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Vol. 302, Issue 1, 197-204, July 2002
-Conotoxin-MII-Sensitive Presynaptic Nicotinic Acetylcholine
Receptors in Rat Striatum
Department of Biology and Biochemistry, University of Bath, Bath,
United Kingdom (A.J.M., S.W.); Institute for Behavioral Genetics,
University of Colorado, Boulder, Colorado (P.W., M.M., A.C.C.); and
Departments of Biology and Psychiatry, University of Utah, Salt Lake
City, Utah (J.M.M.)
The plant alkaloid methyllycaconitine (MLA) is considered to be a
selective antagonist of the 
7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16%) [3H]dopamine release from rat striatal
synaptosomes stimulated with 10 µM nicotine. Other 7-selective
antagonists had no effect. Similarly, MLA (50 nM) inhibited
[3H]dopamine release evoked by the partial agonist
(2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene (UB-165)
(0.2 µM) by 37%. In both cases, inhibition by MLA was surmountable
with higher agonist concentrations, indicative of a competitive
interaction. At least two subtypes of presynaptic nAChR can modulate
dopamine release in the striatum, and these nAChR are distinguished by
their differential sensitivity to -conotoxin-MII (-CTx-MII). MLA
was not additive with a maximally effective concentration of
-CTx-MII (100 nM) in inhibiting [3H]dopamine release
elicited by 10 µM nicotine or 0.2 µM UB-165, suggesting that both
toxins act at the same site. This was confirmed in quantitative binding
assays with 125I--CTx-MII, which displayed saturable
specific binding to rat striatum and nucleus accumbens with
Bmax values of 9.8 and 16.5 fmol/mg of
protein, and Kd values of 0.63 and 0.83 nM,
respectively. MLA fully inhibited 125I--CTx-MII binding
to striatum and nucleus accumbens with a Ki value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and -CTx-MII interact with a
presynaptic nAChR of subunit composition 3/6
23* on dopamine
neurons. The use of MLA as an 7-selective antagonist should be
exercised with caution, especially in studies of nAChR in basal ganglia.
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