Psychopharmacology

, Volume 224, Issue 2, pp 223–230

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge

  • Mary Ann C. Stephens
  • Mary E. McCaul
  • Elise M. Weerts
  • Gary Wand
Original Investigation

DOI: 10.1007/s00213-012-2742-9

Cite this article as:
Stephens, M.A.C., McCaul, M.E., Weerts, E.M. et al. Psychopharmacology (2012) 224: 223. doi:10.1007/s00213-012-2742-9

Abstract

Rationale

The serotonergic and opioidergic neurotransmitter systems are critical regulators of the hypothalamic–pituitary–adrenal (HPA) axis through their respective excitatory and inhibitory inputs. Serotonin transporter (5-HTT) genotype has been studied as a marker of HPA axis dysregulation and for predicting risk of psychopathology, with mixed findings.

Objectives

We stimulated the HPA axis with naloxone, an opioid receptor antagonist, to examine cortisol reactivity based on 5-HTT-linked polymorphic region (5-HTTLPR) genotypes.

Methods

Healthy community volunteers (N = 78) received intravenous (IV) placebo followed by sequential doses of IV naloxone (50, 100, 200, and 400 μg/kg) every 30 min. Plasma cortisol was measured every 15 min. Participants were genotyped for the long (L) and short (S) alleles of the 5-HTT gene and for rs25531 (A/G) in the 5-HTTLPR repetitive element and compared by the 5-HTTLPR/rs25531 genotype (triallele) and by the 5-HTTLPR genotype (biallele) classification.

Results

In triallele analyses, individuals with one or more LA alleles showed higher cortisol response to naloxone compared with individuals with no LA alleles. In biallele analyses, less robust effects were found, although individuals with two L alleles showed a higher cortisol response compared with other genotypes.

Conclusions

Naloxone blockade leads to a greater activation of the HPA axis among individuals with the LA allele. Including rs25531 in the analysis with the 5-HTTLPR genotype appears more sensitive in detecting genetic differences in naloxone-induced cortisol than when using only the 5-HTTLPR genotype. Future research should investigate the interactive effects between the serotonergic and opioidergic systems on HPA axis dysregulation and psychopathophysiology.

Keywords

Serotonin transporter5-HTTSLC6A4NaloxoneHypothalamic–pituitary–adrenalHPA axisCortisolEndogenous opioids

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Mary Ann C. Stephens
    • 1
  • Mary E. McCaul
    • 1
    • 2
  • Elise M. Weerts
    • 1
  • Gary Wand
    • 1
    • 2
  1. 1.Department of Psychiatry and Behavioral SciencesThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA