Glutamate release in human cerebral cortex and its modulation by 5‐hydroxtryptamine acting at h 5‐HT1D receptors

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Abstract
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. 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‐HT1B/5‐HT1D receptor agonist sumatriptan mimicked 5‐HT (EC50=6.4 nM; maximal effect ≃50%); the effect of sumatriptan was also methiothepin‐sensitive. Selective 5‐HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5‐HT. The 5‐HT1B/5‐HT1D receptor ligand GR 127935 and the 5‐HT2C/5‐HT1B/5‐HT1D receptor ligand metergoline were unable to prevent the 5‐HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5‐HT1A receptor antagonists also displayed intrinsic agonist activity. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5‐HT1D than for h 5‐HT1B receptors. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release‐inhibiting presynaptic heteroreceptors that appear to belong to the h 5‐HT1D subtype. British Journal of Pharmacology (1998) 123, 45–50; doi:10.1038/sj.bjp.0701581