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The Journal of Neuroscience, April 15, 2003, 23(8):3176
Differential Desensitization and Distribution of Nicotinic
Acetylcholine Receptor Subtypes in Midbrain Dopamine Areas
Julian R. A.
Wooltorton,
Volodymyr
I.
Pidoplichko,
Ron S.
Broide, and
John A.
Dani
Division of Neuroscience, Baylor College of Medicine, Houston,
Texas 77030-3498
Although many psychopharmacological factors contribute to nicotine
addiction, midbrain dopaminergic systems have received much attention
because of their roles in reinforcement and associative learning. It is
generally thought that the mesocorticolimbic dopaminergic system is
important for the acquisition of behaviors that are reinforced by the
salient drives of the environment or by the inappropriate stimuli of
addictive drugs. Nicotine, as obtained from tobacco, can activate
nicotinic acetylcholine receptors (nAChRs) and excite midbrain neurons
of the mesocorticolimbic system. Using midbrain slices from rats,
wild-type mice, and genetically engineered mice, we have found
differences in the nAChR currents from the ventral tegmental area (VTA)
and the substantia nigra compacta (SNc). Nicotinic AChRs containing the
 7 subunit (7* nAChRs) have a low expression density.
Electrophysiological analysis of nAChR currents, autoradiography of
[125I]--bungarotoxin binding, and in
situ hybridization revealed that 7* nAChRs are more highly
expressed in the VTA than the SNc. In contrast,  2* nAChRs are move
evenly distributed at a higher density in both the VTA and SNc. At the
concentration of nicotine obtained by tobacco smokers, the slow
components of current (mainly mediated by 2* nAChRs) become
essentially desensitized. However, the minority 7* component
of the current in the VTA/SNc is not significantly desensitized by
nicotine in the range  100 nM. These results suggest that
nicotine, as obtained from tobacco, can have multiple effects on the
midbrain areas by differentially influencing dopamine neurons of the
VTA and SNc and differentially desensitizing 7* and non-7 nAChRs.
Key words:
ventral tegmental area; substantia nigra; nicotine
addiction; mesolimbic; 7; 2
Copyright © 2003 Society for Neuroscience 0270-6474/03/2383176-10$05.00/0
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