The novel 5-HT1A receptor antagonist (S)-UH-301 prevents (R)-8-OH-DPAT-induced decrease in interstitial concentrations of serotonin in the rat hippocampus.
Previous studies have demonstrated that the novel 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) analogue (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin ((S)-UH-301) is able to antagonize several behavioural and biochemical effects of the 5-HT1A receptor agonist 8-OH-DPAT in the rat. In the present study in vivo microdialysis was used to evaluate the effects of (S)-UH-301 on interstitial concentrations of 5-hydroxytryptamine (5-HT), its metabolite 5-hydroxyindoloacetic acid (5-HIAA), and the catecholamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dorsal hippocampus of freely moving rats. Furthermore, the effects of (S)-UH-301 on (R)-8-OH-DPAT-induced changes in dialysate hippocampal concentrations of 5-HT and metabolites were examined. Neither 5-HT nor metabolites were significantly influenced by (S)-UH-301 (1.25, 2.5, 5.0 mg/kg s.c.). In contrast, (R)-8-OH-DPAT (100 micrograms/kg s.c.) decreased interstitial concentrations of 5-HT (to 45% of baseline) and 5-HIAA (to 75%), and increased concentrations of DOPAC (to 165%) and HVA (to 155%). Pretreatment with (S)-UH-301 (2.5 mg/kg s.c.) 20 min before (R)-8-OH-DPAT (100 micrograms/kg s.c.) abolished the 5-HT and metabolite response to (R)-8-OH-DPAT. These data indicate that (S)-UH-301 is able to antagonize (R)-8-OH-DPAT-induced biochemical effects in vivo without producing any effects when given alone. Thus, the present study contributes to the characterization of (S)-UH-301 as a 5-HT1A receptor antagonist with low intrinsic activity.
Nomikos
G G
GG
Department of Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Arborelius
L
L
Svensson
T H
TH
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003956:Dialysis; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists; D013237:Stereoisomerism
D012702:Serotonin Antagonists; C064282:UH 301; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin