Fig 1.
Conceptual, simplified model of pathways associated with MDD and their interactions in the presynaptic DA and 5-HT terminals.
The model accounts for separate cytosolic and vesicular compartments in the two terminals, which share the same extracellular space. The latter is an important “collective” location for processes that take place outside the neurons, in particular, in the synaptic cleft or in glial cells. Metabolites are represented with white boxes and participating enzymes with black ellipses. Metabolites in dashed boxes are important but not necessarily located in the compartment where they are represented. Prefixes s, c, v, e, and p refer to metabolites in the serum, cytosol, vesicles, extracellular space and pool of proteins, respectively. Cortisol/corticosterone (CORT) is represented by a white diamond. Serum tyrosine, phenylalanine, tryptophan, enzymes and CORT are independent variables that remain constant during a given experiment. The strongest inhibitory effects are represented with dotted lines. Abbreviations: 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HIAL, 5-hydroxyindoleacetaldehyde; 5-HT, 5-hydroxytryptamine or serotonin; 5-HTP, 5-hydroxytryptophan; AADC, l-amino acid decarboxylase; ALDH, aldehyde dehydrogenase; COMT, catechol O-methyltransferase; DA, dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; HAAO, 3-hydroxyanthranilate 3,4-dioxygenase; HVA, homovanillic acid; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; KP, kynurenine pathway; KYN, kynurenine; KYNA, kynurenic acid; KYNU, kynureninase; LAT, L-type amino acid transporter; L-DOPA, l-3,4-hydroxyphenylalanine; MAO, monoamine oxidase; PHE, phenylalanine; QPRT, quinolinate phosphoribosyltransferase; QUIN, quinolinic acid; SERT, serotonin transporter; TDO, tryptophan-2,3-dioxygenase; TH, tyrosine hydroxylase; TPH2, tryptophan hydroxylase 2; TRP, tryptophan; TYR, tyrosine; VMAT2, vesicular monoamine transporter 2.
Table 1.
Metabolite changes predicted by the model in comparison to corresponding values found in the literature.
Abbreviations: 5-HT, serotonin; COMT, catechol O-methyltransferase; DA, dopamine; DAT, dopamine transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; MAO, monoamine oxidase; SERT, serotonin transporter; TPH2, tryptophan hydroxylase 2; VMAT2, vesicular monoamine transporter 2.
Fig 2.
New steady-state values of dependent variables in response to a 50% increase in CORT.
The percent changes were calculated in comparison to the corresponding values under control conditions (CORT at baseline of 100%). Also shown are the ratios QUIN/KYNA and KYNA/3-HK, which reflect the balance between levels of key metabolites.
Table 2.
Summary of general assumptions made during model design.
Fig 3.
Notable changes in key dependent variables in response to cortisolemia and treatment.
(A) Two-fold increase in the activity of VMAT2. (B) 95% Inhibition of the transporter SERT. (C) 50% Inhibition of the activity of enzyme KMO. (D) Combined inhibition of SERT (↓95%) and KMO (↓50%). Time courses are shown on the left and percent changes after treatment on the right of each panel. CORT is increased by 50% at day 8 and “treatment” starts at day 25 (black triangles).
Table 3.
Summary of the specific assumptions used during model design.