Glutamate release in human cerebral cortex and its modulation by 5-hydroxtryptamine acting at h 5-HT_1D receptors

Abstract

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours.

2. The Ca²⁺-dependent K⁺ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC₅₀=2.9 nM; maximal effect ≃50%). The inhibition caused by 5-HT was antagonized by the 5-HT₁/5-HT₂ receptor antagonist methiothepin. The 5-HT_1B/5-HT_1D receptor agonist sumatriptan mimicked 5-HT (EC₅₀=6.4 nM; maximal effect ≃50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT_1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT.

3. The 5-HT_1B/5-HT_1D receptor ligand GR 127935 and the 5-HT_2C/5-HT_1B/5-HT_1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT_1A receptor antagonists also displayed intrinsic agonist activity.

4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT_1D than for h 5-HT_1B receptors.

5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT_1D subtype.

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