Direct Activation by Dopamine of Recombinant Human 5-HT_1A Receptors: Comparison with Human 5-HT_2C and 5-HT₃ Receptors

The effects of dopamine (DA) on the function of human 5-HT_1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT_1A, 5-HT_2C, and 5-HT₃) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT_1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC₅₀ values of 4.2 nM and 11.2 μM. Maximal responses induced by DA were 85 ± 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT_1A antagonist, WAY-100635 (50 μM). In CHO-K1 cells expressing 5-HT_1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [ ³H]-8-OH-DPAT with IC₅₀ values of 10.2 nM and 1.4 μM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT_2C receptors, 5-HT and DA induced inward currents with respective EC₅₀ values of 6.2 nM and 67.7 μM. Magnitudes of maximal DA induced currents were 42 ± 3% of maximal 5-HT responses and blocked by the 5-HT₂ antagonist, piperazine (1 μM). In oocytes expressing 5-HT₃ receptors, 5-HT and DA induced fast inward currents with respective EC₅₀ values of 2.1 μM and 266.3 μM. Maximal DA induced currents were 37 ± 3% of maximal 5-HT responses and blocked the specific 5-HT₃ antagonist LY-278584 (0.1 μM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT₃ > 5-HT_1A > 5-HT_2C, and relative efficacy increased in the order of 5-HT_1A > 5-HT_2C > 5-HT₃. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors.