Table 3. Summary of the specific assumptions used during model design.

Assumption	Comments
TYR, PHE and TRP inhibit each other.	Since these LNAA compete for the transport through the BBB, they reduce their competitors’ net fluxes through LAT-1.
TYR and PHE have just two fates: protein synthesis or synthesis of L-DOPA.	About 90% of the TYR and PHE are used for protein synthesis and 10% for the synthesis of L-DOPA [110]. Furthermore, 90% of the production of LDOPA uses TYR as substrate, since TYR is the preferred substrate of TH.
It is assumed that about 80% of L-DOPA is committed to the synthesis of DA and the remaining 20% is methylated by COMT.	This assumption is reasonable because the majority of L-DOPA is decarboxylated to DA.
At steady state, the concentration of L-DOPA is 10% of the level of cytosolic DA.	Exact proportions are unknown, but similar assumptions were made for other models in the literature [33,48].
Vesicular DA and 5-HT correspond to 98% of the intracellular DA and 5-HT, while the remaining 2% is in the cytosol.	It is generally assumed, and implemented in other models, that most of the intracellular DA is located in the vesicles of dopaminergic neurons [33,48]. The same assumption is made here for serotonergic neurons.
Homovanillic acid (HVA) is considered to exist only in the extracellular space.	The proposed model does not include astrocytes and other glial cells that are involved with the dynamics of HVA. However, COMT is active in the DAergic neurons, so that HVA can also be directly influenced by cytosolic DOPAC.
TRP is assumed to have only three fates: protein synthesis, synthesis of 5- HTP or kynurenine.	It is assumed that about 10% of TRP is used to protein synthesis, whereas 35% is committed to the synthesis of 5-HTP and the remaining 55% is used in the synthesis of kynurenine [79].
It is assumed that about 80% of 5-HTP are committed toward the synthesis of serotonin.	Although 5-HTP plays several peripheral roles, the vast majority is used for the biosynthesis of 5-HT [111].
At the steady state, the concentration of 5-HTP is 10% of the cytosolic serotonin.	A similar assumption is made for DA and L-DOPA.
eDA/e5HT = 1	According to the literature, the ratio of eDA/e5HT is between 0.71 and 2, with a tendency toward the lower level [112–115].
iDA/i5HT = 0.5	According to the literature, 0.5 < iDA/i5HT < 0.8, with a tendency toward the lower level [27,116–118].
i5HT/e5HT = 850	This value was taken from Adell et al. [119].
e5HIAA/e5HT = 800	The extracellular concentration of 5-HIAA is much higher than the extracellular concentration of 5-HT [120].
i5HIAA/e5HIAA = 0.5	This value was taken from Adell et al. [119]. Note that i5HIAA is the tissue concentration of 5-HIAA and had to be converted to cytosolic concentration.
iDOPAC/eDOPAC = 0.5	A similar assumption was made for the serotonergic metabolites, intra- and extracellular 5-HIAA. Note, again, that iDOPAC is the tissue concentration of DOPAC and had to be converted to cytosolic concentration, since DOPAC is not present in the vesicle compartment.
cDOPAL/cDOPAC = 200	DOPAL has been quantified as the precursor aldehyde of DOPAC in the substantia nigra of human brains [121]. We adopted the same ratio for the extracellular compartment (eDOPAL/eDOPAC = 200).
Cytosolic DA and 5-HT inhibit their own synthesis.	DA inhibits its own synthesis by competing with the cofactor tetrahydrobiopterin (BH4) for the binding site of the enzyme TH [122,123]. We assumed that 5-HT inhibitis its own synthesis by means of a similar competing mechanism.
D2 is the only auto-receptor whose activity was taken into account; extracellular DA modulates TH activity through D2.	No other receptors that modulate DA synthesis and release were taken into account, since our study focuses on the presynaptic dopaminergic nerve terminal, where D2 is most prevalent.
5-HT1B is the only autoreceptor whose activity was taken into account; extracellular 5-HT modulates TPH2 activity through 5-HT1B.	No other receptors that modulate 5-HT synthesis and release were taken into account, since our work focuses on the presynaptic serotonergic nerve terminal, where 5-HT1B is most prevalent.
Extracellular DA competes with extracellular 5-HT for SERT	Although all biogenic monoamine transporters are promiscuous, only the competition of DA for SERT was considered, since the affinity of 5-HT for DAT is much lower than DA for SERT [124–126].
TPH2, AADC and VMAT2 have a functional and physical coupling similar to TH, AADC and VMAT2	It has been shown that TH, AADC and VMAT2 have a functional and physicial coupling, so that DA is directly transported into vesicles as soon as it is synthetized [127,128]. We assume that TPH2, AADC and VMAT2 behave in the same way.
KYNA, 3-HK and 3-HAA inhibit the activity of ALDH in the brain.	Even at low concentrations, these kynurenine metabolites can reduce the ALDH activity by 40% or more in the liver [26]. Although ALDH is not the only enzyme involved in the catalysis of DOPAL and 5-HIAL, these aldehydes are mainly oxidized by ALDH [129].
IDO-TDO, MAO, KAT, and HAAO activities are increased under chronic stress.	A substantial body of research supports these assumptions [74,130–132].