Effects of co-administration of a monoamine oxidase inhibitor and a 5-HT1A receptor antagonist on 5-hydroxytryptamine cell firing and release

We report the effects of the monoamine oxidase inhibitor, tranylcypromine, combined with the 5-HT1A receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl cyclohexanecarboxamide (WAY 100635), on both 5-hydroxytryptamine (5-HT) cell firing and cortical extracellular 5-HT in the rat. Tranylcypromine inhibited 5-HT cell firing in the dorsal raphe nucleus dose-dependently (ED(50) 5 mg/kg i.v.). In microdialysis experiments, tranylcypromine (5 mg/kg i.v.) increased extracellular 5-HT in the frontal cortex. WAY 100635 (0.1 mg/kg i.v.) both reversed the inhibition of 5-HT cell firing and facilitated the increase in extracellular 5-HT. In conclusion, WAY 100635 enhances the effect of tranylcypromine on presynaptic 5-HT function. These data are relevant to clinical evidence that co-therapy with a 5-HT1A receptor antagonist improves the antidepressant efficacy of a monoamine oxidase inhibitor.