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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