Comparison of brain serotonin transporter using [I-123]-ADAM between obese and non-obese young adults without an eating disorder.

Cerebral serotonin metabolism has an important but controversial role in obesity. However, it is not given enough attention in morbidly obese young adults. We used single photon emission computed tomography (SPECT) with [I-123]-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) to investigate changes in serotonin transporter (SERT) availability in 10 morbidly obese young adults without an eating disorder (M/F = 5/5, body mass index (BMI): 40.3 ± 4.1 kg/m2, percentage of body fat (BF%): 46.0 ± 3.9%) and 10 age- and sex-matched non-obese controls (BMI: 20.3 ± 1.2 kg/m2, BF%: 20.6 ± 8.9%). All participants underwent SPECT at 10 min and 6 h after an injection of 200 MBq of [I-123]-ADAM. The SERT binding site (midbrain) was drawn with cerebellum normalization. The BF% and fat distribution were measured using dual-energy X-ray absorptiometry. The midbrain/cerebellum SERT binding ratios (2.49 ± 0.46 vs. 2.47 ± 0.47; p = 0.912) at 6 h were not significantly different between groups, nor was the distribution of the summed images at 10 min (1.36 ± 0.14 vs. 1.35 ± 0.11; p = 0.853). There were no significant correlations between midbrain/cerebellum SERT binding ratio and age, BMI, BF%, or fat distribution. No significant difference in SERT availability in the midbrain between morbidly obese and non-obese young adults without an eating disorder indicates an unmet need for investigating the role of cerebral serotonin in obesity.

Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT.

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Probing the Serotonin Transporter Availability Among Male Cigarette Smokers: A SPECT Study With [123I] ADAM.

OBJECTIVE: Genetic studies have suggested that the serotonin transporter (SERT) could be associated with cigarette smoking. However, evidence from neuroimaging is scarce. The aim of the present study was to examine the SERT availability among cigarette smokers by using single-photon emission computed tomography (SPECT). METHODS: Sixteen male smokers and 32 controls were enrolled. The SERT availability was measured by SPECT with a radiotracer, [I] ADAM, which is highly sensitive and specific to SERT. RESULTS: No significant difference in SERT availability was found between 2 groups in the midbrain (smokers: 2.12 ±â€Š0.70, nonsmokers: 2.13 ±â€Š0.63; P = 0.86), basal ganglia (smokers: 0.83 ±â€Š0.30, nonsmokers:0.90 ±â€Š0.39; P = 0.95), or thalamus (smokers: 1.14 ±â€Š0.41, nonsmokers: 1.20 ±â€Š0.38; P = 0.88). No significant association was found between the SERT availability, and either the breath carbon monoxide level or the score of the Fagerström Test for Nicotine Dependence. CONCLUSIONS: Whether the SERT availability in the brain is altered in smokers remains unclear.

Association between the serotonin transporter and cytokines: Implications for the pathophysiology of bipolar disorder.

BACKGROUND: Reduced brain serotonin transporter (SERT) has been demonstrated in bipolar disorder (BD). The aim of this study was to explore the potential role of cytokines on reduced SERT in BD. METHODS: Twenty-eight BD type I patients and 28 age- and gender-matched healthy controls (HCs) were recruited. Single photon emission computed tomography with the radiotracer 123I ADAM was used for SERT imaging. Regions of interest included the midbrain, thalamus, putamen and caudate. Seven cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-1ß, IL-4, IL-6 and IL-10, were measured using an enzyme linked immune-sorbent assay. RESULTS: SERT availability in the midbrain and caudate was significantly lower in BD compared to HCs. IL-1ß was significantly lower, whereas IL-10 was significantly higher in BD compared to HCs. Multiple linear regression analyses revealed that there were associations between cytokines, IL-1α, IL-1ß, IL-6 and SERT availability in the midbrain but not in the thalamus, putamen and caudate. Furthermore, linear mixed effect analyses demonstrated that these associations were not different between HCs and BD. CONCLUSION: While many cytokines have been proposed to be important in the pathophysiology of BD, our results demonstrated that significant associations between cytokines and SERT availability may explain the role of cytokines in mood regulation. However, these associations were not different between HCs and BD, which imply the role of these cytokines is not specific for BD.

Neither cortisol nor brain-derived neurotrophic factor is associated with serotonin transporter in bipolar disorder.

Converging evidence indicates the hypothalamus-pituitary-adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. (123)I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder.

