Serotonin Transporter Availability Research Articles

Increased dopamine D2/D3 receptor and serotonin transporter availability in male rats after spontaneous remission from repeated social defeat-induced depression; a PET study in rats

Most pharmacological treatments for depression target monoamine transporters and about 50 % of treated patients attain symptomatic remission. Once remission is attained, it is hard to distinguish the changes on brain monoaminergic transmission induced by the antidepressants, from those associated to remission per se. In this study, we aimed at studying the brain of spontaneously remitted rats from repeated social defeat (RSD)-induced depression in terms of dopamine D2/D3 receptor and serotonin transporter (SERT) availability, showing absence of depressive symptoms 2 weeks after RSD. We combined behavioral tests and positron emission tomography (PET) with [11C]raclopride and [11C]DASB to explore the changes in dopamine D2/D3 receptor and serotonin transporter (SERT) availability, respectively. Male rats submitted to RSD showed increased peripheral corticosterone levels, decreased body weight and anhedonia, as measured with the sucrose preference test, 1 day after RSD, confirming depressive-like symptoms. These depressive-like symptoms were no longer present 2 weeks after RSD. Rats that recovered from depressive-like symptoms showed decreased D2/D3 receptor binding in the caudate putamen and increased SERT availability in the brainstem, insular cortex, midbrain and thalamus, compared to control non-stressed animals. Our study shows that remission of depressive-like symptoms does not just “normalize” monoaminergic transmission, as changes in dopaminergic and serotonergic neurotransmission linger in several brain regions even after depressive-like symptoms have already resolved. These results provide new insights into the brain changes associated to remission in the RSD-induced depression model in rats.

Pitavastatin attenuates hypercholesterolemia-induced decline in serotonin transporter availability

IntroductionHypercholesterolemia is associated with increased inflammation and impaired serotonin neurotransmission, potentially contributing to depressive symptoms. However, the role of statins, particularly pitavastatin, in modulating serotonin transporter (SERT) function within this context remains underexplored. This study aimed to investigate whether pitavastatin counteracts the neurobiological effects of hypercholesterolemia.MethodsLow-density lipoprotein receptor knockout (LDLR−/−) mice on a C57BL/6 background were assigned to three groups: a control group fed a standard chow diet, a group fed a high-fat diet (HFD), and a third group fed a high-fat diet supplemented with pitavastatin (HFD + Pita). We evaluated the effects of HFD with or without pitavastatin on lipid profiles, inflammatory markers, and SERT availability using small-animal positron emission tomography (PET) scans with the radioligand 4-[18F]-ADAM over a 20-week period.ResultsPitavastatin treatment in HFD-fed mice significantly reduced both total cholesterol and LDL cholesterol levels in HFD-fed mice compared to those on HFD alone. Elevated inflammatory markers such as IL-1α, MCP-1/CCL2, and TNF-α in HFD mice were notably decreased in the HFD + Pita group. PET scans showed reduced SERT availability in the brains of HFD mice; however, pitavastatin improved this in brain regions associated with mood regulation, suggesting enhanced serotonin neurotransmission. Additionally, the sucrose preference test showed a trend towards increased preference in the HFD + Pita group compared to the HFD group, indicating a potential reduction in depressive-like behavior.ConclusionOur findings demonstrate that pitavastatin not only lowers cholesterol and reduces inflammation but also enhances SERT availability, suggesting a potential role in alleviating depressive symptoms associated with hypercholesterolemia. These results highlight the multifaceted benefits of pitavastatin, extending beyond its lipid-lowering effects to potentially improving mood regulation and neurotransmitter function.

Relationships between Serotonin Transporter Availability and the Global Efficiency of the Executive Control Brain Network.

The diverse effects of serotonin on cognition may emerge from the modulation of large-scale brain networks that support distinct cognitive processes. Yet, the specific effect of serotoninergic modulation on the properties of these networks remains elusive. Here, we used a simultaneous PET-fMRI scanner combined with graph theory analyses to investigate the modulation of network properties by the Serotonin Transporter (SERT) availability measured in the dorsal raphe nucleus (DRN). We defined global efficiency as the average mean of efficiencies over all pairs of distinct nodes of specific brain networks, and determined whether SERT levels correlated with the global efficiency of each network. SERT availability in the DRN correlated negatively with the global efficiency of the executive control brain network, which is engaged in cognitive control and directed attention. No relationship was observed between SERT availability and the global efficiency of the default mode or the salience brain networks. These findings indicate a specific role of serotoninergic modulation in the executive control brain network via a change in its global efficiency.

