Long-term nicotine treatment decreases striatal α6 nicotinic acetylcholine receptor sites and function in mice

alpha-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 alpha-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 I-125-epibatidine and I-125-A85380 (3-[2-(S)-azetidinyl-methoxy] pyridine), but not I-125-alpha-bungarotoxin, receptors in cortex and striatum. We observed an unexpected reduction (30%) in striatal I-125-alpha-conotoxin MII sites, which occurred because of a decrease in B-max. 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 [H-3] dopamine release. A decline was obtained with nicotine treatment that was caused by a selective decrease in alpha-conotoxin MII-sensitive but not alpha-conotoxin MII-resistant dopamine release. These results may explain previous findings that nicotine treatment decreased striatal nAChR-mediated dopamine function, despite an increase in [H-3] nicotine (alpha 4*) sites. The present data suggest that the alpha 6* 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 alpha 6* receptor sites and function.