RT Journal Article
SR Electronic
T1 Long-Term Nicotine Treatment Decreases Striatal α6* Nicotinic Acetylcholine Receptor Sites and Function in Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1639
OP 1647
DO 10.1124/mol.104.006429
VO 67
IS 5
A1 Albert Lai
A1 Neeraja Parameswaran
A1 Mirium Khwaja
A1 Paul Whiteaker
A1 Jon M. Lindstrom
A1 Hong Fan
A1 J. Michael McIntosh
A1 Sharon R. Grady
A1 Maryka Quik
YR 2005
UL http://molpharm.aspetjournals.org/content/67/5/1639.abstract
AB α-Conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) are distinct from other subtypes in their relatively restricted localization to the striatum and some other brain regions. The effect of nicotine treatment on nAChR subtypes has been extensively investigated, with the exception of changes in α-conotoxin MII-sensitive receptor expression. We therefore determined the consequence of long-term nicotine administration on this subtype and its function. Nicotine was given in drinking water to provide a long-term yet intermittent treatment. Consistent with previous studies, nicotine exposure increased 125I-epibatidine and 125I-A85380 (3-[2-(S)-azetidinylmethoxy]pyridine), but not 125I-α-bungarotoxin, receptors in cortex and striatum. We observed an unexpected reduction (30%) in striatal 125I-α-conotoxin MII sites, which occurred because of a decrease in Bmax. This decline was more robust in older (>8-month-old) compared with younger (2–4-month-old) mice, suggesting age is important for nicotine-induced disruption of nAChR phenotype. Immunoprecipitation experiments using nAChR subunit-directed antibodies indicate that alterations in subunit-immunoreactivity with nicotine treatment agree with those in the receptor binding studies. To determine the relationship between striatal nAChR sites and function, we measured nicotine-evoked [3H]dopamine release. A decline was obtained with nicotine treatment that was caused by a selective decrease in α-conotoxin MII-sensitive but not α-conotoxin MII-resistant dopamine release. These results may explain previous findings that nicotine treatment decreased striatal nAChR-mediated dopamine function, despite an increase in [3H]nicotine (α4*) sites. The present data suggest that the α6* nAChR subtype represents a key factor in the control of dopamine release from striatum, which adapts to long-term nicotine treatment by down-regulation of α6* receptor sites and function.