Neuropeptide S selectively inhibits the release of 5-HT and noradrenaline from mouse frontal cortex nerve endings.
OBJECTIVE
Neuropeptide S (NPS) is a recently identified neurotransmitter/neuromodulator able to increase arousal and wakefulness while decreasing anxiety-like behaviour. As several classical transmitters play a role in arousal and anxiety, we here investigated the possible presynaptic regulation of transmitter release by NPS.


METHODS
Synaptosomes purified from mouse frontal cortex were prelabelled with [(3)H]5-hydroxytryptamine (5-HT), noradrenaline, dopamine, choline, D-aspartate or GABA and depolarized in superfusion with 12-15 mmol.L(-1) KCl to evoke [(3)H]neurotransmitter exocytosis. NPS was added at different concentrations (0.001 to 100 nmol.L(-1)).


RESULTS
NPS behaved as an extremely potent inhibitor of the evoked overflow of [(3)H]5-HT and [(3)H]noradrenaline exhibiting EC50 values in the low picomolar range. The inhibitory action of NPS on [(3)H]5-HT release was mimicked by [Ala(2)]NPS that was, however, about 100-fold less potent than the natural peptide. NPS (up to 100 nmol.L(-1)) was unable to affect the depolarization-evoked overflow of [(3)H]D-aspartate and [(3)H]GABA. The neuropeptide only weakly reduced the overflow of [(3)H]dopamine and [(3)H]ACh when added at relatively high concentrations.


CONCLUSIONS
NPS, at low picomolar concentrations, can selectively inhibit the evoked release of 5-HT and noradrenaline in the frontal cortex by acting directly on 5-hydroxytryptaminergic and noradrenergic nerve terminals. These direct effects may explain only in part the unique behavioural activities of NPS, while an indirect involvement of other transmitters, especially of glutamate, must be considered.
Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, Genova 16148, Italy. lraiter@pharmatox.unige.it
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Salvadori
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D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D009411:Nerve Endings / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D009479:Neuropeptides; D018377:Neurotransmitter Agents; D012701:Serotonin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000109:Acetylcholine; D004298:Dopamine; D009638:Norepinephrine