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Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol

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Abstract

Rationale

Animal models suggest that neuroactive steroids contribute to alcohol’s acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3*2 in the gene encoding the enzyme 3α-HSD2/17β-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD).

Objectives

The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3*2 affects neuroactive steroid synthesis.

Methods

Sixty-five Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 years) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals, and genotype was examined as a moderator of alcohol’s effects. Levels of the neuroactive steroid 5α-androstane-3α,17β-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS.

Results

Initially, carriers of the AD-protective AKR1C3*2 G allele had higher levels of 5α-androstane-3α,17β-diol relative to the precursor 3α,5α-androsterone than C allele homozygotes. AKR1C3*2 G allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs.

Conclusions

The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17β-reduction of androsterone relative to androstanediol and on alcohol’s sedative effects may help to explain the association of AKR1C3*2 with AD.

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Acknowledgments

This study was supported by NIH grants R01 AA015606 (to JC), K24 AA13736 (to HRK), P60 AA03510 (University of Connecticut Alcohol Research Center), and M01 RR06192 (University of Connecticut General Clinical Research Center). The authors thank Timothy Pond, Linda Burian, Kaitlin Miller, and Pamela Fall for their expert technical assistance in the conduct of this study.

Conflict of interest

VM, RF, and JC have no disclosures to make. HK has been a consultant or advisory board member for the following pharmaceutical companies: Alkermes, Lilly, Lundbeck, Pfizer, and Roche. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by Lilly, Lundbeck, AbbVie, Ethypharm, and Pfizer.

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Authors and Affiliations

  1. Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT, 06030-1410, USA

    Verica Milivojevic & Jonathan Covault

  2. Department of Medical Sciences, Frank Netter School of Medicine, Quinnipiac University, North Haven, CT, USA

    Richard Feinn

  3. Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Henry R. Kranzler

  4. VISN4 MIRECC, Philadelphia VAMC, Philadelphia, PA, USA

    Henry R. Kranzler

  5. Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA

    Verica Milivojevic

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  1. Verica Milivojevic
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  2. Richard Feinn
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  3. Henry R. Kranzler
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  4. Jonathan Covault
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Correspondence to Jonathan Covault.

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Milivojevic, V., Feinn, R., Kranzler, H.R. et al. Variation in AKR1C3, which encodes the neuroactive steroid synthetic enzyme 3α-HSD type 2 (17β-HSD type 5), moderates the subjective effects of alcohol. Psychopharmacology 231, 3597–3608 (2014). https://doi.org/10.1007/s00213-014-3614-2

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  • DOI: https://doi.org/10.1007/s00213-014-3614-2

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