Autoradiographic studies of 5-HT1A-receptor-stimulated [35S]GTPgammaS-binding responses in the human and monkey brain.
G-protein activation mediated by serotonin 5-HT1A receptors in human and monkey brain was investigated by using quantitative autoradiography of agonist-stimulated [35S]GTPgammaS binding to whole-hemisphere brain sections. [35S]GTPgammaS binding was stimulated by the mixed 5-HT1A/1B/1D agonist L 694247 (10 microm) in human brain regions enriched in 5-HT1A binding sites [e.g. hippocampus (132-137%), superficial layers of the neocortex (37-61%), and cingulate and entorhinal cortex (34 and 32%, respectively)]. L 694247 caused virtually no stimulation in regions with 5-HT1B/1D receptors, such as substantia nigra, caudate nucleus and putamen. Similar results were obtained with monkey brain sections. The L 694247-mediated [35S]GTPgammaS-binding responses in human and monkey brain sections were antagonized by the selective, silent 5-HT1A antagonist WAY 100635 (10 microm). The 5-HT1B inverse agonist SB 224289 (10 microm) did not affect the [35S]GTPgammaS-binding response of L 694247. The distribution pattern of the [35S]GTPgammaS-binding response and the antagonist profile suggest the L 694247-induced response in human and monkey brain is mediated by 5-HT1A receptors. A weak stimulation of [35S]GTPgammaS binding was also observed in human hippocampus with either 10 microm 8-OH-DPAT (25 +/- 4%) or naratriptan (42 +/- 2%) compared with that obtained with L 694247. In conclusion, G-protein activation by 5-HT1A receptors can be measured in human and monkey brain sections. L 694247 appears to possess higher efficacy at 5-HT1A receptors compared with 8-OH-DPAT and naratriptan.
Dupuis
D S
DS
Cellular and Molecular Biology Department, Centre de Recherche Pierre Fabre, Castres, France.
Pauwels
P J
PJ
Radu
D
D
Hall
H
H
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry / Q000502:physiology*; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000032:analysis* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D014316:Tritium; D014363:Tryptamines / Q000494:pharmacology
D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013462:Sulfur Radioisotopes; D014363:Tryptamines; D014316:Tritium; C085632:L 694247; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C106783:naratriptan