Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms

Abstract

In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the "Brain Reward Cascade" (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications.

Keywords: Brain reward circuitry; Dopamine; Neuro-nutrient therapy; Neuroadaptagen Amino-Acid Therapy™ (NAAT); Neurogenetics; Nutrigenomics; Reward Deficiency Syndrome(RDS); Reward Genes.

Figure 1

Interaction of neurotransmitters within the mesolimbic reward system. (Modified from Erickson C (2007). The Science of Addiction .W.W. Norton & Co.: New York, New York).

Figure 2

Brain reward cascade (normal and hypodopaminergic state). 2A. Happy Brain: Represents the normal physiologic state of the neurotransmitter interaction at the mesolimbic region of the brain. Briefly, serotonin in the hypothalamus stimulates neuronal projections of methionine enkephalin in the hypothalamus that, in turn, inhibits the release of GABA in the substania nigra, thereby allowing for the normal amount of Dopamine to be released at the Nucleus Accumbens (NAc); reward site of the brain [13]. 2B Unhappy Brain: Represents hypodopaminergic function of the mesolimbic region of the brain. The hypodopaminergic state is due to gene polymorphisms as well as environmental elements, including both stress and neurotoxicity from aberrant abuse of psychoactive drugs (i.e. alcohol, heroin, cocaine etc) and genetic variables [13].

Figure 3

Blood brain barrier and protein transport. (Modified from Marc et al. [30].)

Figure 4

Neurotransmitter transport across the blood brain barrier.

Figure 5

Sites of BRC and relapse. (Modified from brain illustration: http://prorecovery.blogspot.com).

Figure 6

qEEG analysis of NAAT vs. placebo in psychostimulant addicts. (Modified with permission Blum et al. 2010 [57]).

Figure 7

fMRI study comparing the NAAT (termed Synaptose) with Placebo one hour-hour after dosing in abstinent heroin dependent patients in China. This 2X2 design experiment shows the resting state of the fMRI scan of the same five protracted abstinent Heroin addicts one hour after receiving an acute dose of Placebo or NAAT. The scan represents the effect of an acute dose of NAAT on the caudate-accumbens-putamen brain region. Notice in the blue circles that there is a strong activation of the dopamine reward site. Moreover, NAAT induced a “normalization” of the putamen region-purple circles. It is hypothesized that NAAT caused dopaminergic agonistic activation of dopamine D2 receptors promoting enhanced reward and normalization (Modified: Liu et al. [unpublished]; Blum et al. 2011). Liu et al. unpublished 2010.

Figure 8

AMA Rate NAAT (depicted as SGX) vs Placebo in Cocaine and Alcohol. (Modified with permission Blum et al. 1988 [28] Blum et al. 1989 [61])

Figure 9

NAAT variant increases focus in healthy volunteers. (Modified from Defrance et al. 1997 [70].)

Figure 10

Stress as measured by skin conductance: Placebo vs. NAAT [69]. The Skin Conductance Level (SCL) Y axis, is shown for both the substance AP (placebo) and investigational substance AI (NAAT). The curves for the two groups mirror one another up to day seven. The lower SC value of the NAAT group indicates less stress. (Modified from Blum et al. 2009 [62]).

Figure 11

Relapse Prevention Studies: Controls Compared to NAAT Oral (depicted as SGX). (Modified from Blum et al. [66] and Blum et al. [75]).

Figure 12

The Chronic Abstinence Symptom Severity Scale with IV and oral NAAT compared to oral NAAT alone. (Miller etal 2012 (in press) [47]).

Figure 13

CASS-R pre and post oral and IV (after 5 days) [47]. (Miller et al. 2012 in press [47].)

Figure 14

Relapse in number of Recovering Subjects. (Miller et al. 2012 in press [47].)