Differences in limbic metabolism according to variation of the 5HTTLPR polymorphism of serotonin transporter: A pilot pet study
Graff-Guerrero A., Alexánderson-Rosas E., Altamirano-Ley J., Estrada-Sanchez G., Gómez-Martín D., Méndez JC., Zárate-Morales A., Flores-Moreno A., López-Durán F., Flores-Castillo B., Drucker-Colín R., De La Fuente JR., De La Fuente-Sandoval C., Camarena-Medellín B., Aguilar-Garcia A., Fresán-Orellana A., Apiquián R., Nicolini H.
Serotoninergic neurotransmitter system seems to be a promising candidate for a biological marker in psychiatry since has been involved in the pathogenesis of various neuropsychiatry disorders, like affective disorders. The target site of action of some antidepressant drugs such fluoxetine is the serotonin (5HT) transporter (5HTT). The function of 5HTT is the reuptake of the serotonin released in the synaptic cleft and determines the magnitude and duration of the postsynaptic receptor-mediated signaling, thus playing a pivotal role in the fine-tuning of 5HT neurotransmission. A functional polymorphism in promoter region of the 5HTF-(5HTTLPR) gene (SLC6A4) has been shown to modulate the 5HTT reuptake capacity, brain 5HTT binding sites and 5HTT mRNA quantity. The activity of the promoter region of the 5HTT gene is dependent of two allelic variants (long; L and short; S). Cultured lymphoblast homozygous for the L alleled (L/L) has higher concentration of 5HTT mRNA and express nearly twofold greater 5HT reuptake compared with cells with either one (L/S) or two copies (S/ S) of the S allele. In vivo human brain studies quantifying binding levels of 5HTT using SPECT have shown heterogeneous results between L/L, L/S or S/S carriers. Control S carriers subjects have less available 5HTT in the raphe than homozygous to L allele. No differences in the diencephalons, thalamus, hypothalamus and mesencephalonpons regions have been shown. Behavioral studies have associated individual's carries of S allele more likely to present mood disorders, anxiety-related personality traits, acquired conditioned fear responses and impulsive behavior. Functional brain imaging techniques have frequently implicated in the processing of these behaviors and disorders fronto-cortical and limbic structures. Recently has been explored the functional temporal amygdala neural activity, assessed by functional magnetic resonance imaging, in response to fearful stimuli in healthy subjects. Those carriers of S allele exhibit greater amygdale activity. To our knowledge, no study, has evaluated the differences of basal brain metabolism among the HTTLPR genotype. The propose of this preliminary study, was to compare the basal metabolic activity, obtained by positron emission tomography (PET), in fronto-cortical and limbic structures of non-psychiatric patients, to sustain differences in the basal neural activity among homozygous to this function polymorphism. In this study we performed PET scans with (18) F-fluorodeoxyglucose (FDG) as radiotracer in 14 non-psychiatrically ill individuals (screened by SCID-I, RV). All subjects were genotyped for the SLC6A4. The comparison groups were constituted as follows: S/S (n=8) vs. L/L (n=6). The analysis of PET images was performed using SPM2 software considering as significant only those limbic regions with a p-corrected < 0.01 and cluster of at least 10 voxels. In a secondary analysis a correlation between the metabolic activity of the areas with main differences among groups were performed. We found a significant increase of brain metabolism in those S/S individuals vs. L/L homozygous subjects in the following areas: left and right Fusiform Gyrus (Brodmann Area (BA) 37 and 19 respectively) (T = 5.11, p < 0.001; T = 5.05, p < 0.001 respectively). Left anterior cerebellum (T = 5.70, p < 0.001). Right superior Parietal and right posterior Cingulate (BA 7 and 31) (T = 8.03, p < 0.001 both). Left anterior Cingulate (BA 42) (T = 3.04, p < 0.01). Left Caudate (T = 4.03, p < 0.001). Left and right superior Frontal Gyrus (AB 8 and 9) (T = 3.66, p < 0.01 and T = 4.54, p < 0.001, respectively). Right inferior Frontal Gyrus (BA 47) (T = 4.47, p < 0.001). Right and left Amygdale (BA 38) (T = 4.16, p < 0.001 and T = 3.75, p < 0.01, respectively). Left superior Temporal Gyrus (BA 29) (T = 3.82, p < 0.01). In contrast those areas where we found an increased metabolism of those L/L individuals vs. S/S were: Left middle Frontal Gyrus (BA 8 and 9) (T = 3.38, p < 0.01) and right superior Frontal Gyrus (BA 9) (T = 2.93, p < 0.01). The correlation analysis showed higher correlation coefficients among limbic structures in the S/S groups than in the L/L group. Right Amygdale - Left Amygdale (S/S = 0.541 vs. L/L = 0.101); Left Amygdale - Left anterior Cingulate (S/S = 0.722 vs. L/L = 0.475); Left anterior Cingulate - Right posterior Cingulate (S/S = 0.720 vs. L/L = -0.094); Right Amygdale - Left anterior Cingulate (S/S = 0.867 vs. L/L = 0.610); Right Amygdale - Right posterior Cingulate (S/S = 0.586 vs. L/L = -.246). Our results shows differences in basal metabolism between homozygous individuals to alleles S and alleles 1 of the 5HTTLPR. A major basal metabolism in limbic system, like anterior and posterior cingulate and amygdale, and also other structures like fusiform gyruses, dorsolateral prefrontal cortex and superior temporal cortex was found in homozygotes to S allele. On the contrary, homozygote subjects to L allele presented a greater metabolism on bilateral frontal structures. The selective increase in basal metabolism found in our results could reflect an "hiperexcitability state" of these structures, with a larger repercussion to stimulus with an emotional meaning in S/S subjects in comparison to the L/L ones. This would support a major susceptibility in these subjects to develop an anxiety-depression spectrum disorder. The observed correlation between regions, shows a greater functional coupling (connectivity) between limbic structures (both amygdales, anterior and posterior cingulate) in S/S in comparison to L/L subjects. There is also a correlation between limbic and cortical structures (frontal, bilateral and left fusiform). This could explain that, in S/S individuals, any sensorial afference could induce an important effect on structures involved in emotional processing (frontal and limbic) making, these individuals prone to the development of affective disorders. Both, the structure and the global cerebral functioning (endophenotypes) are determined by interactions between genetic information and environment. However, genes can determine or promote a conduct in some environments, specially if we consider that they can promote susceptibility for some conduct (intelligence, personality traits, psychopathology, etc).