Effects of Serotonin Transporter Promoter Polymorphisms on Serotonin Function

Abstract

The serotonin transporter promoter polymorphism (5-HTTLPR) has been associated with vulnerability to stress-induced depressive symptoms and with the speed and rate of response to antidepressant treatment. The goal of the present study was to evaluate the association between the 5-HTTLPR and the functional response of the serotonin system as measured by the neuroendocrine and cerebral metabolic response to intravenous administration of the selective serotonin reuptake inhibitor citalopram in normal control subjects. Genotyping was performed for 5-HTTLPR insertion/deletion polymorphism long (l) and short (s) variant alleles. The ll genotype was compared with the combined sl þ ss and with the ss genotype alone. Citalopram plasma concentrations did not differ significantly between groups. The s allele was associated with a less of an increase in prolactin and cortisol than the ll genotype. The s allele was associated with greater decreases in left frontal, precentral and middle temporal gyri compared to the ll genotype. The ll genotype was associated with greater decreases in right frontal, insula and superior temporal gyrus compared to the ss genotype. These findings suggest that 5-HTTLPR is associated with an altered functional response of the serotonin system, which may represent a neurobiologic substrate for the differential response to antidepressant treatment in late life and the emergence of neuropsychiatric symptoms in neurodegenerative disorders.

Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol

“…To date, a limited number of human studies have directly considered the impact of 5-HTT genotype on measures of HPA function. These investigations found no association of 5-HTT genotype with plasma cortisol, 66,72 although Smith et al 66 observed a trend towards blunted cortisol and prolactin response to acute pharmacologic increase of serotonin in those with the s allele. Most of these investigations did not examine basal levels, and were conducted on small samples of younger adults, with limited power to test genotype differences.…”

“…Others argue that s allele status confers increased vulnerability to a range of behavioral symptoms secondary to agerelated neurodegenerative processes, particularly in response to stress. 66 Thus, the phenotype associated with the 5-HTT s/l alleles may result from developmental, functional or neurodegenerative effects of the serotonin transporter polymorphism or a combination of these effects.…”

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…For example, most neuroendocrine tests of central serotonergic function have shown blunted responses in s allele carriers; these include smaller prolactin increases in response to fenfluramine, clomipramine or citalopram. [86][87][88] On the other hand, the prolactin response to meta-chlorphenylpiperazine (m-CPP) was enhanced in ss homozygotes. 49 Unlike fenfluramine, clomipramine and citalopram, which act directly on the serotonin transporter to increase extracellular serotonin, the m-CPP is a postsynaptic 5-HT agonist, inducing prolactin release via its action on the 5-HT2C receptors.…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…Furthermore, healthy 5-HTTLPR l/l individuals show significantly greater prolactin responses than s/s individuals after challenge with the tricyclic antidepressant clomipramine 361 or the SSRI citalopram. 362 Thus, it appears that heavy drinking, withdrawal from cocaine use and 5-HTTLPR genotype are associated with altered hormonal responses to 5-HT challenges, which may indicate SV.…”