PET evaluation of central serotonergic neurotransmission in women

Abstract: The serotonin (5-HT) system is of central interest in the patophysiology and treatment of several psychiatric disorders including depression, anxiety and suicide. In women, functioning of the 5-HT system is of particular importance since they have been found to suffer more often from 5-HT-associated disorders compared to men. The aim of the present thesis was to further explore the central serotonergic system in women by examining 5- HT1A receptors and 5-HTT binding in two psychiatric disorders, borderline personality disorder (BPD) and premenstrual dysphoric disorder (PMDD), during different phases of the menstrual cycle and in relation to gender. In the first study positron emission tomography (PET) and [11C]WAY100635 were used to examine 5-HT1A receptors in control group of women and in women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). The 5-HT1A binding potential (BP) was measured in six regions of interest and calculated according to the simplified reference tissue model (SRTM). For the region of dorsal raphe nuclei, there was a significant difference between the groups in the change of 5-HT1A receptor binding. The study provides principally new support in vivo, for a serotonergic dysregulation in women with PMDD. In the second study, PET and selective radioligands [11C]WAY100635 and [11C]MADAM were used to study differences in 5-HT1A receptors and 5-HTT BPs between healthy women and men. The BPs were estimated both on the level of anatomical regions and voxel wise, derived by the SRTM and wavelet/Logan plot parametric image techniques respectively. The volume of interest (VOI)-based analysis revealed higher mean 5-HT1A BP and lower mean 5-HTT BP values in women compared to men. The parametric analysis of [11C]WAY100635 and [11C]MADAM images showed similar results to those obtained with VOI analysis. In women, a positive correlation between 5-HT1A receptor and 5-HTT BPs for the region of hippocampus was found. Sex differences in 5-HT1A receptor and 5-HTT binding may reflect biological distinctions in the 5-HT system contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety. The result may help understanding sex differences in drug treatment responses to drugs affecting the 5-HT system. In the third study, healthy women were investigated in the follicular and luteal phase of the menstrual cycle with radioligands [11C]WAY100635 and [11C]MADAM to study 5-HT1A and 5-HTT BPs. The BPs values were quantified using the SRTM. The phases of the menstrual cycle were characterized by transvaginal ultrasound (TVS) and plasma levels of hormones estradiol (E2), progesterone (P4), follicle stimulating hormone (FSH) and luteinising hormone (LH). The 5-HT1A receptor and 5-HTT BPs did not significantly differ between follicular and luteal phases in any of the investigated regions. There were no significant correlations between hormones E2 or P4 and 5-HT1A receptors BP or 5-HTT BP in any of the regions, neither did the change in plasma E2 or P4 correlate with the change in 5-HT1A BP or 5-HTT BP values in brain regions. The results provide principally new in vivo evidence on human female biology, suggesting no difference in 5-HT1A receptors and 5-HTT binding between the phases of the menstrual cycle in healthy women that can be revealed with the present methodology. In the fourth study, 5-HT1A receptor BP in female patients with BPD and controls were examined. Out of two hundred female patients with BPD, seven met inclusion criteria (i.e. drug naïve including, no previous or present alcohol or drug abuse/dependency). Eight age and sex matched controls were recruited. PET and selective radioligand [11C]WAY100635 were used to study brain 5-HT1A receptor BP in dorsolateral prefrontal cortex, anterior cingulate, orbitofrontal cortex, amygdala, hippocampus, insula, temporal cortex and dorsal raphe nuclei. BP was estimated using the SRTM. Compared to controls, women with BPD had a significantly lower 5-HT1A receptor BP in the brain regions examined. The results suggest a lower 5-HT1A receptor BP in drug naïve patients with BPD. The finding corroborates previous studies suggesting the impairment of the 5-HT system in patients with BPD. In conclusion, the present thesis provides new evidence for the implication of the serotonin system in psychiatric disorders in women, effects of gonadal hormones and sex differences in serotonergic neurotransmission.