EFFECTS OF WAY-100635 AND (-)-5-ME-8-OH-DPAT, A NOVEL 5-HT1A RECEPTORANTAGONIST, ON 8-OH-DPAT RESPONSES

The neurochemical profile at both post and presynaptic 5-MT1A receptor s of a novel 8-hydroxp-2-(di-n-propylamino)tetralin (8-OH-DPAT) analog , 5-methyl-8-hydroxy-2-(di-n-propylamino)tetralin ((+/-)-5-Me-8-OH-DPA T) and its stereoisomers was determined and compared to that of the hi ghly selective 5-MT1A receptor antagonist, 4-(2-methoxyphenyl)-1-piper azinyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide (WAY 100635). We evalu ated their effects on 8-OH-DPAT-induced decrease in cAMP production, o n 8-OH-DPAT-induced decrease in rat ventral hippocampal extracellular 5-hydroxytryptamine (5-MText) levels and in body temperature in mice. Both (+/-)- and (-)-5-Me-8-OH-DPAT blocked the 8-OH-DPAT-induced inhib ition of forskolin-stimulated cAMP production. Moreover, while having no significant effect when injected alone, (+/-)-, (-)-5-Me-8-OH-DPAT and WAY 100635 antagonized the 8-OH-DPAT-induced decrease in 5-MText i n rats and hypothermia in mice. By contrast, the (+) isomer inhibited the cAMP synthesis and did not modify the 8-OH-DPAT response on 5-MTex t in ventral hippocampus. These data suggest that (+/-)-5-Me-8-OH-DPAT acts selectively, its activity residing in the(-) enantiomer, this la tter compound acting similarly to WAY 100635 as a full, selective and silent 5-MT1A antagonist. (C) 1998 Elsevier Science B.V.