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 analysed 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 antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride), administered alone or in combination. GR 127935, injected alone, increased 5-HT turnover with maximal effects approximately 50% above the control levels in the four brain regions 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 but 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 reaching 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%, respectively) concentrations. The synergistic effect of the two receptor antagonists on the 5-HT turnover and the terminal release of 5-HT indicate somatodendritic 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 itself for the evoked 5-HT release when the reuptake mechanism is intact.

Influence of 5-HT1B/1D receptors on dopamine release in the guinea pig nucleus accumbens: a microdialysis study.

To clarify whether serotonin (5-HT) 5-HT1B/1D receptors are involved in dopamine (DA) release, extracellular levels of DA were monitored by in vivo microdialysis during various conditions. 5-HT (10 microM) alone, and together with the 5-HT1B/1D receptor antagonist. GR127935 (10 microM), or the 5-HT1B/1D agonist, sumatriptan (1 microM), were perfused into the nucleus accumbens of freely moving guinea pigs. A 10-fold increase in the extracellular concentration of DA was obtained during administration of 5-HT alone. The 5-HT-induced DA elevation was not significantly affected by co-administration of sumatriptan (MANOVA; P > 0.05) but markedly attenuated by coperfusion of GR127935 (MANOVA; P = 0.02). Neither GR127935 nor sumatriptan, when administered alone, significantly affected extracellular DA levels. These results suggest that, in the DA-rich nucleus accumbens, 5-HT1B/1D receptors are not involved in the modulation of DA release during normal tonic or basal conditions but may take part in the regulation of DA release when synaptic 5-HT levels are very high.