Serotonin transporter availability may moderate the association between perceiving stress and depressive tendencies - A SPECT with 5-HTTLPR genotyping study.

It was found that serotonin transporter (SERT) gene (5-HTTLPR) polymorphism may moderate the association between perceiving stress and depressive tendency. Although SERT availability in the central nervous system could be associated with 5-HTTLPR polymorphism, whether SERT availability moderates the association between stress and depressive tendency is unclear. This study aimed to investigate whether there is a SERT availability×environmental stress interaction effect, as well as a gene-by-environmental (G×E) interaction effect, using single-photon emission computed tomography (SPECT) with a serotonin transporter radiotracer, [(123)I]ADAM. 87 healthy volunteers were enrolled. The SERT availability was approximated using SPECT with [(123)I]ADAM. Stress and depressive tendencies were measured by the Recent Life Change Questionnaire (RLCQ) and the Taiwanese Depression Questionnaire (TDQ), respectively. A significant interaction of sex×RLCQ×thalamic SERT availability on the TDQ was found, and this effect was robust after controlling for the effect of the SS genotype. The interaction of RLCQ×thalamic SERT availability on the TDQ was significant among males. In particular, a significant association between RLCQ and TDQ (Spearman correlation, ρ=0.64, p<0.01) was found among male subjects with a lower level of thalamic SERT availability. SERT availability may play a role in depressive tendency when under perceived stress among healthy individuals, independent of G×E. This finding provides new evidence that confirms the role of the serotonergic system in the association between stress and depression. Males with lower levels of SERT availability may be more vulnerable to the effects of negative life events.

Quantifying midbrain serotonin transporter in depression: a preliminary study of diagnosis and naturalistic treatment outcome.

INTRODUCTION: Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain. METHODS: In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment. RESULTS: A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT. DISCUSSION: The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.

Small-animal single-photon emission computed tomographic imaging of the brain serotoninergic systems in wild-type and mdr1a knockout rats.

The pharmacokinetic properties of radiotracers are crucial for successful in vivo single-photon emission computed tomographic (SPECT) imaging. Our goal was to determine if MDR1A-deficient animals could allow better SPECT imaging outcomes than wild-type (WT) animals for a selection of serotoninergic radioligands. Thus, we compared the performances of 123I-p-MPPI, 123I-R91150, 123I-SB207710, and 123I-ADAM radioligands, for imaging of their respective targets (5-hydroxytryptamine [5-HT]1A, 5-HT2A, 5-HT4, and serotonin transporter [SERT]), in WT and Mdr1a knockout (KO) rats. With 123I-SB207710, virtually no SPECT signal was recorded in the brain of WT or KO animals. For 123I-p-MPPI, low nondisplaceable binding potentials (BPND, mean ± SD) were observed in WT (0.49 ± 0.25) and KO (0.89 ± 0.52) animals. For 123I-ADAM, modest imaging contrast was observed in WT (1.27 ± 0.02) and KO (1.31 ± 0.09) animals. For 123I-R91150, the BPND were significantly higher in Mdr1a KO (3.98 ± 0.65) animals compared to WT animals (1.22 ± 0.26). The pharmacokinetics of 123I-SB207710 and 123I-p-MPPI do not make them ideal tracers for preclinical SPECT neuroimaging. 123I-ADAM showed adequate brain uptake regardless of Mdr1a expression and appeared suitable for preclinical SPECT neuroimaging in both animal strains. The use of Mdr1a KO animals significantly improved the brain penetration of 123I-R91150, making this animal strain an interesting option when considering SPECT neuroimaging of 5-HT2A receptors in rat.

Lower availability of midbrain serotonin transporter between healthy subjects with and without a family history of major depressive disorder - a preliminary two-ligand SPECT study.

PURPOSE: Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD. METHODS: Eight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [¹²³I] 2-((2-((dimethylamino) methyl) phenyl)thio)-5-iodophenylamine (ADAM) and [(99m)Tc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment. RESULTS: SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups. CONCLUSIONS: The results with regard to the midbrain SERT level suggest the heritability of MDD.

123I-ADAM SPET imaging of serotonin transporter in patients with epilepsy and comorbid depression.

BACKGROUND: Purpose of the study was to investigate alterations in midbrain serotonin transporter (SERT) binding in patients with epilepsy and symptoms of depression compared to patients with epilepsy with no symptoms of depression. METHODS: We studied 12 patients with epilepsy (7 patients had focal and 5 had generalized epilepsy syndromes). The presence of self-reported symptoms of depression was assessed using Beck Depression Inventory (BDI) and the Emotional State Questionnaire (EST-Q). The binding potential of the SERT was assessed by performing brain single photon emission tomography (SPET) using the SERT radioligand 2-((2-((dimethylamino)methyl)phenyl)thio)-5-(123)iodophenylamine (123I-ADAM). RESULTS: Seven patients had BDI and EST-Q subscale scores greater than 11 points, which was interpreted as the presence of symptoms of depression. We found that 123I-ADAM binding was not significantly different between patients with epilepsy with and without symptoms of depression. In addition, 123I-ADAM binding did not show a significant correlation to either BDI or EST-Q depression subscale scores and did not differ between patients with focal vs. generalized epilepsy. CONCLUSION: The results of our study failed to demonstrate alterations of SERT binding properties in patients with epilepsy with or without symptoms of depression.

Serotonin transporter availability in the midbrain and perceived social support in healthy volunteers.

OBJECTIVE: Serotonin modulates human behavior and emotion. Recent evidence implies that a higher level of serotonergic activity could be associated with a higher level of perceived social support. This study aimed to examine the correlation between serotonin transporter (SERT) availability and perceived social support scores in healthy volunteers. METHODS: 111 healthy participants, 50 males and 61 females, were enrolled from the community and completed the Measurement of Support Function questionnaire. Single photon emission computed tomography (SPECT) with [(123)I] ADAM was performed to examine SERT availability. RESULTS: Perceived social support was positively correlated with SERT availability (Spearman's ρ=0.29, p<0.01; χ(2)=7.57, p<0.01), particularly in males (Spearman's ρ=0.37, p<0 .01; χ(2)=11.77, p<0.01). Censored regressions indicated that these associations are not influenced by a ceiling effect and remained significant after controlling the effect of age. CONCLUSIONS: This result confirmed the correlation between perceived social support and central serotonergic activity. However, this correlation was present only in males.

5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model.

Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of (123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine((123)I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.

Probing the association between dexamethasone-induced cortisol suppression and serotonin transporter availability among drug-free patients with major depressive disorder--a small-sample SPECT study with [¹²³I]ADAM.

The association between hypothalamo-pituitary-adrenal (HPA) axis function and the serotonergic system could be involved in the mechanism of depression. However, neuroimaging evidence is scarce. The aim of the present study was to probe the association between dexamethasone suppression test response and serotonin transporter (SERT) availability in drug-free patients with major depressive disorder (MDD). Seventeen MDD patients (five males and twelve females) were recruited. SPECT with [(123)I] ADAM was used to measure the midbrain SERT availability, and HPA axis function was measured by the dexamethasone suppression test (DST). The association was significant when considering all participants (ρ=0.69, p=0.002). This association may have clinical implications for the treatment of MDD.

Change over time in brain serotonin transporter binding in major depression: effects of therapy measured with [(123) I]-ADAM SPECT.

Several studies have reported low brain serotonin transporter (SERT) binding in individuals with major depression. We hypothesized that the SERT standardized uptake ratio (SUR) values using [(123) I]-ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [(123) I]-ADAM scans were acquired before and after 12 weeks of CBT from 20 depressed subjects and on two occasions 12 weeks apart from 10 nondepressed, healthy volunteers. The primary outcome measure was change over time in SUR values in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated low pretreatment mean SUR values that significantly increased over time in the midbrain (P = .011), right medial temporal lobe (P = .008), and left medial temporal lobe (P = .000) regions. Treatment responders showed a significant increase over time in SUR values in left medial temporal lobe (P = .029) and right medial temporal lobe (P = .007) regions. Partial and nonresponder subjects also showed a significant increase over time in SUR values in the left medial temporal region (P = .040) (vs. healthy volunteers), but to a lesser degree. The findings suggest that low pretreatment SERT binding may increase over time in some depressed individuals who experience symptom improvement.

Effects of [123I]ADAM, a serotonin transporter radiopharmaceutical, on pregnant Sprague-Dawley rats.

