Premium
Effects of nicotine in the dopaminergic system of mice lacking the alpha4 subunit of neuronal nicotinic acetylcholine receptors
Author(s) -
Marubio L. M.,
Gardier A. M.,
Durier S.,
David D.,
Klink R.,
ArroyoJimenez M. M.,
McIntosh J. M.,
Rossi F.,
Champtiaux N.,
Zoli M.,
Changeux JP.
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2003.02564.x
Subject(s) - nicotine , dopamine , nicotinic agonist , dopaminergic , chemistry , acetylcholine receptor , nicotinic acetylcholine receptor , medicine , substantia nigra , endocrinology , pharmacology , neuroscience , receptor , biology , biochemistry
The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the α4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the α4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with 125 I α‐conotoxin MII. These receptors are comprised of the α4, β2 and α6 nAChR subunits and non‐α4, β2, and α6 nAChR subunits. Non‐α4 subunit‐containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild‐type mice. Despite the fact that both wild‐type and α4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine‐elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild‐type and mutant mice in basal activity in both habituated and non‐habituated environments. Interestingly, mutant mice sustain an increase in cocaine‐elicited locomotor activity longer than wild‐type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that α4‐containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs.