Genetics of addiction to substances of abuse: reward system, neuroplasticity and genetic susceptibility

Introduction Substance abuse is a public health problem resulting from the interaction between exposure, neuroadaptations, and genetic susceptibility. This review aimed to synthesize recent evidence on the genes and neurobiological systems involved in the development of substance abuse. Methods A literature review was conducted, primarily of articles published within the last 10 years. MEDLINE/PubMed, Scopus, Web of Science, ScienceDirect, and specialized genetic and biomedical information resources were consulted, yielding 158 references on the genetics of addiction, neurotransmission, neuroplasticity, and the use of alcohol, nicotine, cannabis, cocaine, and opioids were included. Results Addiction arises from the interaction between repeated exposure to substances of abuse, persistent neuroadaptations, and genetic susceptibility. The main neurobiological alterations involve the ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala, and hippocampus, with participation from the dopaminergic, glutamatergic, GABAergic, opioid, endocannabinoid, cholinergic, serotonergic, and noradrenergic systems. Genetic variants in and have been associated with susceptibility to developing substance use disorders. Furthermore, chronic exposure alters pathways such as cAMP/PKA, CREB, FosB, AP-1, and ERK, which promotes tolerance, dependence, sensitization, and relapse. However, most of the described variants contribute only to a limited extent to susceptibility to substance abuse, and their magnitude may differ depending on the substance, methodological differences between studies, and the type of population studied. Conclusions Susceptibility to addiction may arise from a complex interaction between genetic, neurobiological, and potentially environmental factors. However, larger functional, population-based, and multi-ethnic studies are needed to validate these associations and determine their usefulness in prevention, risk stratification, and personalized therapies.