Open AccessLocalized low‐level re‐expression of high‐affinity mesolimbic nicotinic acetylcholine receptors restores nicotine‐induced locomotion but not place conditioning
Author(s) -
Mineur Y. S.,
Brunzell D. H.,
Grady S. R.,
Lindstrom J. M.,
McIntosh J. M.,
Marks M. J.,
King S. L.,
Picciotto M. R.
Publication year - 2009
Publication title -
genes, brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.315
H-Index - 91
eISSN - 1601-183X
pISSN - 1601-1848
DOI - 10.1111/j.1601-183x.2008.00468.x
Subject(s) - ventral tegmental area , nicotinic agonist , nicotine , conditioned place preference , creb , acetylcholine receptor , chemistry , dopamine , neuroscience , pharmacology , knockout mouse , dopaminergic , endocrinology , medicine , receptor , biology , biochemistry , gene , transcription factor
High‐affinity, β2‐subunit‐containing (β2*) nicotinic acetylcholine receptors (nAChRs) are essential for nicotine reinforcement; however, these nAChRs are found on both gamma‐aminobutyric acid (GABA) and dopaminergic (DA) neurons in the ventral tegmental area (VTA) and also on terminals of glutamatergic and cholinergic neurons projecting from the pedunculopontine tegmental area and the laterodorsal tegmental nucleus. Thus, systemic nicotine administration stimulates many different neuronal subtypes in various brain nuclei. To identify neurons in which nAChRs must be expressed to mediate effects of systemic nicotine, we investigated responses in mice with low‐level, localized expression of β2* nAChRs in the midbrain/VTA. Nicotine‐induced GABA and DA release were partially rescued in striatal synaptosomes from transgenic mice compared with tissue from β2 knockout mice. Nicotine‐induced locomotor activation, but not place preference, was rescued in mice with low‐level VTA expression, suggesting that low‐level expression of β2* nAChRs in DA neurons is not sufficient to support nicotine reward. In contrast to control mice, transgenic mice with low‐level β2* nAChR expression in the VTA showed no increase in overall levels of cyclic AMP response element‐binding protein (CREB) but did show an increase in CREB phosphorylation in response to exposure to a nicotine‐paired chamber. Thus, CREB activation in the absence of regulation of total CREB levels during place preference testing was not sufficient to support nicotine place preference in β2 trangenic mice. This suggests that partial activation of high‐affinity nAChRs in VTA might block the rewarding effects of nicotine, providing a potential mechanism for the ability of nicotinic partial agonists to aid in smoking cessation.