Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum

Reference:

Mogg, A. J., Whiteaker, P., McIntosh, J. M., Marks, M., Collins, A. C. and Wonnacott, S., 2002. Methyllycaconitine is a potent antagonist of alpha-conotoxin-MII-sensitive presynaptic nicotinic acetylcholine receptors in rat striatum. Journal of Pharmacology and Experimental Therapeutics, 302 (1), pp. 197-204.

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Official URL:

http://dx.doi.org/10.1124/jpet.302.1.197

Abstract

The plant alkaloid methyllycaconitine (MLA) is considered to be a selective antagonist of the alpha7 subtype of neuronal nicotinic acetylcholine receptor (nAChR). However, 50 nM MLA partially inhibited (by 16%) [H-3] dopamine release from rat striatal synaptosomes stimulated with 10 muM nicotine. Other alpha7-selective antagonists had no effect. Similarly, MLA (50 nM) inhibited [H-3] dopamine release evoked by the partial agonist (2-chloro-5-pyridyl)- 9-azabicyclo[4.2.1] non-2-ene (UB-165) (0.2 muM) 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 alpha-conotoxin-MII (alpha-CTx-MII). MLA was not additive with a maximally effective concentration of alpha-CTx-MII (100 nM) in inhibiting [H-3] dopamine release elicited by 10 muM nicotine or 0.2 muM UB-165, suggesting that both toxins act at the same site. This was confirmed in quantitative binding assays with I-125-alpha-CTx-MII, which displayed saturable specific binding to rat striatum and nucleus accumbens with B-max values of 9.8 and 16.5 fmol/mg of protein, and K-d values of 0.63 and 0.83 nM, respectively. MLA fully inhibited I-125-alpha-CTx-MII binding to striatum and nucleus accumbens with a K-i value of 33 nM, consistent with the potency observed in the functional assays. We speculate that MLA and alpha-CTx-MII interact with a presynaptic nAChR of subunit composition alpha3/alpha6beta2beta3* on dopamine neurons. The use of MLA as an alpha7-selective antagonist should be exercised with caution, especially in studies of nAChR in basal ganglia.

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