Abstract
BackgroundAlthough converging evidence has suggested that nicotinic acetylcholine receptors (nAChR) play a role in the modulation of GABA release in rat hippocampus, the specific involvement of different nAChR subtypes at presynaptic level is still a matter of debate. In the present work we investigated, using selective α7 and α4β2 nAChR agonists, the presence of different nAChR subtypes on hippocampal GABA nerve endings to assess to what extent and through which mechanisms they stimulate endogenous GABA release.Methodology/FindingsAll agonists elicited GABA overflow. Choline (Ch)-evoked GABA overflow was dependent to external Ca2+, but unaltered in the presence of Cd2+, tetrodotoxin (TTX), dihydro-β-erythroidine (DHβE) and 1-(4,4-Diphenyl-3-butenyl)-3-piperidinecarboxylic acid hydrochloride SKF 89976A. The effect of Ch was blocked by methyllycaconitine (MLA), α-bungarotoxin (α-BTX), dantrolene, thapsigargin and xestospongin C, suggesting that GABA release might be triggered by Ca2+ entry into synaptosomes through the α7 nAChR channel with the involvement of calcium from intracellular stores. Additionally, 5-Iodo-A-85380 dihydrochloride (5IA85380) elicited GABA overflow, which was Ca2+ dependent, blocked by Cd2+, and significantly inhibited by TTX and DHβE, but unaffected by MLA, SKF 89976A, thapsigargin and xestospongin C and dantrolene. These findings confirm the involvement of α4β2 nAChR in 5IA85380-induced GABA release that seems to occur following membrane depolarization and opening calcium channels.Conclusions/SignificanceRat hippocampal synaptosomes possess both α7 and α4β2 nAChR subtypes, which can modulate GABA release via two distinct mechanisms of action. The finding that GABA release evoked by the mixture of sub-maximal concentration of 5IA85380 plus sub-threshold concentrations of Ch was significantly larger than that elicited by the sum of the effects of the two agonists is compatible with the possibility that they coexist on the same nerve terminals. These findings would provide the basis for possible selective pharmacological strategies to treat neuronal disorders that involve the dysfunction of hippocampal cholinergic system.
Highlights
It is well known that the activation of specific nicotinic acetylcholine receptor subtypes enhances the release of glutamate, noradrenaline, and acetylcholine from rodent hippocampal nerve endings [1,2]. nicotinic acetylcholine receptors (nAChR) seem to play a role in the modulation of the release of GABA in the same brain area, the specific involvement of the different nAChR subtypes may be more complex and is still a matter of debate
The existence of a7 and non-a7 nAChRs on nerve endings has been challenged by the results of Kanno et al [20], who showed that both receptor subtypes exert some modulatory effects on GABA release via a multi-synaptic control, as they do not have a sufficient potency to modulate the release under the control of a single synapse
We investigated the effect of nAChR activation on the release of endogenous GABA from rat purified isolated hippocampal synaptosomes
Summary
It is well known that the activation of specific nicotinic acetylcholine receptor (nAChR) subtypes enhances the release of glutamate, noradrenaline, and acetylcholine from rodent hippocampal nerve endings [1,2]. nAChRs seem to play a role in the modulation of the release of GABA in the same brain area, the specific involvement of the different nAChR subtypes may be more complex and is still a matter of debate. NAChRs seem to play a role in the modulation of the release of GABA in the same brain area, the specific involvement of the different nAChR subtypes may be more complex and is still a matter of debate. Some studies suggest that the b2 subunit is the component of all the nAChRs that modulate [3H]GABA release in mouse brain synaptosomes [13,14], and exclude the presence of a7 nAChR subtypes. Converging evidence has suggested that nicotinic acetylcholine receptors (nAChR) play a role in the modulation of GABA release in rat hippocampus, the specific involvement of different nAChR subtypes at presynaptic level is still a matter of debate. In the present work we investigated, using selective a7 and a4b2 nAChR agonists, the presence of different nAChR subtypes on hippocampal GABA nerve endings to assess to what extent and through which mechanisms they stimulate endogenous GABA release
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