Dopamine/dopaminergic system metabolism

Levodopa can pass the blood-brain barrier (unlike dopamine), where it is converted into dopamine, and thus acts by topping up the CNS dopaminergic system. Levodopa is most usually given with carbidopa or benser-azide (dopa-decarboxylase inhibitors), which prevent the wasteful peripheral metabolism of levodopa. This allows lower doses of levodopa to be given, which results in fewer adverse effects. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

The antischizophrenic actions of these drugs may not consist simply of postsynaptic blockade of hyperactive dopamine systems. Such a blockade occurs within hours, while most symptoms improve over weeks. This discrepancy in the latency to therapeutic effect has been hypothesized to be linked to drug-induced changes in dopaminergic activity after initiation of therapy, dopamine turnover increases, but after continued antipsychotic treatment, tolerance develops and dopamine metabolism returns to normal. This downward adjustment of dopaminergic activity is consistent with the decreased plasma concentrations of the dopamine metabolite homovanillic acid, an observation that correlates temporally with the clinical response to drug treatment. 

None of the TCAs seem to have an effect on dopaminergic neurotransmission in the central nervous system (CNS). This has been supported by the lack of alterations in dopamine receptor sensitivity in chronically treated patients who have shown response to treatment (Sugrue, 1983). More recent investigations have also shown that administration of DMI to depressed subjects had no effect on levels of homovanillic acid, the principal metabolite of dopamine, in a measure of brain neurotransmitter production. In this investigation, DMI administration did increase norepinephrine production and overall cerebral metabolism (Lambert, 2000). 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

A model for the action of cocaine and amphetamine at a dopaminergic synapse in the central nervous system. Cocaine (right side) blocks the dopamine reuptake transporter (DAT). Amphetamine (left side) has several effects. It enters the nerve ending via reverse transport by the DAT and displaces dopamine (DA) from vesicles by altering their pH. It also inhibits dopamine metabolism by MAO in the nerve ending. The increased intraneuronal dopamine causes reversal of the DAT and dopamine floods into the synapse. 

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