ANTAGONISTS OF 5-HT4 RECEPTOR-MEDIATED RESPONSES IN ADULT HIPPOCAMPAL-NEURONS

The study of serotonin-4 (5-HT4) receptors in the central nervous syst em has been hindered by the lack of effective, selective antagonists. However, recently, several novel compounds have been synthesized and s hown to act as antagonists at 5-HT4 receptors in smooth muscle and emb ryonic neurons in culture. In the present study, intracellular electro physiological recordings were used to test the effects of three of the se compounds: endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl dro-6-methoxy- 2-oxo-1H-benzimidazole-1-carboxylate (DAU 6285), 2-(methylsulfonylamin o)ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate (GR 113 808) and 2-diethylaminoethyl-(2-methoxy-4-amino-5-chloro) benzoate (SD Z 205-557) on the 5-HT4 reduction of the afterhyperpolarization seen i n adult CA1 hippocampal neurons in brain slices. GR 113808, SDZ 205-55 7 and DAU 6285 all functioned as competitive antagonists at these 5-HT 4 receptors. Although all three compounds tested acted as effective an tagonists, they differed considerably in potency. When the potency of these antagonists at the 5-HT4 receptor that mediates the reduction of the afterhyperpolarization was compared with that observed for 5-HT4 receptors in biochemical and binding assays, an excellent correlation was observed. Among the antagonists tested, GR 113808 was the most pot ent (pA(2) = GR 113808 > SDZ 205-507 > DAU 6285). It exhibited an appa rent affinity for the 5-HT4 receptors in the low nanomolar range but d id not antagonize 5-HT1A, beta-adrenergic or muscarinic receptor-media ted responses when applied at concentrations two orders of magnitude h igher. These results demonstrate the usefulness of these compounds in the physiological identification of 5-HT4 receptor-mediated responses in central neurons. The availability of these antagonists should great ly facilitate the identification of additional 5-HT4-mediated response s in the adult central nervous system.