Partial agonistic activity of R- and S-enantiomers of 8-OH-DPAT at 5-HT1A receptors.

In this study, the 5-HT1A agonistic activity of R- and S-enantiomers of the prototypical 5-HT1A agonist 8-OH-DPAT was investigated using in vivo microiontophoresis and the hypothermic response in rats. Both the R- and S-enantiomers suppressed current-dependently the firing activity of dorsal hippocampus CA3 pyramidal neurons. The number of spikes suppressed/nA of R-(+)-OH-DPAT was about 2-fold greater than that of S-(-)-OH-DPAT, which indicates greater agonistic activity of the R-enantiomer. The determination of the effectiveness of 5-HT in suppressing the firing activity of CA3 pyramidal neurons prior to and during application of either the R- or S-enantiomer showed that both compounds antagonized the effect of 5-HT, thus demonstrating their partial agonistic activity. Racemic 8-OH-DPAT produced a dose-dependent hypothermia which was attenuated by the 5-HT1A antagonist pindolol, but not by the nonselective 5-HT antagonist methysergide. Similarly, both R- and S-enantiomers induced a dose-dependent hypothermia, which was greater and longer lasting in the case of R-(+)-OH-DPAT when compared to S-(-)-OH-DPAT. In conclusion, R-(+)-OH-DPAT, displayed a greater agonistic activity at 5-HT1A receptors than S-(-)-OH-DPAT, both in suppressing firing activity of CA3 pyramidal neurons and in decreasing body temperature. Nevertheless, both compounds behaved as partial agonists.