PARTIAL AGONISTIC ACTIVITY OF R-ENANTIOMERS AND S-ENANTIOMERS OF 8-OH-DPAT AT 5-HT1A RECEPTORS

In this study, the 5-HT1A agonistic activity of R- and S-enantiomers o f 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 activi ty of dorsal hippocampus CA(3) 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-ena ntiomer. The determination of the effectiveness of 5-HT in suppressing the firing activity of CA(3) pyramidal neurons prior to and during ap plication of either the R- or S-enantiomer showed that both compounds antagonized the effect of 5-HT, thus demonstrating their partial agoni stic activity, Racemic 8-OH-DPAT produced a dose-dependent hypothermia which was attenuated by the 5-HT1A antagonist pindolol, but not by th e nonselective 5-HT antagonist methysergide. Similarly, both R- and S- enantiomers induced a dose-dependent hypothermia, which was greater an d longer lasting in the case of R-(+)-OH-DPAT when compared to S-(-)-O H-DPAT. In conclusion, R-(+)-OH-DPAT displayed a greater agonistic act ivity at 5-HT1A receptors than S-(-)-OH-DPAT, both in suppressing firi ng activity of CA(3) pyramidal neurons and in decreasing body temperat ure, Nevertheless, both compounds behaved as partial agonists.