EFFECTS OF 5-HT3 RECEPTOR ANTAGONISTS ON BINDING AND FUNCTION OF MOUSE AND HUMAN GABA(A) RECEPTORS

Both 5-HT3 receptor antagonists and benzodiazepine receptor ligands ha ve effects on anxiety, and alter the behavioral action of ethanol. For these reasons, we tested the ability of several 5-HT3 receptor antago nists to inhibit the ligand binding and function of the gamma-aminobut yric acid(A)/benzodiazepine receptor Cl- channel complex of mouse brai n membranes. MDL 72222 (1-a-H-3-a-5-aH-optropan-3yl-3,5-dichlorobenzoa te) and LY 278584 icyclo[3.2.1.]oct-3-yl)-1H-indazole-3-carboxamide) i nhibited [H-3]flunitrazepam binding with K-i values of approximately 2 0 mu M; ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid este r) was more potent with a K-i of 0.8 mu M. ICS 205-930 (50 mu M) had n o effect on [H-3]muscimol binding. ICS 205-930, MDL 72222, and LY 2785 84 all inhibited the binding of [S-35]TBPS (tert-butylbicyclophosphoro thionate) with K-i values of approximately 10 mu M and reduced muscimo l-dependent Cl-36(-) flux into mouse cortical microsacs by 30-45% at a concentration of 10 mu M. ICS 205-930, MDL 72222, and LY 278584 (at m icromolar concentrations) reduced GABA-gated chloride currents studied in Xenopus oocytes expressing human alpha(1) beta(1) gamma(2S) GABA(A ) receptor subunits. ICS 205-930 differed from the other two 5-HT3 rec eptor antagonists in that it induced a biphasic effect on GABA-gated c urrents: at concentrations from 0.1 to 5 mu M it potentiated GABA resp onses, whereas at higher concentrations (50-100 mu M) it produced inhi bition. The stimulatory action induced by ICS 205-930 was due to inter action at the benzodiazepine recognition site because expression of th e gamma(2) subunit was required and Ro 15-1788 (1 mu M) completely pre vented the potentiation caused by ICS 205-930. Thus, several 5-HT3 rec eptor antagonists inhibit benzodiazepine binding and affect GABA(A) re ceptor function. These actions are most pronounced for ICS 205-930 and likely involve direct affects on the GABA/benzodiazepine complex rath er than interactions with 5-HT3 receptors.