Effects of 5-HT3 receptor antagonists on binding and function of mouse and human GABAA receptors.
Both 5-HT3 receptor antagonists and benzodiazepine receptor ligands have effects on anxiety, and alter the behavioral action of ethanol. For these reasons, we tested the ability of several 5-HT3 receptor antagonists to inhibit the ligand binding and function of the gamma-aminobutyric acidA/benzodiazepine receptor Cl- channel complex of mouse brain membranes. MDL 72222 (1-a-H-3-a-5-aH-optropan-3yl-3,5-dichlorobenzoate) and LY 278584 (1-methyl-N-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-1H-indazole-3- carboxamide) inhibited [3H]flunitrazepam binding with Ki values of approximately 20 microM; ICS 205-930 (3 alpha-tropanyl-1H-indole-3-carboxylic acid ester) was more potent with a Ki of 0.8 microM. ICS 205-930 (50 microM) had no effect on [3H]muscimol binding. ICS 205-930, MDL 72222, and LY 278584 all inhibited the binding of [35S]TBPS (tert-butylbicyclophosphorothionate) with Ki values of approximately 10 microM and reduced muscimol-dependent 36Cl- flux into mouse cortical microsacs by 30-45% at a concentration of 10 microM. ICS 205-930, MDL 72222, and LY 278584 (at micromolar concentrations) reduced GABA-gated chloride currents studied in Xenopus oocytes expressing human alpha 1 beta 1 gamma 2S GABAA receptor subunits. ICS 205-930 differed from the other two 5-HT3 receptor antagonists in that it induced a biphasic effect on GABA-gated currents: at concentrations from 0.1 to 5 microM it potentiated GABA responses, whereas at higher concentrations (50-100 microM) it produced inhibition. The stimulatory action induced by ICS 205-930 was due to interaction at the benzodiazepine recognition site because expression of the gamma 2 subunit was required and Ro 15-1788 (1 microM) completely prevented the potentiation caused by ICS 205-930. Thus, several 5-HT3 receptor antagonists inhibit benzodiazepine binding and affect GABAA receptor function. These actions are most pronounced for ICS 205-930 and likely involve direct affects on the GABA/benzodiazepine complex rather than interactions with 5-HT3 receptors.
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
R L
RL
Klein
E
E
Sanna
S J
SJ
McQuilkin
P J
PJ
Whiting
R A
RA
Harris
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014326:Tropanes / Q000494:pharmacology; D000077526:Tropisetron; D014982:Xenopus laevis
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D007191:Indazoles; D007211:Indoles; D011963:Receptors, GABA-A; D012702:Serotonin Antagonists; D014326:Tropanes; C061531:LY 278584; D005442:Flumazenil; D005445:Flunitrazepam; D000077526:Tropisetron; C037476:tert-butylbicyclophosphorothionate; C042253:bemesetron