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ADDICTION & AMINO ACID THERAPY

WHY THE ADDICTIVE BRAIN FAVORS AMINO–ACID

THERAPY [NAT™] by Dr Blum & Colleagues


It has been established that after prolonged abstinence from

drugs of choice, individuals will experience a more euphoric high,

which can lead to relapse. This clinically observed “super sensitiv12

Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Blum et al.

ity” might point toward the existence of genetic dopaminergic polymorphisms.


Paradoxically, it is interesting to note that bromocriptine,

a dopaminergic agonist, causes an increase in brain

reward activity in individuals who carry the DRD2 A1 allele compared

to DRD2 A2 carriers. Since A1 carriers, in comparison to A2

carriers, exhibit much lower D2 receptor density, A1 carriers should

theoretically experience a reduced sensitivity to dopamine agonist

activity. However, low D2 receptor density corresponds to increased

reward sensitivity to bromocriptine. Furthermore, with

chronic or long-term D2 agonists-therapy, there is a proliferation of

D2 receptors in vitro. However, in vivo studies show the opposite a

downregulation of D2 receptors after Bromocriptine administration

[242]. This unexpected activity may make clear the importance of

utilizing amino acid therapy. Before dopamine is synthesized Lamino

acid decarboxylase undergoes striatal activity, which is

associated with the A1 allele. Specifically, Laakso et al. [243] reported

that the A1 allele corresponds to the increased activity of

striatal L-amino acid decarboxylase in healthy Finish subjects

[243]. They found that heterozygous carriers of the A1 allele

(A1/A2; 10 subjects) had significantly higher [18%] ([18F] -

FDOPA uptake in the putamen than subjects without the A1 allele

(A2/A2; 23 subjects).


These results are evidence that carriers of the A1 allele have

increased activity of L-amino acid decarboxylase, which is an

important enzyme for trace amine synthesis, and which is present in

the final step of dopamine synthesis. This biochemical finding is

beneficial for carriers of the A1 allele having reduced DRD2 receptors.

It seems reasonable that because of this known deficit the

brain has set up a protective mechanism to drive more dopamine

synthesis. As such the lower D2 expression due to the A1 polymorphism

(a risk for all addictive behaviors) may be overcome by increased

activity of L-amino acid decarboxylase, especially when

confronted with increased amino acid precursors like Lphenylalanine

and l-tyrosine part of amino-acid therapy as suggested

herein.



Carriers of the DRD2 A1 allele, then, may have an interesting

intrinsic -protective mechanism waiting for amino-acid introduction

such as L-phenylalanine and L-tyrosine (rate-limiting substrates in

the synthesis of dopamine). Moreover, Ortez et al. [244] recently

reported that in “tyrosine hydroxylase deficiency” the dopamine

transporter (DAT) and vesicular monoamine transporter type 2

were up-regulated leading to a hypodopaminergic trait [244]. Kim

et al. [245] also showed that locomotor activity responses of these

Dopamine-deficient (DA-/-) mice to dopamine D2 receptor agonists

were 13-fold greater than the response elicited from wild-type mice

[245]. Moreover, when Vrshek-Schallhorn et al. investigated the

effects of the Acute Tyrosine Phenylalanine Depletion (ATPD) on

decision making and reward, it was found that carriers with this

amino-acid deficiency experienced an attenuated reward and reduce

decision-making ability, as measured by the Iowa Gambling Task

[34].

Separate and different from the effects of genetic mutations

(variations and polymorphisms), the environment via epigenetics

may produce profound effects that impact drug and non-drug seeking

behaviors by changing gene expression. Many new insights

have come from recent understanding, of how the environment

through epigenetics modifies gene expression which alters brain

function. By the insertion of methyl groups into histones on the

chromatin structure of the gene, the chromatin can (wrap tightly)

and turn off; or by the insertion of acetyl groups into histones the

gene chromatin structure can (unfurl) and be turned on. In fact,

chronic cocaine in mice induces a noticeable shift of the balance

from genetics to epigenetics whereby there is an enhanced sensitivity

to drugs and addiction risk. A single injection of cocaine can

cause changes in gene expression in the NAc. It has been

established that in the absence of drug addiction (possibly even in

non-substance addiction, for example, gambling) methyl type

marks predominate keeping certain genes quite. However, cocaine

causes acetyl groups to predominate and chromatin to loosen and

genes involved in the pleasurable response to drugs or behaviors to

come alive. The importance of dopaminergic homeostasis including

the usual expression of the DRD2 gene has been recently

underscored by an analysis of epigenetic effects linked to this gene.

Hillemacher et al. evaluated epigenetic DNA-methylation

patterns in the DRD2-gene in lifetime history of pathological gamblers

and provided evidenced for significantly higher methylation

levels in non-abstinent (12 to 30 months) and participants without

treatment-seeking behavior compared to abstinent gamblers [246].

Consequently, the authors determined that indeed there is a pathophysiological

relevance of altered DRD2-expression caused by

changes in DNA methylation in pathologic gambling. Moreover,

Groleau et al. found that women with bulimic-spectrum disorder

compared to women without an eating disorder showed significant

increases in DRD2 methylation levels particularly in those women

who were sexually abused during childhood [247].

These genetic and epigenetic effects may carry over to future

generations and could explain why better compliance to amino-acid

therapy as protective mechanism especially in carriers of the D2

receptor-deficient DRD2 A1 allele [241, 248]. We now must ask if

“dopamine agonist therapy” such as with KB220 variants can

reduce methylation and increase acetyl groups to enhance DRD2

expression even in DRD2 A1 allele carriers leading to increased

DA function and reduction of drug and non-drug seeking behaviors?


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