α-Bungarotoxin-Sensitive Nicotinic Receptors Indirectly Modulate [3H]Dopamine Release in Rat Striatal Slices via Glutamate Release

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Abstract
Nicotinic agonists elicit the release of dopamine from striatal synaptosomes by acting on presynaptic nicotinic acetylcholine receptors (nAChRs) on dopamine nerve terminals. Both α3β2* and α4β2 nAChR subtypes (but not α7* nAChRs) have been implicated. Here, we compared nAChR-evoked [3H]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 [3H]dopamine release was best fitted to a two-site model, giving EC50 values of 241 nM and 5.1 μM, whereas only the higher-affinity component was observed in synaptosome preparations (EC50 = 134 nM). Responses to a high concentration of anatoxin-a (25 μM) in slices (but not in synaptosomes) were partially blocked by ionotropic glutamate receptor antagonists (kynurenic acid, 6,7-dinitroquinoxaline-2,3-dione) and by α7*-selective nAChR antagonists (α-bungarotoxin, α-conotoxin-ImI, methyllycaconitine) in a nonadditive manner. In contrast, the α3β2-selective nAChR antagonist α-conotoxin-MII partially inhibited [3H]dopamine release from both slice and synaptosome preparations, stimulated with both low (1 μM) and high (25 μM) concentrations of anatoxin-a. Antagonism by α-conotoxin-MII was additive with that of α7*-selective antagonists. These data support a model in which α7* 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-α7* 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.

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