The 5-HT1A receptor antagonist robalzotan completely reverses citalopram-induced inhibition of serotonergic cell firing

Abstract 5-HT 1A receptor antagonists have been suggested to increase the efficacy of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors in the treatment of depression by enhancing the increase in brain 5-HT induced by 5-HT reuptake blockade. Here, the novel 5-HT 1A receptor antagonist robalzotan [( R )-3- N , N -dicyclobutylamino-8-fluoro-3,4-dihydro-2 H -1-benzopyran-5-carboxamide hydrogen (2 R , 3 R ) tartrate monohydrate] (12.5, 25, 50, 100 μg/kg, i.v.) was found to completely reverse the acute inhibitory effect of citalopram (300 μg/kg i.v.) or paroxetine (100 μg/kg, i.v.) on the activity of 5-HT neurons in the dorsal raphe nucleus in rats. Robalzotan (5, 50 μg/kg, i.v.) by itself increased the firing rate of the majority of 5-HT cells studied. The present results suggest that robalzotan may indeed augment the increases in 5-HT output induced by selective 5-HT reuptake inhibitors by antagonizing the feedback inhibition of 5-HT cell firing produced by such drugs. Thus, robalzotan may be effective by enhancing the action of selective 5-HT reuptake inhibitors or as monotherapy in the treatment of depression.