Association of Serotonin Transporter (SERT) Polymorphisms with Opioid Dependence and Dimensional Aspects of Cocaine Use in a Caucasian Cohort of Opioid Users

Vadim Yuferov; Eduardo R Butelman; Matthew Randesi; Wim van den Brink; Peter Blanken; Jan M van Ree; Mary Jeanne Kreek

doi:10.2147/NDT.S286536

Association of Serotonin Transporter (SERT) Polymorphisms with Opioid Dependence and Dimensional Aspects of Cocaine Use in a Caucasian Cohort of Opioid Users

Neuropsychiatr Dis Treat. 2021 Feb 25:17:659-670. doi: 10.2147/NDT.S286536. eCollection 2021.

Authors

Vadim Yuferov^#¹, Eduardo R Butelman^#¹, Matthew Randesi¹, Wim van den Brink², Peter Blanken³, Jan M van Ree⁴, Mary Jeanne Kreek¹

Affiliations

¹ Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, 10065, USA.
² Amsterdam University Medical Centers, Location Academic Medical Center, Department of Psychiatry, University of Amsterdam, Amsterdam, The Netherlands.
³ Parnassia Addiction Research Centre, The Hague, The Netherlands.
⁴ Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

^# Contributed equally.

Abstract

Introduction: A functional tandem repeat polymorphism in the promoter of the serotonin transporter (SERT) gene (SLC6A4) has been studied for association to neuropsychiatric conditions, including substance use disorders. Short (S) forms of this repeat result in reduced transcription, and presumably greater synaptic levels of serotonin, which are involved in opioid and cocaine-induced reward. Dual exposure to heroin and cocaine is a common pattern of poly-drug use and is associated with considerable morbidity. We hypothesize that SLC6A4 variants are associated with cocaine exposure in subjects with an opioid dependence diagnosis (OD), and also in non-dependent opioid users (NOD). Other single nucleotide polymorphisms (SNPs) of SLC6A4 may also be likewise associated.

Materials and methods: This study determined whether variants of the SLC6A4 promoter repeats and two intronic SNPs, rs16965628 and rs2066713, are associated with categorical diagnoses of opioid dependence (DSM-IV criteria) and with dimensional aspects of cocaine use, in a Caucasian cohort (n=591). Three groups of subjects were examined: (1) 276 subjects with opioid dependence diagnosis (OD); (2) 163 subjects who had used opioids for non-medical reasons but never had an opioid dependence diagnosis (NOD); (3) 152 healthy controls (HC).

Results: Aside from high exposure to heroin in the OD group, relatively high exposure to cocaine was detected in both OD and NOD groups. The SERT repeat genotype (classified as "long-long" [LL] versus "short-long" plus "short-short" [SL+SS]) was not associated with categorical opioid dependence diagnoses. A nominally signiﬁcant association was identiﬁed with the [SL+SS] genotype of SLC6A4 and cocaine KMSK scores ≥"cutpoint" for a cocaine dependence diagnosis (p=0.026). The [SL+SS] genotype was associated with more rapid cocaine escalation than the LL genotype. No signiﬁcant associations of rs16965628 and rs2066713 SNPs were found overall.

Conclusion: The functional SERT promoter tandem repeat genotype may be associated to heavy cocaine exposure and more rapid escalation of cocaine use, in persons with and without opioid dependence diagnosis.

Keywords: KMSK scale; SLC6A4; cocaine; escalation; serotonin transporter.