NEUROTRANSMITTER DEPLETION BALANCE BETWEEN SEROTONIN AND DOPAMINE

  The same enzyme catalyzes the conversion of 5-HTP to serotonin and dopa to dopamine. The L-amino acid decarboxylase enzyme  is also known as 5-HTP decarboxylase or dopa decarboxylase. The implications of this fact are profound.

  If you start loading only 5-HTP or dopa into the system, they can decrease dopamine neurotransmitter production or serotonin neurotransmitter production respectively. From a clinical standpoint, what does this look like?

  dopa has been used for a long time in the treatment of Parkinsonism since dopamine neurotransmitter molecules do not cross the blood brain barrier. Dopa is able to cross the blood brain barrier and is freely synthesized into dopamine without biochemical feedback regulation. Long-term loading of dopa without the use of 5-HTP leads to depletion of serotonin neurotransmitter levels one of the causes of this is that dopa competitively inhibits 5-HTP at the general decarboxylase enzyme.

  The medical literature lists depression as a side effect of long-term dopa administration in treatment of Parkinsonism. The literature further indicates that this is a serotonin driven depression that responds to the most serotonin specific antidepressant - citalopram (Celexa or Lexapro). The real problem is that unopposed dopa use has depleted serotonin neurotransmitter levels to the point that depression develops.

  The synthesis of serotonin, dopamine, or norepinephrine is illustrated in to the right. Peripheral administration of only 5-HTP or only dopa will decrease the synthesis of the other system (dopamine or serotonin respectively). With administration of only one precursor of 5-HTP, tyrosine, or levodopa, the administered precursor dominates the enzyme and compromises proper synthesis of the other system’s neurotransmitter levels through competitive inhibition.  This is due to the fact that the same enzyme catalyzes the conversion of 5-HTP to serotonin and dopa to dopamine.  

          The aromatic L-amino acid decarboxylase enzyme is also known as 5-HTP decarboxylase enzyme or dopa decarboxylase enzyme, as well as the general decarboxylase enzyme. The implications of this fact are profound. The administration of only 5-HTP or dopa will compete with and inhibit the synthesis of the opposite precursor (dopamine and serotonin respectively) at the enzyme. 

          In people suffering with Parkinsonism, the long-term administration of dopa with insufficient serotonin precursors will result in depression and a host of other problems. The literature is very clear that this depression is a serotonin dependent depression, which responds optimally to the most serotonin specific reuptake inhibitor, citalopram.

Serotonin and Dopamine Metabolism

The Monoamine Oxidase (MAO) enzyme metabolize serotonin and the catecholamines (dopamine, norepinephrine, and epinephrine). The COMT metabolizes dopamine, norepinephrine, and epinephrine as well as illustrated to the left. The implications are profound.  The levels of these two enzyme systems are not static; they fluctuate in response to changing neurotransmitter levels.  When serotonin, dopamine, or norepinephrine levels are increased with administration of 5-HTP, tyrosine or levodopa, enzymatic activity also increases.

            If you administer dopa or 5-HTP, the activity of MAO and COMT increases due to the increase in dopamine or serotonin levels respectively.  The problem occurs when dopa is administered without 5-HTP, both dopamine and serotonin will be subjected to increases in metabolism by the MAO enzyme systems.  However, serotonin will not experience an increase in production, which leads to further depletion.  The same rule is true of 5-HTP administered without the use of dopamine precursors.  The bottom line is that the administration of unopposed 5-HTP or dopa will deplete the other system as a result of the increased metabolism of MAO and COMT.

Serotonin and Dopamine Uptake

  In order for the synthesis of the monoamine neurotransmitter molecules to occur, the precursors 5-HTP, tyrosine, levodopa, and cysteine must undergo uptake into the cells performing synthesis.  This process occurs in numerous places throughout the body, as listed in table 1 to the right.  The “cation transporter type 1” (OCT) found in the proximal convoluted renal tubule cells are a prototype for 5-HTP, tyrosine, levodopa, and cysteine uptake, see the illustration below.

  Neurotransmitter molecules synthesized by the kidneys from dopa and 5-HTP is the source of serotonin, dopamine, or norepinephrine found in the urine during urinary neurotransmitter testing.  serotonin, dopamine, or norepinephrine are synthesized by the kidneys, then excreted into the urine or secreted into the system.  Uptake is affected by administration of a single unbalanced precursor such as 5-HTP, tyrosine, or dopa or improperly balanced 5-HTP, tyrosine, or dopa which may overwhelm and compete with uptake of the other 5-HTP, tyrosine, levodopa, and cysteine. Administration of only dopa inhibits uptake of 5-HTP. Administration of only 5-HTP has the same effect on dopa uptake. 

  The illustration below represents a proximal tubule cell in the kidney. The serotonin, dopamine, or norepinephrine filtered by the glomerulous are metabolized by the MAO and COMT of the proximal tubule cell. Very little of the serotonin, dopamine, or norepinephrine filtered at the glomerulous makes it to the final urine.

   From a clinical standpoint, long-term use of dopa becomes ineffective as the serotonin is depleted. In order to regain control of symptoms when dopa quits working, 5-HTP needs to be started. But this has not been the standard approach in medicine. In medicine when the dopa quits working the approach is to increase the dopa dosing which depletes serotonin even more.

  These same observations are also true when only 5-HTP is used in treatment. Over time, 5-HTP depletes dopamine, norepinephrine, and epinephrine levels. Eventually, when dopamine levels drop low enough, 5-HTP becomes ineffective and the side effects of dopamine, norepinephrine, and epinephrine depletion occur. 5-HTP and dopa must be provided in proper balance for optimal results. For years doctors have depleted serotonin levels in people suffering with Parkinson by prescribing only dopa with no 5-HTP and when the problems of serotonin depletion occurred to include the dopa no longer working, depression and a host of other problems these doctors did not know what they were looking at and simply increased the dopa dosing making the real cause of the problem worse, "serotonin depletion from dopa."