
Reboxetine: Attenuation of Intravenous Nicotine Self-Administration in Rats
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November 1, 2002;
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