Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It "Blowin' in the Wind"?

Abstract

Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, "the answer is blowin' in the wind," and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality.

Keywords: Genetic Addiction Risk Severity (GARS) Test; dopamine; hypodopaminergia; pro-dopamine regulation (KB220).

Figure 1

This cartoon figure illustrates some of the interactions of several neurotransmitter pathways in the Brain Reward Cascade (BRC) system. Environmental stimulation in the hypothalamus causes the release of serotonin, which, in turn, via, for example, 5HT-2a receptors activates (green equals sign) opioid peptides, releasing them into the hypothalamus. The opioid peptides have two distinct effects via two different opioid receptors. The first inhibits (red hash sign) through the mu-opioid receptor (possibly via enkephalin), which projects to the substantia nigra GABAA neurons, and the second stimulates (green equal sign) cannabinoid neurons (e.g., 2-archydonoglcerol and anandamide) through beta-endorphin-linked delta receptors, which, in substantia nigra, inhibit GABAA neurons. Activated cannabinoids, mostly 2-archydonoglcerol, can also disinhibit (red hash sign) substantia nigra GABAA neurons indirectly by activating G1/0-coupled CB1 receptors. Similarly, dorsal raphe nuclei (DRN) glutamate neurons can disinhibit substantia nigra GABAA neurons indirectly through the activation of GLU M3 receptors (red hash sign). Stimulated GABAA neurons will powerfully (red hash signs) inhibit VTA glutaminergic drive via GABAB 3 neurons. VTA glutamate neurons project to dopamine neurons through NMDA receptors (green equals sign), where they preferentially release dopamine at the nucleus accumbens, shown as a bullseye, indicating euphoria (a motivational response).

Figure 2

A schematic of RDS. This figure illustrates the categorization of RDS behaviors, showing which behaviors are addictive, impulsive, obsessive, and personality disorders. Sub-categories divide addictive behaviors into substance and non-substance related and impulsive into disruptive/impulsive and spectrum disorders. These behaviors have dopaminergic dysfunction in common: acute excess or chronic deficit of dopamine release in the brain reward circuitry.

Figure 3

Summary of RDS Phenotype. This illustrates the relationship between endophenotypes and phenotype in RDS (modified from [126]).