Dextromethorphan moderates reward deficiency associated with central serotonin transporter availability in 3,4-methylenedioxy-methamphetamine-treated animals.

The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.

The Relationship between Character Traits and In Vivo Cerebral Serotonin Transporter Availability in Healthy Subjects: A High-Resolution PET Study with C-11 DASB.

To elucidate the potential roles of serotonergic activity in human character traits (i.e., self-directedness, cooperativeness, and self-transcendence), we investigated the relationship between these character traits and serotonin transporter (5-HTT) in healthy subjects. Twenty-four participants underwent High-Resolution Research Tomograph-positron emission tomography scans with [11C]DASB. To quantify 5-HTT availability, binding potential (BPND) of [11C]DASB was obtained using the simplified reference tissue model. The Temperament and Character Inventory was used to assess subjects' levels of three character traits. There were no significant correlations between the three character traits. Self-directedness was significantly positively correlated with [11C]DASB BPND in the left hippocampus, left middle occipital gyrus, bilateral superior parietal gyrus, left inferior parietal gyrus, left middle temporal gyrus (MTG), and left inferior temporal gyrus (ITG). Cooperativeness was significantly negatively correlated with [11C]DASB BPND in the median raphe nucleus. Self-transcendence was significantly negatively correlated with [11C]DASB BPND in the right MTG and right ITG. Our results show significant correlations between the three character traits and 5-HTT availability in specific brain regions. In particular, self-directedness was significantly positively correlated with 5-HTT availability, suggesting that a goal-oriented, self-confident, and resourceful character may be related to higher serotonergic neurotransmission.

Journal Digest: CBT With Cardiac Rehab, PMDD Neurochemistry, and More

Journal Digest: CBT With Cardiac Rehab, PMDD Neurochemistry, and More

Amygdala substructure volumes and serotonin transporter in first-episode, drug- naïve major depressive disorder: A pilot study

IntroductionAmygdala and serotonergic system abnormalities have been documented in major depressive disorder (MDD). However, most studies have been conducted on recurrent MDD, and only a few have assessed their interaction. This study aimed to concurrently examine both the amygdala and serotonergic systems and their clinical relevance in first-episode, drug-naïve MDD. MethodsThis study included 27 patients with first-episode, drug-naïve MDD and 27 age- and gender-matched healthy controls (HCs). The amygdala substructure volumes were performed with Freesurfer from a 1.5 T magnetic resonance image. Serotonin transporter (SERT) availability was detected by single-photon emission computed tomography with 123I-ADAM. The Benjamini-Hochberg method was applied to adjust for multiple comparisons. ResultsNo significant difference was found in the amygdala substructure volume and SERT availability between the two groups, respectively. Within MDD patients, the right medial, cortical nucleus, and centromedial volumes were positively associated with caudate SERT availability, respectively. Moreover, the right lateral nucleus volume in the amygdala was positively correlated with depression severity. However, these significances did not survive correction for multiple testing. ConclusionsThere were no significant abnormalities in the amygdala substructure volumes and SERT availability in patients with first-episode, drug-naïve MDD. We did not observe an association between amygdala substructure volume and serotonergic dysregulation and their correlations with depression severity in patients with MDD. A larger sample size is warranted to elucidate the actual correlation.

Binding potential changes of SERT in patients with depression are associated with remission: A prospective [¹²³I]β-CIT-SPECT study.

