Effect of Novel α-Conotoxins on Nicotine-Stimulated [3H]Dopamine Release from Rat Striatal Synaptosomes

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Abstract
Nicotine's action on the midbrain dopaminergic neurons is mediated by nicotinic acetylcholine receptors (nAChRs) that are present on the cell bodies and the terminals of these neurons. Previously, it was suggested that one of the nAChR subtypes located on striatal dopaminergic terminals may be an α3β2 subtype, based on partial inhibition of nicotine-stimulated [3H]dopamine release by α-conotoxin MII, a potent inhibitor of heterologously expressed α3β2 nAChRs. More recent studies indicated that α-conotoxin MII also potently blocks α6-containing nAChRs. In the present study, we have examined the nAChR subtype(s) modulating [3H]dopamine release from striatal terminals by using novel α-conotoxins that have 37- to 78-fold higher selectivity for α6-versus α3-containing nAChRs. All of the peptides partially (20-35%) inhibit nicotine-stimulated [3H]dopamine release with IC50 values consistent with those obtained with heterologously expressed rat α6-containing nicotinic acetylcholine receptors. These results, together with previous studies by others, further support the idea that α6-containing nicotinic receptors modulate nicotine-stimulated dopamine release from rat striatal synaptosomes.