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. 2022 Oct 14;12(10):1719.
doi: 10.3390/jpm12101719.

Should Reward Deficiency Syndrome (RDS) Be Considered an Umbrella Disorder for Mental Illness and Associated Genetic and Epigenetic Induced Dysregulation of Brain Reward Circuitry?

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Should Reward Deficiency Syndrome (RDS) Be Considered an Umbrella Disorder for Mental Illness and Associated Genetic and Epigenetic Induced Dysregulation of Brain Reward Circuitry?

Kenneth Blum et al. J Pers Med. .

Abstract

Reward Deficiency Syndrome (RDS) is defined as a breakdown of reward neurotransmission that results in a wide range of addictive, compulsive, and impulsive behaviors. RDS is caused by a combination of environmental (epigenetic) influences and DNA-based (genetic) neurotransmission deficits that interfere with the normal satisfaction of human physiological drives (i.e., food, water, and sex). An essential feature of RDS is the lack of integration between perception, cognition, and emotions that occurs because of (1) significant dopaminergic surges in motivation, reward, and learning centers causing neuroplasticity in the striato-thalamic-frontal cortical loop; (2) hypo-functionality of the excitatory glutamatergic afferents from the amygdala-hippocampus complex. A large volume of literature regarding the known neurogenetic and psychological underpinnings of RDS has revealed a significant risk of dopaminergic gene polymorphic allele overlap between cohorts of depression and subsets of schizophrenia. The suggestion is that instead of alcohol, opioids, gambling disorders, etc. being endophenotypes, the true phenotype is RDS. Additionally, reward deficiency can result from depleted or hereditary hypodopaminergia, which can manifest as a variety of personality traits and mental/medical disorders that have been linked to genetic studies with dopamine-depleting alleles. The carrying of known DNA antecedents, including epigenetic insults, results in a life-long vulnerability to RDS conditions and addictive behaviors. Epigenetic repair of hypodopaminergia, the causative basis of addictive behaviors, may involve precision DNA-guided therapy achieved by combining the Genetic Addiction Risk Severity (GARS) test with a researched neutraceutical having a number of variant names, including KB220Z. This nutraceutical formulation with pro-dopamine regulatory capabilities has been studied and published in peer-reviewed journals, mostly from our laboratory. Finally, it is our opinion that RDS should be given an ICD code and deserves to be included in the DSM-VI because while the DSM features symptomology, it is equally important to feature etiological roots as portrayed in the RDS model.

Keywords: Genetic Addiction Risk Severity (GARS) test; Reward Deficiency Syndrome (RDS); addiction; brain reward cascade; dopamine homeostasis; epigenetics; hypodopaminergia; pro-dopamine regulation (KB220Z).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mesolimbic Brain Reward Cascade. This cartoon illustrates the interaction of known major neurotransmitter pathways involved in the Brain reward Cascade (BRC). In the hypothalamus, environmental stimulation results in the release of serotonin, which in turn, via, for example, 5 HT-2 a receptors activate (green equal sign) the subsequent release of opioid peptides from opioid peptide neurons. Then, in the Substantia Nigra, the opioid peptides move to possibly two different opioid receptors with different effects. One that inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin) to GABAA neurons. Another stimulates (green equal sign) cannabinoid neurons (the Anandamide and 2-arachidonoylglycerol, for example) through beta-endorphin-linked delta receptors, which inhibit GABAA neurons. Furthermore, when activated, cannabinoids, primarily 2-arachidonoylglycerol, can indirectly disinhibit (green hash sign) GABAA neurons through activation of G1/0 coupled to CB1 receptors. In the Dorsal Raphe Nuclei (DRN), glutamate neurons can then indirectly disinhibit GABAA neurons in the Substantia Nigra through activation of GLU M3 receptors (green hash sign). GABAA neurons, when disinhibited, will in turn, powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB 3 receptors. At the Nucleus Accumbens, Acetylcholine (ACH) neurons may stimulate both muscarinic (red hash) and Nicotinic (green hash) receptors. Finally, Glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (green equal sign) to preferentially release dopamine at the Nucleus Accumbens (NAc), shown as a bullseye that indicates a euphoria, or “wanting” response. The result is dopamine release; low release is (endorphin deficiency), where unhappiness is felt. General (healthy) happiness depends on the dopamine homeostatic tonic set point (with permission) [22]. Notably, various hypotheses explained the findings that led to the modern known correlates of neurotransmitter interactions within this brain reward circuitry. Hypothalamus = serotonin and opioid peptides; Substantia Nigra = Cannabinoids, and GABA; Dorsal Raphe Nuclei = Glutamine and GABA; Ventral Tegmental Area(VTA) = Glutamine and acetylcholine, and Nucleus Accumbens = Dopamine.
Figure 2
Figure 2
Reward Deficiency Syndrome schematic (with permission from Blum et al. [46]).

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References

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