20.2.2.2 Dopaminergic System

Before we can discuss drugs that enhance the dopaminergic system for use in the treatment of Parkinson’s disease, we need to understand the dopaminergic system. The first step in the dopaminergic system is the synthesis of dopamine. In a dopaminergic neurone, dopamine is synthesized from L-dopa in the presence of the enzyme L-aromatic acid decarboxylase (Figure 20.5).

Figure 20.5 The dopaminergic system (Copyright QUT, Sheila Doggrell)

The dopamine (DA) is then stored in a storage vesicle until the nerve is activated. Once, an action potential reaches the nerve ending, there is an increased level of Ca²⁺, and this associated with vesicles moving to the cell membrane and dopamine being released. The released dopamine then acts at its receptors on the postjunctional membrane to initiate some cell signaling and a final action.

We can enhance the dopaminergic system at a number of sites in this part of the dopaminergic system. For example we can promote the synthesis of dopamine, promote the release of dopamine, or stimulate the dopamine receptors.

Dopamine is inactivated either by neuronal reuptake (which is similar process as that observed with noradrenaline and 5-hydroxytryptamine) or by metabolism. The metabolism involves 3 enzymes; monoamine oxidase (MAO), aldehyde reductase (AD) and catechol-O-methyl transferase (COMT). The enzymes act on the dopamine in sequence either firstly monoamine oxidase, followed by aldehyde reductase and COMT or COMT followed by monoamine oxidase and aldehyde reductase (Fig 20.6).

Figure 20.6 Metabolism of dopamine (Copyright QUT, Sheila Doggrell)

Although, the intermediate metabolites are different depending on the order of the enzymes (metabolites A and B), the final metabolite is the same (metabolite C).

Importantly, if we inhibit these enzymes, it will lead to a build up of dopamine, which is another way to enhance the dopaminergic system. Thus, drugs that inhibit either monoamine oxidase or catechol-O-methyl transferase will increase the levels of dopamine.