Depression and anxiety are among the leading causes of societal burden. Abnormalities in 5-hydroxytryptamine (5-HT; serotonin) neurotransmission are known to be associated with depressive and anxiety symptoms. The rostral projections of brainstem dorsal (DRN) and median (MRN) raphe nuclei are the main sources of forebrain 5-HT. The expression, turnover and distribution of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in 5-HT biosynthesis in the DRN and MRN are complex, in keeping with the existence of different subpopulations of 5-HT neurons in this area. In the present study, we measured the expression of TPH2 mRNA in the DRN and MRN using in situ hybridization in three genetically modified mouse models, all relevant to depression and anxiety, and matched wild-type controls. Our results show quantitative modifications in TPH2 mRNA expression in the three main subregions of the DRN as well as the MRN in relation to changes in serotonergic, glutamatergic and endocannabinoid neurotransmission systems. Thus, there were significant decreases in TPH2 transcript levels in 5-HT transporter (5-HTT)-/- mutant mice, whereas increases were observed in the vesicular glutamate transporter 1 hemi knock out (VGLUT1+/-) and cannabinoid receptor 1 mutant (CB1R-/-) mice. Based on these findings, we suggest that TPH2 mRNA expression is under the influence of multiple messenger systems in relation to presynaptic and/or postsynaptic feedback control of serotonin synthesis that, 5-HTT, VGLUT1 and CB1R seem to be involved in these feedback mechanisms. Finally, our data are in line with previous reports suggesting that TPH2 activity within different raphe subregions is differentially regulated under specific conditions.