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Dopamine Research

Dopamine Metabolism, by Abelard Lindsay

Dopamine is a neurotransmitter that is, among other things, associated with motivation, short-term memory, creativity and personality [1][2][3].

It is metabolized into epinephrine and norepinephrine to increase alertness and attention [4]. It must be properly balanced and metabolized for optimal benefit. Too much dopamine can result in manic states [5] and too little can cause depression and lack of motivation [6].

Dopamine metabolism can be metaphorically compared to a factory process where raw materials such as L-Phenylalanine and L-Tyrosine, which are amino acids present in foods, are transformed by various workers (enzymes) who use various materials (cofactors) in each transformation step. The intermediate products of this metabolism are used to transmit signals through the body and the brain [7].

Unlike a regular factory, the intermediate products are the useful aspects of production and are used primarily in signaling.

At the beginning of dopamine metabolism, the dietary amino acid L-Phenylalanine is converted into L-Tyrosine by phenylalanine hydroxylase, and L-Tyrosine into L-Dopa by tyrosine hydroxylase.

Studies suggest that tyrosine hydroxylase is upregulated by phosphorylated CREB, which is activated during cAMP/PKA driven long-term potentiation [8]. This is one of the theorized mechanisms of action of CILTEP. Tyrosine hydroxylase activity is the rate limiting step in this metabolic process [12].

Further down the metabolic chain from L-Tyrosine is L-Dopa, which is also available as a drug and in the supplement mucuna pruriens [13].

L-Dopa’s synthesis into dopamine is supported by the active form of vitamin B6, known as pyridoxal phosphate, commonly abbreviated as p5p , and the enzyme dopadecarboxylase [14].

Some intermediate products of dopamine metabolism act as an agonist at the TAAR1 receptor [15]. This receptor is primarily targeted by ADHD drugs [16].

It causes increases in cAMP levels in the cell [17]. Unlike forskolin, the aforementioned ADHD drugs cause efflux of stored dopamine into the synaptic cleft via modulation of the dopamine transporter protein known as DAT [18][19].

This efflux leads to increases in dopamine in the synaptic cleft, producing fast increases in arousal.

From reading through a lot of anecdotal experiences and research, that it appears to be undesirable to rapidly raise neurotransmitter levels in the synaptic cleft above a given baseline, as it can lead to excessive arousal and unbalanced cognitive effects.

It’s better to help the “factory” produce optimally by supplying cofactors and optimally helping and directing each intermediate reaction and postsynaptic metabolic pathways.

Another place that products from dopamine metabolism operate is in the dopamine receptors themselves. The D1, D2, D3, D4, and D5 receptors all respond to dopamine in the brain and have various cognitive related effects. D2 receptors modulate prolactin, [20] which some studies suggest is linked to the male sexual refractory time [21].

Direct agonists for these receptors are usually in the class of dopamine agonist drugs that are sometimes prescribed for Parkinson’s symptoms [22][23][24]. D1 and D2 are involved in novelty detection [25] and sexual desire [26].

While D1 and D5 are involved in memory formation [27], D2 and D3 are associated with addiction [28] and compulsions [29]. D4 is involved with cognitive performance [30].

The various mood, addiction, compulsion and sexual influencing effects of dopamine agonists in the brain and various accounts of socially undesirable behavior under the administration of direct dopamine agonists [31] (usually in Parkinsons treatment) leads me to avoid the direct stimulation of these pathways.

It appears that it is better to provide cofactors to aid and assist in metabolism along dopaminergic pathways than to directly activate receptors with agonists.

However, direct agonists certainly have their uses.

Dopamine is converted into norepinephrine with vitamin C (ascorbic acid) as a cofactor via the enzyme dopamine b-hydroxylase. That is further converted to epinephrine via phenylethanolamine n-methyltransferase with SAMe as a cofactor. You can read more about SAMe in an earlier essay “The SAM Cycle And The Brain”.

Dopamine can also be converted to the TAAR1 agonist 3Methoxytyramine via the enzyme COMT [32].

COMT inhibition is an interesting area of exploration in cognitive enhancement.

There is a gene polymorphism, the val158met polymorphism, that influences the rate at which dopamine is processed into further metabolic intermediates via the COMT enzyme. The quick processing polymorphism is called val/val and the more slowly processing polymorphism is called met/met.

In one study, participants with the val/val gene had lower scores on a memory test known as dual n­back [33]. Another study suggests that those with the met158 allele have better cognitive performance.

To quote the study “The low activity met158 allele has been associated with improved working memory, executive functioning, and attentional control, but also with a higher risk of anxietyrelated behaviors” [34].

It is interesting to note that Luteolin is a substrate for COMT [35], so variations in the COMT allele might account for different anecdotal effects of Luteolin from artichoke extract.

How we metabolize dopamine is a core contributor to mood and cognitive function.


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