GLUTAMATE RELEASE IN HUMAN CEREBRAL-CORTEX AND ITS MODULATION BY 5-HYDROXTRYPTAMINE ACTING AT H 5-HT1D RECEPTORS

1 The release of glutamic acid and its modulation by 5-hydroxytryptami ne (5-HT) in the human brain has been investigated in synaptosomal pre parations from fresh neocortical samples obtained from patients underg oing neurosurgery to reach deeply sited tumours. 2 The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a con centration-dependent manner (EC50 = 2.9 nM; maximal effect similar or equal to 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 simil ar or equal to 50%); the effect of sumatriptan was also methiothepin-s ensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3 The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergol ine were unable to prevent the 5-HT effect; instead they inhibited glu tamate release, their effects being abolished by methiothepin. Some 5- HT1A receptor antagonists also displayed intrinsic agonist activity. 4 The effect of sumatriptan was prevented by ketanserin, a drug known t o display much higher affinity for recombinant h 5-HT1D than for h 5-H T1B receptors. 5 We propose that neocortical glutamatergic nerve termi nals in human brain cortex possess release-inhibiting presynaptic hete roreceptors that appear to belong to the h 5-HT1D subtype.