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.