Effects of MDL 73005EF on central pre- and postsynaptic 5-HT1A receptor function in the rat in vivo.
The effects of MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-8- azaspiro[4,5]decan-7,9-dione methyl sulphonate), a novel selective 5-HT1A receptor ligand with putative anxiolytic properties, were explored using models of central pre- and postsynaptic 5-HT1A receptor function in the male rat. MDL 73005EF dose dependently decreased the hippocampal 5-HT output measured by in vivo microdialysis in chloral hydrate-anaesthetised rats and this response was antagonised by the 5-HT1A/B receptor antagonist, pindolol. Local administration of MDL 73005EF had no effect on the hippocampal 5-HT output. MDL 73005EF failed to alter basal plasma adrenocorticotropin (ACTH) levels but, in common with pindolol, attenuated the ACTH response to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In contrast to 8-OH-DPAT, MDL 73005EF significantly increased plasma prolactin but apparently not through a 5-HT receptor-mediated mechanism. The results indicate that MDL 73005EF possesses mixed 5-HT1A receptor agonist/antagonist properties, acting as an agonist at presynaptic 5-HT1A receptors controlling 5-HT release and as an antagonist at postsynaptic 5-HT1A receptors mediating ACTH release.
Gartside
S E
SE
MRC Unit of Clinical Pharmacology, Radcliffe Infirmary, Oxford, U.K.
Cowen
P J
PJ
Hjorth
S
S
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D003956:Dialysis; D004147:Dioxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005277:Fenfluramine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009490:Neurosecretory Systems / Q000187:drug effects; D010869:Pindolol / Q000494:pharmacology; D011388:Prolactin / Q000097:blood / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D004147:Dioxins; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; D013764:Tetrahydronaphthalenes; C063249:binospirone mesylate; D005277:Fenfluramine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D010869:Pindolol