Figure 1. Biosynthetic pathway and some metabolic transformations of dopamine. 1, l-Tyrosine hydroxylase; 2, l-aromatic amino acid (l-DOPA) decarboxylase; 3, dopamine--hydroxylase; 4, monoamine oxidase; 5, condensation; 6, auto-oxidation; 7, polymerization. Note that, on the left side of the dopamine molecule, some reactions are shown leading to cytotoxic metabolites (H₂O₂, (semi)quinones, tetrahydroisoquinolines).

Figure 2. Simplified summary of the basal ganglia's motor circuit and the functional changes following loss of the nigrostriatal dopamine pathway in Parkinson disease. Inhibitory neurons, or effects, are represented by red lines and excitatory neurons by blue lines. The thickness of the lines indicates the level of functional activity of the neurons. Dashed lines indicate degenerated nigrostriatal dopamine neurons. D₁/D₂, postsynaptic D₁ and D₂ receptors; 1, precentral motor areas (areas 4, 6 and supplementary motor area); 2, putamen; 3, lateral globus pallidus; 4, medial globus pallidus; 5, reticular zone of the substantia nigra; 6, subthalamic nucleus; 7, compact zone of the substantia nigra; 8, thalamus (ventral anterior and ventral lateral).

Figure 3. Changes in some nondopamine brain neuron systems in Parkinson disease: comparison with the loss of nigrostriatal dopamine. Note the severe degree of dopamine loss, compared with the distinctly milder reductions in some other neuronal systems. Acc, nucleus accumbens; CAT, choline acetyltransferase; CCK-8, cholecystokinin-8; Ctx, cortex; DA, dopamine; GABA, -aminobutyric acid; Glu, glutamate; 5-HT, 5-hydroxytryptamine (serotonin); (met)enk, (5-methionine)enkephalin; NA, noradrenaline; NT, neurotensin; PPenk, preproenkephalin; Sn, substantia nigra; SP, substance P; Str, striatum (caudate nucleus and putamen).

Figure 4. The steps involved in the cytotoxic action of MPTP on DA neurons. (1) in the glia cells, MPTP is converted by monoamine oxidase B (MAO B) to the actual toxic agent MPP⁺. After diffusing into the extracellular space, MPP⁺ accumulates (2) in the DA neuron via (3) the specific plasma membrane DA transporter. Within the neuron, MPP⁺ is concentrated (4) in the mitochondria, where it blocks respiration by inhibiting the Complex I activity of the respiratory chain (see insert), thereby reducing ATP production and increasing the formation of (toxic) reactive oxygen species (O₂).

A hypothetical Parkinson disease-inducing cytotoxin (PD-Tx) of either environmental or endogenous origin with the properties of a DA transporter substrate would, like MPP⁺, accumulate in the DA neurons, exerting its cytotoxic effects either by an MPP⁺-like mitochondrial site of action or by increasing the intracellular levels of the cytotoxic reactive oxygen species.

D₁, D₂, D₃, D₄ are the subtypes of the DA receptor localized either on the presynaptic terminal (2) or postsynaptically (5). DA storage vesicles (Ves) are also a potential intracellular storage site of MPP⁺.