5-HT1A gene promoter polymorphism and [18F]MPPF binding potential in healthy subjects: a PET study

<p>Abstract</p> <p>Background</p> <p>Previous Positron Emission Tomography (PET) studies of 5-HT_1Areceptors have shown an influence of several genetic factors, including the triallelic serotonin transporter gene-linked polymorphic region on the binding potential (BP_ND) of these receptors. The aim of our study was to investigate the relationship between a 5-HT_1Apromoter polymorphism and the binding potential of another selective 5-HT_1Areceptor antagonist, [¹⁸F]MPPF, in healthy subjects.</p> <p>Methods</p> <p>Thirty-five volunteers, including 23 women, underwent an [¹⁸F]MPPF scan and were genotyped for both the C(-1019)G 5-HT_1Apromoter polymorphism and the triallelic serotonin transporter gene-linked polymorphic region. We used a simplified reference tissue model to generate parametric images of BP_ND. Whole brain Statistical Parametric Mapping and raphe nuclei region of interest analyses were performed to look for an association of [¹⁸F]MPPF BP_NDwith the C(-1019)G 5-HT_1Apromoter polymorphism.</p> <p>Results</p> <p>Among the 35 subjects, 5-HT_1Apromoter genotypes occurred with the following frequencies: three G/G, twenty-one G/C, and eleven C/C. No difference of [¹⁸F]MPPF BP_NDbetween groups was observed, except for two women who were homozygote carriers for the G allele and showed greater binding potential compared to other age-matched women over the frontal and temporal neocortex. However, the biological relevance of this result remains uncertain due to the very small number of subjects with a G/G genotype. These findings were not modified by excluding individuals carrying the S/S genotype of the serotonin transporter gene-linked polymorphic region.</p> <p>Conclusions</p> <p>We failed to observe an association between the C(-1019)G 5-HT_1Apromoter polymorphism and [¹⁸F]MPPF binding in healthy subjects. However our data suggest that the small number of women homozygote for the G allele might have greater [¹⁸F]MPPF BP_NDrelative to other individuals. This finding should be confirmed in a larger sample.</p

Perception of Thermal Pain and the Thermal Grill Illusion Is Associated with Polymorphisms in the Serotonin Transporter Gene

AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho  = -0.58, p<0.001). Individuals in the low 5-HTT-expressing group were significantly less sensitive to heat-pain (p = 0.02) and cold-pain (p = 0.03), compared to the high-expressing group. A significant gender-by-genotype interaction also emerged for cold-pain perception (p = 0.02); low 5-HTT-expressing females were less sensitive. The TGI was rated as significantly more unpleasant (affective-motivational dimension) than painful (sensory-discriminatory dimension), (p<0.001). Females in the low 5-HTT expressing group rated the TGI as significantly less unpleasant than high 5-HTT expressing females (p<0.05), with no such differences among men. CONCLUSION/SIGNIFICANCE: We demonstrate an association between inferred low 5-HTT expression and elevated thresholds to thermal pain in healthy non-depressed individuals. Despite the fact that reduced 5-HTT expression is a risk factor for chronic pain we found it to be related to hypoalgesia for threshold thermal pain. Low 5-HTT expression is, however, also a risk factor for depression where thermal insensitivity is often seen. Our results may thus contribute to a better understanding of the molecular underpinnings of such paradoxical hypoalgesia. The results point to a differential regulation of thermoafferent-information along the neuraxis on the basis of 5-HTT expression and gender. The TGI, suggested to rely on the central integration of thermoafferent-information, may prove a valuable tool in probing the affective-motivational dimension of these putative mechanisms