Dataset Information

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine.

ABSTRACT: Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 mg) and saline in a randomized order. The subjective effects of cocaine were self-reported using a visual analog scale starting prior to the administration of cocaine (-15 min) or saline and up to 20 min after infusion. Participants were evaluated for methylation of the SLC6A4 promoter region and 5-HTTLPR genotype. A series of ANCOVAs for SLC6A4 methylation (high/low) were run for each of ten subjective and three cardiovascular effects controlling for age, sex [utilizing the sex-determining region Y protein (SRY)], and population structure (determined from ancestry informative markers and STRUCTURE software). Participants with SLC6A4 hypermethylation reported greater subjective response to cocaine for 'depressed' relative to participants with SLC6A4 hypomethylation (experiment-wise p = 0.002). These findings indicate that SLC6A4 methylation moderates the 'depressed' subjective effect of cocaine in non-treatment-seeking cocaine-dependent participants.

SUBMITTER: Longtain RB

PROVIDER: S-EPMC8671356 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine.

Longtain Riley B RB Graham David P DP Harding Mark J MJ De La Garza Ii Richard R Nielsen David A DA

Behavioural brain research 20211116

Genetic variation in the serotonin transporter (SLC6A4) has been shown to moderate the acute subjective effects of cocaine. Methylation of the SLC6A4 gene is associated with decreased transcription of the serotonin transporter, leading to increased serotonin in the synapse. In this study, methylation of the SLC6A4 gene was investigated in the moderation of the subjective effects of cocaine. Non-treatment-seeking cocaine-dependent individuals (N = 53) were intravenously administered cocaine (40 m ...[more]

PMID: 34798166

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Project description:BackgroundWe explored the relationship of genetic variants of the serotonin transporter gene SLC6A4, a key regulator of the serotonergic neurotransmission, with both depressive symptoms and plasma interleukin-6 (IL-6) levels.Methods and resultsWe genotyped 20 polymorphisms in 360 male twins (mean age, 54 years) from the Vietnam Era Twin Registry. Current depressive symptoms were measured with the Beck Depression Inventory II. IL-6 was assessed using a commercially available ELISA kit. Genotype associations were analyzed using generalized estimating equations. To study how SLC6A4 genetic vulnerability influences the relationship between depressive symptoms and IL-6, bivariate models were constructed using structural equation modeling. Of the 20 polymorphisms examined, the effective number of independent tests was 6, and the threshold of significance after Bonferroni correction was 0.008. There were 6 single-nucleotide polymorphisms significantly associated with Beck Depression Inventory (P< or =0.008), including rs8071667, rs2020936, rs25528, rs6354, rs11080122, and rs8076005, and 1 single-nucleotide polymorphism was borderline associated (rs12150214, P=0.017). Of these 7 single-nucleotide polymorphisms, 3 were also significantly associated with IL-6 (P<0.008), including rs25528, rs6354, and rs8076005, and the other 4 were borderline associated (P=0.009 to 0.025). The subjects with 1 copy of the minor allele of these 7 single-nucleotide polymorphisms had higher Beck Depression Inventory scores and IL-6 levels. Further bivariate modeling revealed that approximately 10% of the correlation between Beck Depression Inventory and IL-6 could be explained by the SLC6A4 gene.ConclusionsGenetic vulnerability involving the SLC6A4 gene is significantly associated with both increased depressive symptoms and elevated IL-6 plasma levels. Common pathophysiological processes may link depression and inflammation, and implicate the serotonin pathway in neural-immune interactions.

Dataset Information

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine.

Publications

Methylation of the serotonin transporter gene moderates the depressive subjective effect of cocaine.

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