Polymorphism of the serotonin transporter gene modulates brain and physiological responses to acute stress in Japanese men

Abstract

A short (S) variant, compared to a long (L) variant, of the promoter region of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been related to emotional hyper-reactivity. We tested whether the 5HTTLPR could modulate acute stress responses in the brain and, the cardiovascular and neuroendocrine systems. Ten Japanese male participants carrying double copies of the S alleles and 10 Japanese males carrying S and L alleles conducted a mental arithmetic task, and their regional cerebral blood flow by ¹⁵O positron emission tomography and cardiovascular and neuroendocrine parameters were measured. During the acute stress task, the participants with the SS alleles showed stronger reactivity in blood pressure and secretion of epinephrine, compared to the participants with the SL and LL alleles. Furthermore, the SS carriers showed greater activation in stress-related brain regions such as the hypothalamus, cerebellum, midbrain, and pulvinar compared to the SL and LL carriers during the acute stress task. The present findings indicated that the S allele of the 5HTTLPR is associated with greater brain and physiological reactivity to acute stress in Japanese men.

Keywords::

• 5HTTLPR
• acute stress
• blood pressure
• catecholamine
• positron emission tomography (PET)
• serotonin

Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (No. 16330136) and by a Health and Labour Sciences Research Grant on Research on Occupational Safety and Health from Japan Ministry of Health, Labour, and Welfare (No. H17-RODO-5). The authors thank Dr Shuichi Ueno of Tokushima University for his technical advice. Portions of the present study were presented at the 13th Annual Meeting of the Organization for Human Brain Mapping (Chicago, June 2007). The experiment reported in this article complies with the current law of Japan. The 12th author (SF) contributed to this study equally as the first author (HO).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Notes

^1. Recently it has been shown that the L allele includes an adenine (A) –guanine (G) single nucleotide polymorphism in the repeated structure (Nakamura et al. 2000). Unlike the L_A allele, the L_G allele leads to low 5HTT expression, almost equivalent to that of the S allele (Hu et al. 2006). This might cause a wide variation in stress-related 5HTT functions in L allele carriers. However, we chose to conduct main analyses by classifying participants into three genetic groups based on their S and L alleles, because of the small number of participants. Nevertheless, we conducted supplementary analyses for effects of this SNP on each index of psychological, behavioral, physiological, and neuroimaging responses. To distinguish between the L_A and L_G fragments, the PCR product was digested with MspI (Nippon Gene Inc., Tokyo, Japan) and the resulting polymorphic fragments were separated on a 2% agarose gel (L_A: 340, 127, and 62 bp; L_G: 174, 166, 127, and 62 bp). It was shown that the SL + LL group in this study comprised 5 SL_A participants, 3 SL_G participants, 1 L_AL_A participant, and 1 L_GL_G participant. With the small statistical power, no significant effect of the SNP on any dependent variable was observed.