THE EFFECTS OF AN INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND A COMBINED INHIBITOR OF TRYPTOPHAN 2,3-DIOXYGENASE AND 5-HT REUPTAKE IN THE RAT

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl) vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptopha n 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3- [2-(4-pyridyl)vinyl]-1H-indole) of both TDO and 5-hydroxytryptamine (5 -HT) reuptake, were examined on tryptophan catabolism, cerebrospinal f luid (CSF) concentrations of tryptophan and 5-HT and serotonergic-medi ated physiology and behaviour in the rat. The catabolism of L-[ring-2- C-14]tryptophan in vivo was completely inhibited by prior administrati on of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT de pletion produced by p-chloroamphetamine and rapidly decreased dorsal r aphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 2 60% of basal concentration. A maximally effective dose of 680C91 eleva ted a global measure of brain extracellular 5-HT (CSF 5-HT) to concent rations similar to those seen maximally after exogenous tryptophan adm inistration (approx 170% of basal). Maximally effective doses of 709W9 2 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% o f basal) and to concentrations greater than those achieved maximally w ith serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reu ptake inhibitor/tryptophan combination therapy but with a more sustain ed timecourse; such compounds may therefore have superior antidepressa nt efficacy in the clinic.