Synergism between 5-HT1B/1D and 5-HT1A receptor antagonists on turnover and release of 5-HT in guinea-pig brain in vivo

The effects on 5-HT turnover (5-HIAA/5-HT ratio) and extracellular 5-HT and 5-HIAA levels (in vivo microdialysis in freely moving animals) were analys ed in guinea-pig brains following the 5-HT1B receptor antagonist, GR 127935 {N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide}, or the 5-HT1A receptor an tagonist, WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-p yridinyl) cyclohexanecarboxamide trihydrochloride), administered alone or i n combination. GR 127935, injected alone, increased 5-HT turnover with maxi mal effects approximately 50% above the control levels in the four brain re gions examined (hypothalamus, hippocampus, striatum and frontal cortex). GR 127935 significantly increased extracellular concentrations of 5-HT and 5- HIAA in frontal cortex (40%), whereas 5-HIAA, but not 5-HT, was elevated in striatum (20-30%). WAY-100635 did not significantly change 5-HT turnover b ut caused a small significant increase in the extracellular 5-HT and 5-HIAA concentrations in both striatum and frontal cortex. The combined treatment with GR 127935 and WAY-100635 resulted in an increased 5-HT turnover reach ing maximal effects of 70-90% above the control values in all brain regions tested and produced a significant elevation of striatal and frontal cortex extracellular 5-HT (40% and 60%, respectively) and 5-HIAA (60% and 70%, re spectively) concentrations. The synergistic effect of the two receptor anta gonists on the 5-HT turnover and the terminal release of 5-HT indicate soma todendritic 5-HT release and stimulation of inhibitory 5-HT1A receptors at this level. Extracellular 5-HIAA seems to be a better marker than 5-HT itse lf for the evoked 5-HT release when the reuptake mechanism is intact.