Elsevier

Life Sciences

Volume 71, Issue 7, 5 July 2002, Pages 751-757
Life Sciences

Age-related decline of serotonin transporters in living human brain of healthy males

https://doi.org/10.1016/S0024-3205(02)01745-9Get rights and content

Abstract

There is growing interest in serotonin transporter (5-HTT) function in the human brain, since alteration in 5-HTT has been suggested in a variety of neurophychiatric disorders. Age-related decline in postsynaptic 5-HT receptors has been demonstrated in postmortem human studies and in vivo imaging studies, and has been assumed to be related to changes in mental function in the normal aging process. However, few studies have investigated the aging effect on 5-HTT in human brain in vivo, since the availability of suitable ligands has been limited. To investigate the aging effect on 5-HTT in living human brain, we performed positron emission tomography (PET) scans with a selective ligand for 5-HTT, [11C](+)McN5652. We examined 28 healthy male volunteers aged between 20 and 79 years. The uptake was quantified in the thalamus and midbrain by graphical analysis with the cerebellum as a reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. There was a significant age-related decline in BP in the thalamus and midbrain. The decline in [11C](+)McN5652 binding was 9.6% per decade in the thalamus and 10.5% per decade in the midbrain.

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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