Serotonin transport abnormalities are implicated in neuropsychiatric disorders. [(123)I]ADAM ([(123)I]-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) is a novel radiotracer that targets serotonin transporters. We assessed the toxicity of [(123)I]ADAM (18.5 MBq) administered in early- and late-phases (8 and 14 day postfertilization, respectively) of pregnancy. The mortality, clinical status, and gross necropsy were measured in pregnant rats, and the fertility index was measured in rat offspring (weight, clinical observations). We found no dosing-related clinical signs. In conclusion, [(123)I]ADAM was not toxic in an animal pregnancy model.

Low brain serotonin transporter binding in major depressive disorder.

We examined midbrain, medial temporal lobe, and basal ganglia serotonin transporter (SERT) distribution volume ratio (DVR) values in subjects with major depressive disorder versus healthy volunteers using a selective SERT radioligand and single photon emission computed tomography (SPECT). We hypothesized that the DVR value for SERT binding would be lower in depressed versus non-depressed subjects. [(123)I]-ADAM SPECT scans were acquired from 20 drug free, depressed subjects and 20 drug-free depressed subjects and 10 drug-free healthy volunteers. The primary outcome measure was the DVR value for [(123)I]-ADAM uptake in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated significantly lower DVR values in the midbrain, right and left medial temporal lobe, and right and left basal ganglia. There was significant probability that lower DVR values could distinguish between depressed and non-depressed subjects in the midbrain, medial temporal lobe, and the right and left basal ganglia. These findings confirm prior observations of lower SERT binding in depression, and suggest that low SERT binding may represent a putative biomarker of depression. Future studies are needed to confirm these observations.

Association between the dexamethasone suppression test and serotonin transporter availability in healthy volunteer: a SPECT with [(123)I] ADAM study.

Most common psychiatric diseases have been found to be associated with disturbance of both the hypothalamic-pituitary-adrenal (HPA) axis and the brain serotonergic system. The aim of this study was to explore the neuroendocrine relationships between the dexamethasone suppression test (DST) and serotonin transporter (SERT) availability in healthy volunteers. Sixty-six participants (30 males and 36 females) were recruited from the community. The DST suppression rate (D%) is the reduction in cortisol level from Day 1 (D1) to Day 2 (D2) in proportion to the Day 1 cortisol level (D%=(D1-D2)/D1×100%). SPECT with [(123)I] ADAM was used to measure SERT availability. A significant correlation between D% and SERT availability was noted in all subjects (Spearman's ρ=0.26, p=0.03) and in the male subjects (Spearman's ρ=0.41, p=0.02). SERT availability may be sensitive to changes in DST, especially in males.

The association between availability of serotonin transporters and time to relapse in heroin users: a two-isotope SPECT small sample pilot study.

Neuroimaging evidence supporting an association between either dopamine or serotonin and time to relapse of heroin users is limited. In this two-isotope SPECT small sample (N=9) pilot study, the relationship between the availability of serotonin transporter (SERT) and dopamine transporter (DAT) and the relapse of heroin users was investigated. A significant negative association between SERT availability and time to relapse among those who relapsed (N=7) was found.

Association between somatization subscale score and serotonin transporter availability in healthy volunteers--a single photon emission computed tomography study with [¹²³I] ADAM.

RATIONALE AND OBJECTIVE: Serotonin is one of the key neuromodulators involved in fundamental cerebral functions and behaviors. Previous study has demonstrated that somatization symptoms are probably associated with central serotonergic circuits, which are implicated in anxiety and nociception regulation. This study aims to examine the correlation between somatization subscale score and serotonin transporter (SERT) availability in healthy volunteers. METHODS: Sixty-four healthy participants, 26 males and 38 females, were enrolled from the community and were administered the single somatization subscale of the Chinese symptom checklist 90 revised (SCL90-R). Single photon emission computed tomography with [(123)I] 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine was also performed to examine SERT availability. RESULTS: The somatization scores were negatively correlated with SERT availability (Spearman's ρ = -0.35, p = 0.005), particularly in males (Spearman's ρ = -0.54, p = 0.004). CONCLUSION: This result reconfirmed the correlation between central serotonergic activity and the intensity of somatization symptoms, even in healthy participants. However, a gender difference exists in this correlation.

No seasonal variation in human midbrain serotonin transporter availability in Taiwan.

Sunlight exposure is considered responsible for seasonal serotonin changes. Sixty-six healthy participants were recruited, and single photon emission computed tomography ([¹²³I]-ADAM SPECT) was used to investigate the association between serotonin transporter (SERT) availability and duration of sunlight exposure in Taiwan, a subtropical country. No significant correlation between SERT availability and the duration of sunlight exposure was found.