Age-related decline of serotonin transporters in living human brain of healthy males
Introduction
It has been assumed that alteration in serotonin transporter (5-HTT) function is involved in a number of neuropsychiatric disorders including depression and obsessive-compulsive disorders [1]. Moreover, 5-HTT is a major site of action for a number of antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Age-related declines in postsynaptic 5-HT2 receptors have been consistently reported in postmortem human studies and in vivo imaging studies [2], [3], [4], [5]. Unlike 5-HT2 receptors, reports on the aging effect of 5-HTT from in vitro studies are not consistent either in animals [6], [7] or in postmortem human studies [8], [9], [10], [11], [12]. Recent single photon emission computed tomography (SPECT) studies reported age-related decline of [123I]β-CIT binding in 5-HTT rich regions [13], [14]. However, [123I]β-CIT has high affinity for both dopamine transporter and 5-HTT [15]. Trans-1, 2, 4, 5, 6, 10-β-hexahydro-6-[4-(methylthio)phenyl]pyrrolo[2,1-a]isoquinoline (McN5652) has been characterized by high affinity and selectivity for 5-HTT [16]. Positron emission tomography (PET) studies of humans have shown that [11C](+)McN5652 binding was observed in the known high-density areas of 5-HTT regions [17]. In this study, using PET with [11C](+)McN5652, we aimed to investigate the effect of the normal aging process on 5-HTT in living healthy male human brain.
Section snippets
Subjects
Twenty-eight healthy male volunteers aged 20 to 79 years (mean ± SD, 37.7 ± 16.6; 13 subjects between 20–29 years old, 4 between 30–39, 3 between 40–49, 5 between 50–59, 2 between 60–69, 1 between 71–79) participated in this study. They were considered to be healthy, based on their medical histories, physical and neurological examinations, and magnetic resonance imaging (MRI) of the brain. None was taking any medication. Written informed consent was obtained from all participants. This study
Results
The cerebellar time activity curves did not differ significantly between young (20–39 years old) and aged subjects (40–79 yeas old); there was neither a main effect of group nor group-by-time interaction according to repeated measures ANOVA with Greenhouse-Geisser correction (age-group F1.65, 43.0 = 0.93, p = 0.39; group-by-time interaction F1, 26 = 3.35, p = 0.08).
The BP value showed a significant inverse correlation with age in the thalamus [r = −0.64, p < 0.0003] and the midbrain [r = −0.54,
Discussion
This study showed that 5-HTT binding in the thalamus and midbrain of the living human brain decreased with the normal aging process.
Diverse results have been reported in postmortem human studies [8], [9], [10], [11], [12]. The inconsistency of the in vitro results can be explained by factors such as causal disease for death, suicidality, prior medication and limited age range of subjects, or selectivity of the ligand and different experimental conditions [25]. On the other hand, a PET study of
Acknowledgements
Professor Toru Nishikawa and Emeritus Professor Michio Toru, Section of Psychiatry and Behavioral Science, Graduate School of Tokyo Medical and Dental University are greatly acknowledged. We wish to extend our gratitude to Mr. Nakajima for operation of the PET scanner, and to Mr. Kawakami and the cyclotron personnel for synthesizing the radioligand. This research was supported by the PET project of the National Institute of Radiological Sciences, and was partly supported by a Grant-in-Aid for
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2019, Neurobiology of AgingCitation Excerpt :Over the last several decades, one of the most consistently observed findings in molecular imaging studies of human brain 5-HT targets is a decline with healthy aging. Studies of different receptor types and transporters have revealed small to moderate negative effects of age on 5-HT-1A receptors (Rabiner et al., 2002; Tauscher et al., 2001), moderate to large effects of age on 5-HT-2A receptors (Sheline et al., 2002; Uchida et al., 2011), and moderate to large effects of age on 5-HT transporters (Fazio et al., 2016; Yamamoto et al., 2002) across adulthood. The only prior summary of the literature on 5-HT in aging, based primarily on postmortem studies, concluded that 5-HT-1A and 5-HT-2A receptors decline with age (Meltzer et al., 1998).