Phenylalanine and Tyrosine Depletion

Abstract

Synonyms Acute tyrosine depletion; Acute tyrosine/phenylalanine depletion Definition The acute phenylalanine/tyrosine depletion (APTD) method was developed as a safe and rapid way to transiently decrease dopamine (DA) neurotransmission in humans. The method entails the administration of a protein mixture that is selectively deficient in amino acids (AA) that are used to make DA. Since ingestion of this mixture decreases the availability of the necessary raw material, the neurotransmitter's synthesis and availability for release decrease as well. A manipulation based on the same principles – acute tryptophan depletion (ATD) – is widely used to transiently decrease serotonin transmission. See entry " ▶ Acute Tryptophan Depletion " by Simon N. Young. Current Concepts and State of Knowledge The Catecholamine Metabolic Pathway DA is a monoamine. As the name suggests it is made from a single amine, in this case the essential AA, phenylalanine. Essential AAs are those that we need to obtain from our diet. When we ingest protein, phenylalanine is cleaved, and the liver enzyme phenylalanine hydroxylase (PH) adds a hydroxyl group (oxygen + hydrogen, OH) to yield tyrosine. Tyrosine, in turn, can also be obtained from our diet. Irrespective of how we obtain it, tyrosine can then be carried across the blood-brain barrier by a two-tiered transport system (one active and saturable, the other diffusional) that acts on various large neutral AAs (LNAA: phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine, and methionine). Tyrosine can then enter DA neurons via a similar transport system on the cell's membrane. Inside the DA cell, tyrosine is a substrate for tyrosine hydroxylase (TH). TH adds a second OH group to yield 3,4-dihydroxy-L-phenylalanine, more commonly known as L-dopa. L-dopa is then a substrate for L-aromatic amino acid decarboxylase (AAAD or AADC) producing DA. Finally, vesicular monoamine transporters remove DA molecules from the cytosol and place them in storage vesicles. Within noradrenergic neurons, these vesicles contain dopamine-b-hydroxylase (DbH), an enzyme that hydroxylates the DA to norepinephrine (NE). DbH and AADC are 100–1,000 times more active than TH, and the hydroxylation of tyrosine to L-dopa is considered the rate-limiting step (Fig. 1).