ObjectiveThe objective of this study was to evaluate the impact of indices of central nervous system (CNS) serotonin function on cardiovascular reactivity to mental stress.MethodsLumbar puncture was performed on 54 healthy volunteers to obtain cerebrospinal fluid (CSF) for determination of 5-hydroxyindoleacetic acid (5HIAA) levels. Genotypes were determined with respect to a functional polymorphism of the serotonin transporter gene promoter region (5HTTLPR). Subjects then underwent mental stress testing.ResultsPersons with one or two long (l) 5HTTLPR alleles had CSF levels of the major serotonin metabolite, 5HIAA, that were 50% higher than those of persons with thes/s5HTTLPR genotype. Persons with one or twolalleles or higher CSF 5HIAA levels also exhibited greater blood pressure and heart rate responses to a mental stress protocol.ConclusionsThese findings suggest the 5HTTLPR polymorphism affects CNS serotonin function, and they are consistent with the general hypothesis that CNS serotonin function is involved in the regulation of potentially health-damaging biobehavioral characteristics. In particular, thelallele could contribute, through its association with increased cardiovascular reactivity to stress, to increased risk of cardiovascular disease.