Differential regional antagonism of 8-OH-DPAT-induced decrease in serotonin synthesis by two 5-HT1A receptor antagonists.
The effects of two 5-HT1A receptor antagonists, (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2 H-1-benzopyran-5-carboxamide hydrogen (2 R,3 R)-tartrate monohydrate (NAD-299) and N-(2-(1-(2-methoxyphenyl)-piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on the decrease in 5-hydroxytryptophan (5-HTP) accumulation evoked by (RS)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) in rats treated with the decarboxylase inhibitor, 3-hydroxyphenylhydrazine (NSD 1015) were studied in four rat brain regions: hippocampus, hypothalamus, striatum and frontal cortex. Dose-response studies revealed differential effects of both antagonists in the areas examined. Both antagonists were significantly more potent in antagonising the effect of 0.30 and 0.76 micromol/kg s.c. 8-OH-DPAT in hippocampus than in hypothalamus, striatum and frontal cortex in mentioned order. This order of potency was the opposite to that found for 8-OH-DPAT in decreasing the 5-HTP accumulation. Since previous studies by others have indicated that the reserve of somatodendritic 5-HT1A receptors is greater in dorsal raphe nucleus innervating frontal cortex and striatum than in median raphe nucleus which mainly innervates hippocampus, the observed different regional potency of the two 5-HT1A receptor antagonists may be explained by this difference in the 5-HT1A receptor reserve.
Larsson
L G
LG
Biochemical Pharmacology, Preclinical R & D, Astra Arcus, Södertälje, Sweden.
Stenfors
C
C
Ross
S B
SB
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001578:Benzopyrans; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C108607:robalzotan