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. 2022 Feb 10:418:113675.
doi: 10.1016/j.bbr.2021.113675. Epub 2021 Nov 16.

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

Riley B Longtain  1 , David P Graham  2 , Mark J Harding  1 , Richard De La Garza Ii  3 , David A Nielsen  1
Affiliations

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

Riley B Longtain et al. Behav Brain Res. .

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.

Keywords: Cocaine; Epigenetics; Methylation; Serotonin.

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Conflict of interest statement

Conflicts of interest

None.

Figures

Figure 1
Figure 1
CpG Site base pair distances relative to transcriptional start site (TSS), located in a CpG island (per upper strand) and surrounding area (−230 to +143). The primer binding sites are indicated with a double underline. The two CpG sites used to create the factor score (−23 and −35) are shown in gray boxes, while the promotor SP1 sites are underlined. The CpG sites are bolded.
Figure 2
Figure 2
Changes in the factor score of the ‘depressed’ subjective effect relative to time after cocaine administration, split by high and low methylation. The high methylation group is represented by the black line with square time points. Those in the low methylation group are displayed by the gray line with circular time points.
See this image and copyright information in PMC

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