Related Experiment Video
Updated: Aug 7, 2026
Polygraphic Recording Procedure for Measuring Sleep in Mice
Published on: January 25, 2016
SB-334867-A antagonises orexin mediated excitation in the locus coeruleus
E M Soffin1, M L Evans, C H Gill
1Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, UK. ellen_m_soffin@gsk.com
Abstract:
Electrophysiological recordings from identified noradrenergic locus coeruleus (LC) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can triple the firing rate of spontaneously active LC neurones, quantitative pharmacological analysis that determines the receptor subtype(s) mediating the orexinergic response has not yet been performed. Here we demonstrate that the effects of orexin-A are five-fold more potent than orexin-B on LC neuronal excitability. We show further that the orexin receptor antagonist SB-334867-A inhibits the effects of both agonists with pK(B) values similar to those calculated for human OX1 receptors expressed in CHO cells. Finally, we found no evidence for tonic activation of OX1 receptors in LC noradrenergic neurones despite electron microscopic evidence that orexin terminals directly contact these neurones. These data demonstrate that SB-334867-A is a useful tool compound with which to study the physiology of OX1 receptors.
Insights
Orexins directly activate locus coeruleus (LC) neurons, with orexin-A being more potent than orexin-B. The antagonist SB-334867-A selectively blocks these orexinergic effects, indicating OX1 receptor involvement.
Area of Science:
- Neuroscience
- Neuropharmacology
Background:
- Noradrenergic locus coeruleus (LC) neurons are modulated by orexins.
- Orexin-A increases LC neuronal firing rate, but the specific receptor subtypes involved are unclear.
Purpose of the Study:
- To pharmacologically characterize the orexin receptor subtypes mediating effects on LC neurons.
- To evaluate the selectivity of the orexin receptor antagonist SB-334867-A.
Main Methods:
- Electrophysiological recordings from rat LC neurons.
- Application of orexin-A and orexin-B.
- Inhibition studies using the orexin receptor antagonist SB-334867-A.
- Comparison of pKB values with human OX1 receptors expressed in CHO cells.
Main Results:
- Orexin-A is five times more potent than orexin-B in depolarizing LC neurons.
- SB-334867-A inhibited orexin-A and orexin-B effects with pKB values consistent with OX1 receptor antagonism.
- No evidence of tonic OX1 receptor activation in LC neurons was found.
Conclusions:
- Orexin-A and orexin-B act via OX1 receptors to modulate LC neuronal excitability.
- SB-334867-A is a selective OX1 receptor antagonist useful for studying LC neuron physiology.
- Despite direct innervation, tonic OX1 receptor activation in LC neurons is unlikely.
Related Concept Videos
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
01:23Drugs Acting on Autonomic Ganglia: Stimulants
Ganglionic stimulants activate NM nicotinic receptors in autonomic ganglia, falling into two categories: nicotine mimetics [e.g., lobeline, dimethylpiperazine, tetramethylammonium] and muscarinic receptor agonists [e.g., muscarine, methacholine]. The first category's action is rapid and blocked by nicotinic receptor antagonists, while the second category's action is delayed and blocked by atropine-like agents. Nicotine, an alkaloid, affects the heart rate by stimulating sympathetic or...