Differential Inhibition by α-Conotoxin-MII of the Nicotinic Stimulation of [3H]Dopamine Release from Rat Striatal Synaptosomes and Slices

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Abstract

Abstract:

The presynaptic nicotinic modulation of dopamine release from striatal nerve terminals is well established, but the subtype(s) of neuronal nicotinic acetylcholine receptor (nAChR) underlying this response has not been identified. Recently, α-conotoxin-MII has been reported to inhibit potently and selectively the rat α3β2 combination of nAChR subunits. Here we have synthesised the peptide, confirmed its specificity, and examined its effect on the (±)-anatoxin-a-evoked release of [3H]dopamine from rat striatal synaptosomes and slices. α-Conotoxin-MII (112 nM) completely blocked acetylcholine-evoked currents of α3β2 nAChRs expressed in Xenopus oocytes (IC50 = 8.0 ± 1.1 nM). Pairwise combinations of other nicotinic subunits were not blocked by 112 nM α-conotoxin-MII. On perfused striatal synaptosomes and slices, α-conotoxin-MII dose-dependently inhibited [3H]dopamine release evoked by 1 μM (±)-anatoxin-a with IC50 values of 24.3 ± 2.9 and 17.3 ± 0.1 nM, respectively. The dose-response curve was shifted to the right with increasing agonist concentrations. However, the maximal inhibition of responses achieved by α-conotoxin-MII (112 nM) was 44.9 ± 5.4% for synaptosomes and 25.0 ± 4.1% for slices, compared with an inhibition by 10 μM mecamylamine of 77.9 ± 3.7 and 88.0 ± 2.1%, respectively. These results suggest the presence of presynaptic α3β2-like nAChRs on striatal dopaminergic terminals, but the incomplete block of (±)-anatoxin-a-evoked [3H]dopamine release by α-conotoxin-MII also supports the participation of nAChRs composed of other subunits. The lower inhibition found in slices is consistent with an additional indirect nicotinic stimulation of dopamine release via an α-conotoxin-MII-insensitive nAChR.

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