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Dopamine
Glutamate
inputs
Nucleus
accumbens
Desensitization of
acute nicotine
reward signal
Aversive nicotine
craving/withdrawal
Sensitized
incentive salience
TPP
VTA
Dopamine
Nucleus
accumbens
GABA
GABA
Glutamate
inputs
NMDA receptors
"7-containing
ACh receptors
"4#2-containing
ACh receptors
Figure 4 | An integrated model for nicotine reward signalling in the ventral tegmental area
(VTA). a | In the acute stage, the initial activation by nicotine of GABA (!-aminobutyric acid) neurons
in the VTA
32,33,40
produces rewarding effects through a GABA-dependent system that projects to the
tegmental pedunculopontine nucleus (TPP)
69,76,77
. These effects might involve the activation of
presynaptic nicotinic acetylcholine receptors (nAChRs) that contain the "7 subunit, as blockade of
this subunit interferes with the acute rewarding effects of nicotine
80,82
, but leaves the aversive signal
intact
82
. However, nicotine might also exert its motivational effects through direct actions on nAChRs
containing the #2 subunit and located on GABA or dopamine (DA) neurons, as pharmacological
blockade or genetic deletion of this subunit blocks both the aversive and rewarding effects of
nicotine
8,63,82
. In this model, nAChRs are distributed on both VTA neuronal populations, and nicotine-
induced activation of these receptors can therefore regulate the motivational effects of nicotine
through either non-DA or DA systems. b | With repeated nicotine exposure, however, the GABA
system that signals reward becomes desensitized, leading to a net shift in the action of nicotine to
the DA neurons
33,40
. This shift is mediated at least partly by increased glutamatergic input to the DA
system
33
. The shift in the functional balance between GABA and DA neuronal populations in the VTA
might lead to a dysregulated DA signal in the VTA, which in turn leads to the aversive psychological
effects of nicotine craving and withdrawal, and/or to the potentiation of the incentive salience of
nicotine and its compulsive use. NMDA, N-methyl-D-aspartate.
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64 | JANUARY 2004 | VOLUME 5 www.nature.com/reviews/neuro
R E V I E WS
to the addictive potential of nicotine? Studies on the
neurophysiological effects of nicotine within the VTA
provide new insights into how nicotine induces synaptic
plasticity within the mesolimbic DA system. These
studies might disclose a mechanism to account for the
shift from non-DA-mediated reward signalling in
the acute state to the involvement of DA-mediated
transmission in the development of compulsive nicotine
use. However, it will be important to examine how
these in vitro effects of nicotine might relate to what
happens in vivo during the development of addiction.
Finally, research that allows the dissection of the
contribution of specific subunits of the nAChR to the
motivational effects of nicotine and the development of
addiction might ultimately lead to a clear understanding
of which nAChR subunits are involved in the vulnera-
bility to the rewarding properties of nicotine, and how
alterations in specific nAChRs might lead to chronic
nicotine use and dependence.
examine more closely the functional role of DA-mediated
signalling in the early phases of nicotine exposure versus
the chronic state, the available studies in humans and
animals consistently indicate that chronic nicotine
exposure might lead to alterations in DA-mediated sig-
nalling, which might in turn lead to nicotine craving
and compulsive drug-seeking behaviours.
Conclusions and future directions
Despite the widespread effects of nicotine in the CNS,
converging evidence at the behavioural, molecular,
genetic and physiological levels points to the VTA and its
associated DA and non-DA systems as crucial mediators
of the motivational effects of nicotine. However, many
important questions remain to be answered. What func-
tional interactions take place between the systems that
subserve the aversive and rewarding effects of nicotine
during the development of nicotine dependence? Does
this functional interaction determine the vulnerability
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Acknowledgements
The authors thank CIHR for their support.
Competing interests statement
The authors declare that they have no competing financial interests.
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addiction | dopamine | nicotinic acetylcholine receptors
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