Introduction:
Methamphetamine (MA) abuse is a significant social and public health issue on a global scale 1. According to the World Drug Report 2022 (UNDOC) [2], 34 million persons between the ages of 15 and 64, or 0.7% of the world’s population, are expected to have used amphetamines (mainly amphetamine and MA) in the last year. Recent estimates indicate that up to approximately 40% of MA users suffer from psychotic symptoms, such as delusions, impulsivity, and violence, etc. These symptoms can even persist long after MA use is discontinued and may prove refractory to antipsychotic medications2-4. More importantly, regarded as social high-risk factors, these symptoms frequently lead to prominent violence, widespread infectious disease transmission, and other undesirable social negative outcomes 5, 6. Therefore, it’s very necessary to find biological indicators which can warn of these psychotic symptoms in MAUD patients.
The development of MAUD results from the interaction of genetic and environmental variables, with the genetic factors accounting for 33%~79% of the disease 7, 8. Single nucleotide polymorphisms (SNPs) are DNA sequence polymorphisms brought on by variations in a single nucleotide at the genome level. They constitute the third generation marker of the human genetic map and were first identified in 1996. Comprising more than 90% of all known polymorphisms, SNPs are the most common type of heritable variation. Protein expression or function will be significantly impacted by SNPs mutations that occur in the gene coding region or gene regulatory region. Some SNPs can lead to abnormalities in the development and function of related key brain nerves. Studies have shown that the SNPs rs3916965, rs2391191, rs947267, and rs1421292 in the G72 gene9, which encodes the D-amino acid oxidase activator, are associated with MA-induced psychosis, whereas the SNP rs130058, rs1228814, and rs1228814 in the 5HT1bR gene 10, and the SNP rs2070744, rs1799983 in the NO3 gene have no significant association with MA-induced psychosis 11.
The function of epigenetics in disease development, which is considered to be an outcome of environmental influences, has also received considerable attention recently. Compared with genetics, epigenetics, including DNA and histone modifications, refers to the regulation of function without changing the nucleotide sequence of gene12. One of the best known DNA modification processes is DNA methylation, a key epigenetic mechanism that regulates gene expression by altering chromatin structure, DNA conformation, stability, and DNA protein interaction mode 13, 14. DNA methylation is linked to pathophysiological changes in a variety of psychiatric disorders, such as eating disorders 15, depressive disorders 16, schizophrenia17, cocaine use disorder 18, and alcohol dependence 19. DNA methylation has also been shown to be an important gene regulatory mechanism for MA-induced alterations in learning and memory in mouse models 20. Epigenetics plays an important role in regulating MA addiction21. However, few studies have reported about its association with MAUD-related psychotic symptoms.
Dopaminergic neurons and their projections are involved in reward circuits, which are crucial for the development of MAUD. MA and dopamine (DA) share a similar structure. Soon after entering the brain, MA not only promotes the release of DA but also inhibits DA reuptake, thus causing the depletion of DA in nerve terminals, disrupting the balance of DA in the brain, and leading to continuous neuronal excitation and euphoric effect 22. Therefore, the dopamine system-related genes of dopamine receptor type 4 (DRD4) and catechol-O-methyltransferase (COMT), a subtype of dopamine receptors and an enzyme catalyzing dopamine degradation, were chosen for our present study. We sought to determine the relationship between gene polymorphisms, as well as promoter methylation status in COMT and DRD4 genes and psychotic symptoms in MAUD patients.