alpha-Bungarotoxin-sensitive nicotinic receptors indirectly modulate [H-3]dopamine release in rat striatal slices via glutamate release

S Kaiser, S Wonnacott

Research output: Contribution to journalArticlepeer-review

193 Citations (Scopus)

Abstract

Nicotinic agonists elicit the release of dopamine from striatal synaptosomes by acting on presynaptic nicotinic acetylcholine receptors (nAChRs) on dopamine nerve terminals. Both alpha 3 beta 2* and alpha 4 beta 2 nAChR subtypes (but not alpha 7* nAChRs) have been implicated. Here, we compared nAChR-evoked [H-3]dopamine release from rat striatal synaptosome and slice preparations by using the nicotinic agonist anatoxin-a. In the more integral slice preparation, the concentration-response curve for anatoxin-a-evoked [H-3]dopamine release was best fitted to a two-site model, giving EC50 values of 241 nM and 5.1 mu M, whereas only the higher-affinity component was observed in synaptosome preparations (EC50 = 134 nM). Responses to a high concentration of anatoxin-a (25 mu M) in slices (but not in synaptosomes) were partially blocked by ionotropic glutamate receptor antagonists (kynurenic acid, 6,7-dinitroquinoxaline-2,3-dione) and by alpha 7*-selective nAChR antagonists (alpha-bungarotoxin, alpha-conotoxin-ImI, methyllycaconitine) in a nonadditive manner. In contrast, the alpha 3 beta 2-selective nAChR antagonist alpha-conotoxin-MII partially inhibited [H-3]dopamine release from both slice and synaptosome preparations, stimulated with both low (1 mu M) and high (25 mu M) concentrations of anatoxin-a. Antagonism by alpha-conotoxin-MII was additive with that of alpha 7*-selective antagonists. These data support a model in which alpha 7* nAChRs on striatal glutamate terminals elicit glutamate release, which in turn acts at ionotropic glutamate receptors on dopamine terminals to stimulate dopamine release. In addition, non-alpha 7* nAChRs on dopamine terminals also stimulate dopamine release. These observations have implications for the complex cholinergic modulation of inputs onto the major efferent neurons of the striatum.
Original languageEnglish
Pages (from-to)312-318
Number of pages7
JournalMolecular Pharmacology
Volume58
Issue number2
Publication statusPublished - 2000

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