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Gene & Protein in Disease Dopaminergic dysfunction as pre-addiction

1. Introduction assessed early in life via the Genetic Addiction Risk Severity
(GARS) test? In this study, we employed in silico PGx-
The hypothesis posits the existence of a genetically based based analyses to explore the potential for personalized
pre-addiction phenotype arising from limbic dysregulation medicine treatment to align the construct of pre-addiction
of neurotransmitters—particularly dopamine (DA)— to dopaminergic dysregulation across the human lifespan.
across all ages has not yet been discovered. This original We propose that the current approach of using opioids
research uses a novel in silico pharmacogenomics (PGx) to treat opioid dependence is ineffective—comparable to
analysis to provide current evidence that may lead to novel treating alcoholism by administering alcohol. Therefore,
findings in the neurobiology of addiction and even pain. it is necessary to re-evaluate the “standard of care.” Our
It highlights plausible negative impacts of analgesics, such recommendation is for the industry to shift focus toward
as potent opioids augmenting the aging process, leading “inducing dopamine homeostasis” by manipulating the
to unwanted premature deaths, and promoting substance neurotransmitter systems that work together in the BRC
and non-substance behavioral addiction. One goal is to (Figure 1).
substantiate the plausibility and established relevance of
brain reward cascade (BRC) dysregulation and function. Substance use disorders (SUDs) and other addictive
The BRC may represent the molecular, neurobiological, behaviors are still among the most destructive global
and genetic basis for anhedonia and pain sensitivity. It is issues, affecting 176 million people worldwide. In
also the foundation for the reward deficiency syndrome fact, according to the World Drug Report 2021, the
(RDS) construct, first introduced by Blum and colleagues, number of people using drugs is estimated to rise by
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which affects millions. Carriers of some dopaminergic 11% by 2030. One important challenge has been that
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gene polymorphisms (e.g., drd2-A1) are known to be addiction prevention, tertiary treatment, and recovery
at greater risk for premature fatalities. Another question are intertwined with multiple political, socioeconomic,
posed by this research concerns the likelihood of an and public health organizations. In the United States of
identifiable link between RDS and apoptosis (programmed America, stakeholders such as the pharmaceutical industry
cell death). If such a connection exists, could the risk be and the Food and Drug Administration are crucial to the

Figure 1. The mesolimbic brain reward cascade (BRC), featuring the interaction of common BRC neurotransmitter pathways. Environmental stimulation
initiates the release of serotonin in the hypothalamus, which acts via 5HT2A receptors to activate the subsequent release of opioid peptides from opioid
peptide neurons. These peptides then influence activity in the Substantia Nigra through two different opioid receptors. The first type is the mu-opioid
receptor that inhibits GABA neurons, possibly via opioid peptide-like enkephalins. The second type stimulates cannabinoid neurons (e.g., anandamide
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and 2-arachidonoylglycerol) through beta-endorphin-linked delta receptors, which inhibit GABA neurons. When activated, cannabinoids, primarily the
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2-arachidonoylglycerol neurons, can disinhibit GABA neurons indirectly via CB1 receptor activation by G1/0 signaling. The glutamate neurons in the
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dorsal raphe nuclei disinhibit GABA neurons in the Substantia Nigra indirectly through GLU M3 receptor activation. Once disinhibited, GABA neurons
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exert strong inhibition on the ventral tegmental area (VTA) glutaminergic drive via GABAB3 receptors. At the nucleus accumbens, acetylcholine neurons
may inhibit muscarinic receptors and stimulate nicotinic receptors. Glutamate neurons in the VTA activate N-methyl-D-aspartate receptors on dopamine
neurons, leading to the release of dopamine in the NAc. This figure was adapted with permission from https://www.sciencedirect.com/science/article/abs/
pii/S0079612300260226?via%3Dihub.
Volume 4 Issue 3 (2025) 2 doi: 10.36922/gpd.8090