This is something I was racking my brain with for a few hours.
I just can't understand (or find any research/documentation) that shows L-Dopa causing MORE tolerance than any other drug, where even the cessation of the L-Dopa will not diminish tolerance for months, or even years.
I'm curious to know if there is some irreversible damage, that makes L-Dopa uneffective as oppose to a "super tolerance" :think:
....
These are valid questions, and the answers are complex. In particular, they involve the state of the individual's dopamine receptors before the onset of L-DOPA or levodopa treatment, whether or not dopamine agonists, dopa decarboxylase inhibitors, monoamine oxidase B inhibitors, catechol-o-methyltransferase, acetylcholine blockers, and neuroprotectants are used, in what concentrations and combinations, the duration of the treatment, and some extraneous factors.
To highlight some of the inherent complexity I alluded to earlier, consider dopamine receptors. Recall that dopamine is unable to cross the blood brain barrier, and in the cases of Parkinson's, dopamine is completely ineffective therapeutically if administered into peripheral circulation. The immediate metabolic precursor of dopamine, namely, (-)-3-(3,4-dihydroxyphenyl)-l-alanine, also known as levodopa, is transported to the brain by an amino acid transporter (LAT). Once reaching the brain, levodopa is decarboxylated to dopamine via dopa decarboxylase. Recall also that DOPA is the amono acid precursor of dopamine, epinephrine, norepinephrine, and epinephrine. Levodopa is the levorotatory sterioisomer of DOPA.
Now, there are five known dopamine receptors, D1, D2, D3, D4, and D5. These, however, fall into two categories, D1-type (D1 and D5), and D2-type (D2, D3, and D4). All dopamine receptors are metabotropic (G protein-coupled). In fact, most neurotransmitters bind to so-called ionotropic receptors. These are ligand-gated channels that are opened by the binding of neurotransmitters to the channel. Apart from binding to ligand-gated channels, most neurotransmitters also bind to metabotropic receptors (G protein-coupled receptors) that modulate voltage-gated channels. [Voltage-gated channels are those that react to changes in a cell's membrane potential]. The direct interaction of G proteins with the voltage-gated ion channel within the membranes of nerve cells usually targets calcium channels and potassium channels. The interaction of G proteins with calcium channels usually inhibits channel function when presynaptic metabotropic receptors are activated. In the case of post synaptic metabotropic receptors, however, potassium channels are activated. Furthermore, metabotropic receptors can induce effects outside the nerve cell membrane by activating second messengers such as cAMP.
As already stated, all dopamine receptors are metabotropic. Dopamine itself induces a slow inhibiting action on central nervous system neurons, such as dopamine-containing substantia nigra neurons. Here, activating D2-receptors leads to the opening of potassium channels via the Gi coupling protein.
On their part, D1-type dopamine receptors are located in the zona compacta of the substantia nigra. Presynaptically, they are located on striatal axons (both from cortical neurons and from dopaminergic cells in the substantia nigra). Postsynaptically, the D2-type dopamine receptors are located on striatal neurons and presynaptically on sustantia nigra axons emanating from neurons in the basal ganglia.
Most dopaminergic drugs for the treatment of Parkinson's act on D2 receptors, although D1 stimulation increases the overall efficacy of the treatment. On the other hand, dopamine blockers with selective D2 antagonism can cause Parkinson's.
This means that,
ceteris paribus, the state of the dopamine receptors, especially the D2 receptos, plays an important role in L-DOPA/levodopa response. Decreasing responsiveness (increasing tolerance) to L-DOPA/levodopa treatment in parkinsonism can be due to the fact that the daily dose of levodopa must be reduced over time to avoid side effects; and it can also be due to some patients becoming less responsive to levodopa administration, such that previously effective doses fail to produce any therapeutic benefit.
Responsiveness to levodopa treatment may disappear completely and permanently in parkinsonian states because of the disappearance of dopaminergic nigrostriatal nerve terminals; or because of some pathologic processes directly involving the striatal dopamine receptors.
So, in parkinsonian states, the tolerance may be permanent, while this should be extremely unlikely in healthy individuals on controlled and cycled supplementation with dopamine agonists. Remember that in parkinsonism, dopaminergic function is impaired, and this impairment is degenerative (= gets worse over time). Considering that levodopa does not stop the progression of Parkinson's, degenerative dopaminergic impairment ultimately leads to complete loss of dopaminergic function. In such a state, levodopa/L-DOPA
tolerance (non-responsiveness) will be permanent. In healthy individuals (with normal dopaminergic function), however, there is no evidence that tolerance should develop if mega-doses of L-DOPA/levodopa are not administered long-term. Besides, there is also no evidence that tolerance will remain permanent upon cessation of levodopa/L-DOPA or dopamine-agonist administration.