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Stereoselective modulatory actions of oleamide on GABA A receptors and voltage‐gated Na + channels in vitro : a putative endogenous ligand for depressant drug sites in CNS

Stereoselective modulatory actions of oleamide on GABA A receptors and voltage‐gated Na +... cis‐9,10‐octadecenoamide (‘oleamide’) accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. Twenty μM cis‐oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. cis‐oleamide stereoselectively blocked veratridine‐induced (but not K+‐induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 μM). The cis isomer stereoselectively blocked veratridine‐induced (but not K+‐induced) (3H)‐GABA release from mouse synaptosomes (IC50, 4.6 μM). At 20 μM cis‐oleamide, but not trans, produced a marked inhibition of Na+ channel‐dependent rises in intrasynaptosomal Ca2+. The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty‐four μM cis‐oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). cis‐Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 μM suggesting a frequency‐ or state‐dependent block of voltage‐gated Na+ channels. Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage‐gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal. British Journal of Pharmacology (2000) 129, 283–290; doi:10.1038/sj.bjp.0703051 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Stereoselective modulatory actions of oleamide on GABA A receptors and voltage‐gated Na + channels in vitro : a putative endogenous ligand for depressant drug sites in CNS

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Publisher
Wiley
Copyright
2000 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0703051
pmid
10694234
Publisher site
See Article on Publisher Site

Abstract

cis‐9,10‐octadecenoamide (‘oleamide’) accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. Twenty μM cis‐oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. cis‐oleamide stereoselectively blocked veratridine‐induced (but not K+‐induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 μM). The cis isomer stereoselectively blocked veratridine‐induced (but not K+‐induced) (3H)‐GABA release from mouse synaptosomes (IC50, 4.6 μM). At 20 μM cis‐oleamide, but not trans, produced a marked inhibition of Na+ channel‐dependent rises in intrasynaptosomal Ca2+. The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty‐four μM cis‐oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). cis‐Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 μM suggesting a frequency‐ or state‐dependent block of voltage‐gated Na+ channels. Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage‐gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal. British Journal of Pharmacology (2000) 129, 283–290; doi:10.1038/sj.bjp.0703051

Journal

British Journal of Pharmacology – Wiley

Published: Jan 1, 2000

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