Genetic Addiction Risk and Psychological Profiling Analyses for "Preaddiction" Severity Index

Abstract

Since 1990, when our laboratory published the association of the DRD2 Taq A1 allele and severe alcoholism in JAMA, there has been an explosion of genetic candidate association studies, including genome-wide association studies (GWAS). To develop an accurate test to help identify those at risk for at least alcohol use disorder (AUD), a subset of reward deficiency syndrome (RDS), Blum's group developed the genetic addiction risk severity (GARS) test, consisting of ten genes and eleven associated risk alleles. In order to statistically validate the selection of these risk alleles measured by GARS, we applied strict analysis to studies that investigated the association of each polymorphism with AUD or AUD-related conditions, including pain and even bariatric surgery, as a predictor of severe vulnerability to unwanted addictive behaviors, published since 1990 until now. This analysis calculated the Hardy-Weinberg Equilibrium of each polymorphism in cases and controls. Pearson's χ² test or Fisher's exact test was applied to compare the gender, genotype, and allele distribution if available. The statistical analyses found the OR, 95% CI for OR, and the post risk for 8% estimation of the population's alcoholism prevalence revealed a significant detection. Prior to these results, the United States and European patents on a ten gene panel and eleven risk alleles have been issued. In the face of the new construct of the "preaddiction" model, similar to "prediabetes", the genetic addiction risk analysis might provide one solution missing in the treatment and prevention of the neurological disorder known as RDS.

Keywords: behavioral octopus; dopamine homeostasis; epigenetics; genetic addiction risk analysis; neurobiology; preaddiction; reward deficiency syndrome (RDS).

Figure 1

Illustrates the interaction of at least six major neurotransmitter pathways involved in the brain reward cascade (BRC). In the hypothalamus, environmental stimulation causes the release of serotonin, which in turn, via, for example, 5HT-2a receptors, activates (the green, equal sign), the subsequent release of opioid peptides into the hypothalamus. Then, the opioid peptides have two distinct effects, possibly via two different opioid receptors. (A) inhibits (the red hash sign) through the mu-opioid receptor (possibly via enkephalin) and projects to the substantia nigra to GABA_A neurons. (B) stimulates (the green, equal sign) cannabinoid neurons (e.g., anandamide and 2-archydonoglcerol) through beta-endorphin linked delta receptors, which in turn inhibit GABA_A neurons at the substantia nigra. cannabinoids, primarily 2-archydonoglcerol, when activated, can also indirectly disinhibit (the red hash sign) GABA_A neurons in the substantia nigra through activation of G1/0 coupled to CB1 receptors. Similarly, glutamate neurons located in the dorsal raphe nuclei (DRN) can indirectly disinhibit GABA_A neurons in the substantia nigra by activating GLU M3 receptors (the red hash sign). GABA_A neurons, when stimulated, will, in turn, powerfully (the red hash signs) inhibit ventral tegmental area (VTA) glutaminergic drive via GABAB₃ neurons. Finally, glutamate neurons in the VTA will project to dopamine neurons through NMDA receptors (the green, equal sign) to preferentially release dopamine at the NAc shown as a bullseye indicating well-being (with permission Blum et al. [2]).

Figure 2

Schematic illustration linking the current drug abuse crisis and preaddiction.