The Effects of a Selective Inhibitor of Tryptophan 2,3-Dioxygenase and a Combined Inhibitor of Tryptophan 2,3-Dioxygenase and 5-HT Reuptake on Serotonergic Function in the Rat

Abstract

Over the last few decades it has become clear that depression can be effectively treated by elevating serotonergic and/or noradrenergic function in the brain. The close interplay between the ascending serotonergic pathways from the raphe and the ascending noradrenergic pathways from the locus coeruleus at both somatic and presynaptic sites makes it likely that both of these monoaminergic pathways will be altered by drugs acting selectively at enzymes or receptors of either one of these pathways. The role of 5-HT in the amelioration of unipolar depression has gained recent support with the introduction of the clinically effective selective serotonin reuptake inhibitors (SSRIs). However, a problem still unsolved by the introduction of the SSRIs is the slow onset of therapeutic effectiveness of all antidepressants of several weeks. Several lines of evidence suggest that this slow onset of action, particularly for the SSRIs, may be due to an inhibitory autoregulation of the serotonergic pathway after an elevation of synaptic 5-HT caused by activation of the somatodendritic 5-HT1A autoreceptor (Artigas et al.,1994; see Blier and Montigny, 1994). Larger increases in 5-HT than those achieved by the SSRIs may overcome some of the consequences of this inhibitory autoregulation and may therefore hasten the onset of therapeutic effect.