The status of remission in patients with major depressive disorder treated with selective serotonin reuptake inhibitors (SSRIs) is mostly evaluated with clinical rating scales. Morphological correlates of the remission status remain a rare event. Addressing this challenge, we investigated functional correlates of remission by assessment of serotonin and dopamine transporter availability (SERT and DAT) using single-photon emission computed tomography (SPECT). Our purpose was to identify changes in the SERT/DAT binding potential in accordance with the clinical improvement. Nineteen drug-naïve patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis of major depression were included. [¹²³I]2β-carbomethoxy-3β-(4-iodophenyl)tropane(β-CIT) SPECT was obtained from each participant before (baseline) and after 6 weeks (follow-up) of standardized treatment with escitalopram. The [¹²³I]β-CIT-SPECT recordings were acquired 4 hr (SERT-weighted) and 20-24 hr p.i (DAT-weighted), and binding potentials (˜BPND: baseline, follow-up, and rate of change) were calculated for thalamus, midbrain, pons (SERT), and striatum (DAT). From all study participants, neuropsychiatric symptoms were assessed using Hamilton depression (HAM-D) and Beck Depression Inventory scores. At follow-up, patients were divided into responders and nonresponders (as well as remitters and nonremitters). Compared to nonremitted, remitted patients showed over the course of 6 weeks a significantly higher loss of SERT binding potential in the thalamus (p = .036) and in the midbrain (p = .019). Additionally, the correlation of HAM-D with SERT binding potential in the thalamus showed a trend toward significance (p = .057) with higher HAM-D scores (at baseline) leading to lower SERT binding potential. No significant associations were identified for the analysis of baseline prediction of therapy response with SERT and DAT. Our results suggest that patients who remit from their depressive symptoms under escitalopram are characterized by stronger decreases of SERT, indicating that escitalopram blocking of SERT leads to clinical improvement. Therefore, this study shows that measuring SERT availability with SPECT could be an efficient and applicable technique to illustrate a possible underlying pathophysiology of symptom remission in response to treatment. In addition, the present results could help to stimulate new treatment approaches based on SERT and DAT binding. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Relationships between serotonin availability and frontolimbic response to fearful and threatening faces

Serotonin is a critical neurotransmitter in the regulation of emotional behavior. Although emotion processing is known to engage a corticolimbic circuit, including the amygdala and prefrontal cortex, exactly how this brain system is modulated by serotonin remains unclear. Here, we hypothesized that serotonin modulates variability in excitability and functional connectivity within this circuit. We tested whether this modulation contributes to inter-individual differences in emotion processing. Using a multimodal neuroimaging approach with a simultaneous PET-3T fMRI scanner, we simultaneously acquired BOLD signal while participants viewed emotional faces depicting fear and anger, while also measuring serotonin transporter (SERT) levels, regulating serotonin functions. Individuals with higher activity of the medial amygdala BOLD in response to fearful or angry facial expressions, who were temperamentally more anxious, also exhibited lower SERT availability in the dorsal raphe nucleus (DRN). Moreover, higher connectivity of the medial amygdala with the left dorsolateral prefrontal and the anterior cingulate cortex was associated with lower levels of SERT availability in the DRN. These results demonstrate the association between the serotonin transporter level and emotion processing through changes in functional interactions between the amygdala and the prefrontal areas in healthy humans.

Serotonin transporter availability in physically aggressive personality disordered patients: associations with trait and state aggression, and response to fluoxetine.

Characterizing the neuroanatomical basis of serotonergic abnormalities in severe, chronic, impulsive aggression will allow for rational treatment selection, development of novel therapeutics, and biomarkers to identify at-risk individuals. The aim of this study is to identify associations between regional serotonin transporter (5-HTT) availability and trait and state aggression, as well as response to the anti-aggressive effects of fluoxetine. We examined 5-HTT availability using positron emission tomography (PET) imaging with [11C]DASB in personality disordered patients with current physical intermittent explosive disorder (IED; n = 18), and healthy comparison participants (HC; n = 11), in the anterior cingulate cortex (ACC), amygdala (AMY), ventral striatum (VST), and midbrain (MID). After PET imaging, IED patients were treated with fluoxetine 20mg daily (n = 9) or placebo (n = 6) for 12weeks. Trait and state aggression, trait callousness, and childhood trauma were assessed. In IED patients, trait aggression was positively associated with [11C]DASB binding in the ACC and VST; covarying for trait callousness and childhood trauma enhanced these correlations. Baseline state aggression was positively correlated with ACC [11C]DASB in IED patients. Greater baseline VST [11C]DASB binding predicted greater decreases in state aggression with fluoxetine treatment. Consistent with prior reports, ACC 5-HTT is related to trait aggression, and adjusting for factors related to proactive (callousness) and reactive (childhood trauma) aggression subtypes further resolves this relationship. Novel findings of the study include a better understanding of the association between regional 5-HTT availability and state aggression, and the involvement of VST 5-HTT with trait aggression, and with the anti-aggressive effects of fluoxetine.

HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls.

Alterations of hypothalamic-pituitary-adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = -0.49, p = 0.009). The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.

Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy

Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

Regulation of social hierarchy learning by serotonin transporter availability

Learning one’s status in a group is a fundamental process in building social hierarchies. Although animal studies suggest that serotonin (5-HT) signaling modulates learning social hierarchies, direct evidence in humans is lacking. Here we determined the relationship between serotonin transporter (SERT) availability and brain systems engaged in learning social ranks combining computational approaches with simultaneous PET-fMRI acquisition in healthy males. We also investigated the link between SERT availability and brain activity in a non-social control condition involving learning the payoffs of slot machines. Learning social ranks was modulated by the dorsal raphe nucleus (DRN) 5-HT function. BOLD ventral striatal response, tracking the rank of opponents, decreased with DRN SERT levels. Moreover, this link was specific to the social learning task. These findings demonstrate that 5-HT plays an influence on the computations required to learn social ranks.

In vivo correlation of serotonin transporter and 1B receptor availability in the human brain: a PET study

Synaptic serotonin levels in the brain are regulated by active transport into the bouton by the serotonin transporter, and by autoreceptors, such as the inhibitory serotonin (5-HT) 1B receptor which, when activated, decreases serotonin release. Animal studies have shown a regulatory link between the two proteins. Evidence of such coupling could translate to an untapped therapeutic potential in augmenting the effect of selective serotonin reuptake inhibitors through pharmacological modulation of 5-HT1B receptors. Here we will for the first time in vivo examine the relationship between 5-HT1B receptors and serotonin transporters in the living human brain. Seventeen healthy individuals were examined with PET twice, using the radioligands [11C]AZ10419369 and [11C]MADAM for quantification of the 5-HT1B receptor and the 5-HT transporter, respectively. The binding potential was calculated for a set of brain regions, and the correlations between the binding estimates of the two radioligands were studied. [11C]AZ10419369 and [11C]MADAM binding was positively correlated in all examined brain regions. In most cortical regions the correlation was strong, e.g., frontal cortex, r(15) = 0.64, p = 0.01 and parietal cortex, r(15) = 0.8, p = 0.0002 while in most subcortical regions, negligible correlations was observed. Though the correlation estimates in cortex should be interpreted with caution due to poor signal to noise ratio of [11C]MADAM binding in these regions, it suggests a link between two key proteins involved in the regulation of synaptic serotonin levels. Our results indicate a need for further studies to address the functional importance of 5-HT1B receptors in treatment with drugs that inhibit serotonin reuptake.

Serotonin Modulates the Correlations between Obsessive-compulsive Trait and Heart Rate Variability in Normal Healthy Subjects: A SPECT Study with [123I]ADAM and Heart Rate Variability Measurement.

ObjectiveThe impact of serotonergic system on obsessive-compulsive disorder (OCD) is well studied. However, the correlation between OC presentations and autonomic nervous system (ANS) is still unclear. Furthermore, whether the correlation might be modulated by serotonin is also uncertain.MethodsWe recruited eighty-nine healthy subjects. Serotonin transporter (SERT) availability by [123I]ADAM and heart rate variability (HRV) tests were measured. Symptoms checklist-90 was measured for the OC presentations. The interaction between HRV and SERT availability were calculated and the correlation between HRV and OC symptoms were analyzed after stratified SERT level into two groups, split at medium.ResultsThe interactions were significant in the factors of low frequency (LF), high frequency (HF), and root mean square of successive differences (RMSSD). Furthermore, the significantly negative correlations between OC symptoms and the above HRV indexes existed only in subjects with higher SERT availability.ConclusionOC symptoms might be correlated with ANS regulations in subjects with higher SERT availability.

