Changes of BDNF exon IV DNA methylation are associated with methamphetamine dependence.

Aim: We investigated DNA methylation of BDNF in methamphetamine (METH) dependence in humans and an animal model. Materials & methods:BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results:BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion:BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure.

Lay abstract The effects of methamphetamine (METH), an addictive psychostimulant drug, on changes of DNA methylation of an important regulator of neuronal survival, BDNF, were examined in blood of METH-dependent patients and in the brain of METH-administered rats. BDNF methylation was increased in patients and in the prefrontal cortex of METH-administered rats, while rat hippocampus showed a reduction of Bdnf methylation, with an equivalent increase in gene expression. The methylation increases in humans were greatest in those with a METH-induced psychosis. Although a relationship between Bdnf methylation and its expression has not been proven, changes of BDNF DNA methylation are associated with METH dependence, especially METH-dependent psychosis, suggesting that METH neurotoxicity may relate to the effects of changes in BDNF methylation.

Genetic variation of GRIA3 gene is associated with vulnerability to methamphetamine dependence and its associated psychosis.

Methamphetamine (METH) is an addictive psychostimulant drug commonly leading to schizophrenia-like psychotic symptoms. Disturbances in glutamatergic neurotransmission have been proposed as neurobiological mechanisms and the α-amino-3 hydroxy-5 methyl-4 isoxazole propionic acid (AMPA) glutamate receptor has been implicated in these processes. Moreover, genetic variants in GRIAs, genes encoding AMPA receptor subunits, have been observed in association with both drug dependence and psychosis. We hypothesized that variation of GRIA genes may be associated with METH dependence and METH-induced psychosis. Genotyping of GRIA1 rs1428920, GRIA2 rs3813296, GRIA3 rs3761554, rs502434 and rs989638 was performed in 102 male Thai controls and 100 METH-dependent subjects (53 with METH-dependent psychosis). We observed no evidence of association with METH dependence and METH-dependent psychosis in the GRIA1 and GRIA2 polymorphisms, nor with single polymorphisms rs3761554 and rs989638 in GRIA3. An association of GRIA3 rs502434 was identified with both METH dependence and METH-dependent psychosis, although this did not withstand correction for multiple testing. Combining the analysis of this site with the previously-demonstrated association with BDNF rs6265 resulted in a highly significant effect. These preliminary findings indicate that genetic variability in GRIA3 may interact with a functional BDNF polymorphism to provide a strong risk factor for the development of METH dependence in the Thai population.

Increased DNA methylation in the parvalbumin gene promoter is associated with methamphetamine dependence.

AIM: The parvalbumin (PV)-containing subgroup of GABAergic neurons is particularly affected in schizophrenia and animal models of psychosis, including after methamphetamine (METH) administration. We investigated whether METH dependence and METH-induced psychosis may involve an effect on DNA methylation of the PVALB promoter. MATERIALS & METHODS: The methylation of a PVALB promoter sequence was determined in 100 METH-dependent and 102 control subjects using pyrosequencing. RESULTS: A significant increase in PVALB methylation was observed in METH dependence and METH-induced psychosis. No significant effect on long interspersed nucleotide element-1 methylation, a measure of global DNA methylation, was observed. CONCLUSION: These results demonstrate a specific association between elevated PVALB methylation and METH-induced psychosis. This finding may contribute to the GABAergic deficits associated with METH dependence.

Association of polymorphisms in GAD1 and GAD2 genes with methamphetamine dependence.

AIM: Association between polymorphisms in GAD genes and methamphetamine (METH) dependence was investigated in the Thai population. MATERIALS & METHODS: Genotypes of rs769404 and rs701492 in GAD1 and rs2236418 in GAD2 polymorphisms were determined in 100 METH-dependent male subjects and 102 matched controls. RESULTS: The genotype and allele frequencies of rs2236418 (GAD2) were associated with METH dependence and METH with psychosis, in which the G allele was related to increased risk. The presence of the rs769404-rs701492 (GAD1) C-C haplotype was associated with METH psychosis. CONCLUSION: This study indicates that genetic variability in GAD1 and GAD2 contributes to risk of METH dependence and METH psychosis in the Thai population and indicates the role of the GABAergic system in these disorders.

Does elevated peripheral benzodiazepine receptor gene expression relate to cognitive deficits in methamphetamine dependence?

BACKGROUND: Methamphetamine (METH) is a neurotoxin and psychostimulant drug with potent effects on the central nervous system. With chronic METH administration, an inflammatory glial response is observed as a result of METH-induced neurotoxicity. One inflammatory marker is the peripheral benzodiazepine receptor (PBR). OBJECTIVE: The purpose of the present study was to determine whether PBR expression is changed in METH dependence and whether the changes relate to cognitive deficits. METHODS: Reverse transcriptase-polymerase chain reaction was used to investigate PBR gene expression in blood samples taken from 14 male subjects with METH dependence and 14 controls. RESULTS: The results showed a significant increase in PBR gene expression in METH dependence, suggestive of a systemic inflammatory response. The increase remained elevated for more than 1 year following abstinence from METH use, but eventually returned to normal. Subjects with elevated PBR also exhibited a deficit in one domain of the Wisconsin Card Sorting Test. CONCLUSION: The results suggest that systemic inflammatory effects can be associated with chronic METH abuse, and this may relate to the cognitive deficits seen in METH dependence. Copyright © 2016 John Wiley & Sons, Ltd.

BDNF (Val66Met) genetic polymorphism is associated with vulnerability for methamphetamine dependence.

AIM: Association of the brain-derived neurotrophic factor (BDNF) genetic polymorphism rs6265 (Val66Met) with methamphetamine (METH) dependence and METH-induced psychosis was investigated in the Thai population. MATERIALS & METHODS: The rs6265 genotype was determined in 100 male METH-dependent subjects and 102 controls using a real-time PCR high-resolution melt (RT-PCR-HRM) assay. RESULTS: The rs6265 genotype demonstrated significant differences in distribution between METH-dependent subjects and controls in which the frequency of GG genotype versus A-allele carriers was associated with METH dependence. Moreover, a significant effect of genotype on the occurrence of psychosis was found, with a lower frequency of GG genotype associated with METH-induced psychosis. CONCLUSION: The present findings indicate that rs6265 is associated with METH dependence in the Thai population, with the GG genotype greater in METH-dependent subjects but reducing the emergence of METH-dependent psychosis.

Genetic variation of GRIN1 confers vulnerability to methamphetamine-dependent psychosis in a Thai population.

GRIN1 is a gene that encodes the N-methyl-d aspartate (NMDA) receptor subunit1 (NR1). Variations of GRIN1 have been identified as a risk factor for schizophrenia and drug dependence, supporting hypotheses of glutamatergic dysfunction in these disorders. Methamphetamine (METH) is a psychostimulant drug which can induce psychotic symptoms reminiscent of those found in schizophrenia; thus GRIN1 is a candidate gene for vulnerability to METH dependence or METH-dependent psychosis. The present study examined two polymorphisms of GRIN1, rs11146020 (G1001C) and rs1126442 (G2108A), in 100 male Thai METH-dependent patients and 103 healthy controls using PCR-RFLP techniques. Neither polymorphism was significantly associated with METH dependence, although rs1126442 was highly significantly associated with METH-dependent psychosis, in which the A allele showed reduced frequency (P<0.00001). The present findings indicate that the rs1126442 of GRIN1 contributes to the genetic vulnerability to psychosis in METH-dependent subjects in the Thai population.