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Influence of Serotonin Transporter SLC6A4 Genotype on the Effect of Psychosocial Stress on Cognitive Performance: An Exploratory Pilot Study

Beversdorf, David Q., MD*; Carpenter, Allen L., PhD; Alexander, Jessica K., PhD; Jenkins, Neil T., MD, MPH, PhD‡,§; Tilley, Michael R., PhD∥,¶; White, Catherine A., MA#,**; Hillier, Ashleigh J., PhD††; Smith, Ryan M., PhD‡‡; Gu, Howard H., PhD

Cognitive and Behavioral Neurology: June 2018 - Volume 31 - Issue 2 - p 79–85
doi: 10.1097/WNN.0000000000000153
Original Study

Background and Objective: Previous research has shown an effect of various psychosocial stressors on unconstrained cognitive flexibility, such as searching through a large set of potential solutions in the lexical-semantic network during verbal problem-solving. Functional magnetic resonance imaging has shown that the presence of the short (S) allele (lacking a 43–base pair repeat) of the promoter region of the gene (SLC6A4) encoding the serotonin transporter (5-HTT) protein is associated with a greater amygdalar response to emotional stimuli and a greater response to stressors. Therefore, we hypothesized that the presence of the S-allele is associated with greater stress-associated impairment in performance on an unconstrained cognitive flexibility task, anagrams.

Methods: In this exploratory pilot study, 28 healthy young adults were genotyped for long (L)-allele versus S-allele promoter region polymorphism of the 5-HTT gene, SLC6A4. Participants solved anagrams during the Trier Social Stress Test, which included public speaking and mental arithmetic stressors. We compared the participants’ cognitive response to stress across genotypes.

Results: A Gene×Stress interaction effect was observed in this small sample. Comparisons revealed that participants with at least one S-allele performed worse during the Stress condition.

Conclusions: Genetic susceptibility to stress conferred by SLC6A4 appeared to modulate unconstrained cognitive flexibility during psychosocial stress in this exploratory sample. If confirmed, this finding may have implications for conditions associated with increased stress response, including performance anxiety and cocaine withdrawal. Future work is needed both to confirm our findings with a larger sample and to explore the mechanisms of this proposed effect.

*Departments of Radiology, Neurology, and Psychological Sciences and The Thompson Center, William and Nancy Thompson Endowed Chair in Radiology, University of Missouri, Columbia, Missouri

Department of Neuroscience

School of Medicine

Department of Pharmacology

#Department of Neurology, and

**Department of Psychiatry, The Ohio State University, Columbus, Ohio

§Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts

Department of Biology, Central Methodist University, Fayette, Missouri

††Department of Psychology, University of Massachusetts, Lowell, Massachusetts

‡‡Department of Pharmaceutical Sciences and Experimental Therapeutics, University of Iowa, Iowa City, Iowa

Portions of this work were presented at the 37th Annual Meeting of the International Neuropsychological Society, February 2009, Atlanta, Georgia.

Supported in part by grants from the National Institute of Neurological Diseases and Stroke (K23-NS43222) and National Institute on Drug Abuse (R21-DA15734) to D.Q.B., the General Clinical Research Center at The Ohio State University (M01-RR00034 from the National Center of Research Resources of the National Institutes of Health), and the American Academy of Neurology Medical Student Summer Research Scholarship to N.T.J.

The authors declare no conflicts of interest.

Correspondence: David Q. Beversdorf, MD, Departments of Radiology, Neurology, and Psychological Sciences and The Thompson Center, University of Missouri, DC069.10, One Hospital Dr., Columbia, Missouri 65211 (e-mail:

Received July 10, 2017

Accepted March 26, 2018

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