Elsevier

Neuropharmacology

Volume 34, Issue 11, November 1995, Pages 1535-1541
Neuropharmacology

General paper
Anatoxin-a-evoked [3H]dopamine release from rat striatal synaptosomes

https://doi.org/10.1016/0028-3908(95)00122-MGet rights and content

Abstract

Presynaptic nicotinic acetylcholine receptors on striatal nerve terminals modulate the release of dopamine. Using rat striatal synaptosomes loaded with [3H]dopamine, we have characterized the action of the selective nicotinic agonist, (±)anatoxin-a, with respect to [3H]dopamine release, in order to explore the mechanisms coupling nicotinic receptor activation to exocytosis. Anatoxin-a evoked [3H]dopamine release in a concentration-dependent and mecamylamine-sensitive manner, EC50 = 0.11 μM. The maximum [3H]dopamine release elicited by anatoxin-a was only 20% of the maximum elicited by KC1 depolarization; there was no additivity between anatoxin-a and sub-maximal concentrations of KC1. Both agents stimulated Ca2+-dependent release that was equally sensitive to inhibition by 200 μM Cd2+. This result suggests that anatoxin-a-stimulated exocytosis is mediated by Ca2+ influx via voltage-sensitive Ca2+ channels, with little contribution from Ca2+ entering directly through the nicotinic receptor channel. This view is supported by the abolition of anatoxin-a-evoked [3H]dopamine release in Na+-depleted medium. A partial (40%) inhibition by tetrodotoxin was observed. These data suggest that activation of presynaptic nicotinic acetylcholine receptors by anatoxin-a results in an influx of Na+, producing sufficient local depolarization to open voltage-sensitive Ca2+ and Na+ channels. The latter may then amplify the response, activating further Ca2+ channels. The particular voltage-sensitive Ca2+ channels involved remain to be determined.

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      Anatoxin-a and its analogs act as post-synaptic acetylcholine antagonist, blocking acetylcholinesterase activity, resulting in paralysis, exaggerated abdominal breathing, cyanosis, convulsion, and ultimately asphyxiation and death (Aronstam and Witkop, 1981; Dar and Zinder, 1998; Campos et al., 2006). Anatoxin-a and its analogs also affect the release of dopamine, which is a neurotransmitter (Soliakov et al., 1995). Anatoxin-a and its analogs are toxic to birds, cattle, dogs, and fish (Codd et al., 1992, 2005; Mez et al., 1997; Krienitz et al., 2003; Williams et al., 2004, 2006, 2007; Metcalf et al., 2006; Cadel-Six et al., 2007; Wood et al., 2007).

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