Serotonergic system in vivo with [11C]DASB PET scans in GTP-cyclohydrolase deficient dopa-responsive dystonia patients

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [11C]DASB PET scans, a marker of serotonin transporter availability, were performed. Ten DRD, 14 cervical dystonia patients and 12 controls were included. Univariate- and network-analysis did not show differences in binding between DRD patients compared to controls. Sleep disturbances were correlated with binding in the dorsal raphe nucleus (all participants: rs = 0.45, p = 0.04; patients: rs = 0.64, p = 0.05) and participants with a psychiatric disorder had a lower binding in the hippocampus (all participants: p = 0.00; patients: p = 0.06). Post-hoc analysis with correction for psychiatric co-morbidity showed a significant difference in binding in the hippocampus between DRD patients and controls (p = 0.00). This suggests that psychiatric symptoms might mask the altered serotonergic metabolism in DRD patients, but definite conclusions are difficult as psychiatry is considered part of the phenotype. We hypothesize that an imbalance between different neurotransmitter systems is responsible for the non-motor symptoms, and further research investigating multiple neurotransmitters and psychiatry in DRD is necessary.

Accelerated HF-rTMS Modifies SERT Availability in the Subgenual Anterior Cingulate Cortex: A Canine [11C]DASB Study on the Serotonergic System.

Repetitive transcranial magnetic stimulation (rTMS) is thought to partly exert its antidepressant action through the serotonergic system. Accelerated rTMS may have the potential to result in similar but faster onset of clinical improvement compared to the classical daily rTMS protocols, but given that delayed clinical responses have been reported, the neurobiological effects of accelerated paradigms remain to be elucidated including on this neurotransmitter system. This sham-controlled study aimed to evaluate the effects of accelerated high frequency rTMS (aHF-rTMS) over the left frontal cortex on the serotonin transporter (SERT) in healthy beagle dogs. A total of twenty-two dogs were randomly divided into three unequal groups: five active stimulation sessions (five sessions in one day, n = 10), 20 active stimulation sessions (five sessions/day for four days, n = 8), and 20 sham stimulation sessions (five sessions/day for four days, n = 4). The SERT binding index (BI) was obtained at baseline, 24 h post stimulation protocol, one month, and three months post stimulation by a [11C]DASB PET scan. It was found that one day of active aHF-rTMS (five sessions) did not result in significant SERT BI changes at any time point. For the 20 sessions of active aHF-rTMS, one month after stimulation the SERT BI attenuated in the sgACC. No significant SERT BI changes were found after 20 sessions of sham aHF-rTMS. A total of four days of active aHF-rTMS modified sgACC SERT BI one month post-stimulation, explaining to some extent the delayed clinical effects of accelerated rTMS paradigms found in human psychopathologies.

Serotonin transporter is negatively associated with body mass index after glucose loading in humans.

Serotonin transporter (SERT) is a presynaptically localized membrane protein that regulates the serotonin transmission via its reuptake of released serotonin. We hypothesized that glucose loading may change SERT availability from brainstem in humans. An intravenous bolus injection of 18F-FP-CIT was administered after the infusion of glucose or placebo (normal saline), and the emission data were acquired over 90 mins in 33 healthy nonobese subjects. For a volume-of-interest-based analysis, an atlas involving midbrain, and pons was applied. SERT availability, binding potential (BPND), were measured via the simplified reference tissue method with a reference of cerebellum. For a voxel-based analysis, statistical parametric mapping 12 was used with parametric BPND images. BPNDs from midbrain (p=0.8937), and pons (p=0.1115) were not different between glucose and placebo loading. Both of BPNDs from midbrain after glucose, and placebo loading were negatively correlated with body mass index (BMI). BMI showed a trend of negative correlation with glucose-loaded BPND from pons, whereas, placebo-loaded BPNDs from pons did not show any significant association with BMI. In conclusion, SERT availability was negatively correlated with BMI after glucose loading in humans. SERT might have a role in eating behavior through the action of insulin. Further studies are needed to elucidate the underlying mechanism of this phenomenon.

Association Between Lack of Insight and Prefrontal Serotonin Transporter Availability in Antipsychotic-Free Patients with Schizophrenia: A High-Resolution PET Study with [11C]DASB.

BackgroundPrevious studies suggested a link between serotonergic neurotransmission and impaired insight in schizophrenia. In this study, we examined the relationship between serotonin transporter (SERT) availability in regions of the prefrontal cortex (dorsolateral, ventrolateral, ventromedial, and orbitofrontal cortices) and insight deficits in antipsychotic-free patients with schizophrenia using high-resolution positron emission tomography (PET) with [11C]DASB.MethodsNineteen patients underwent [11C]DASB PET and 7-Tesla magnetic resonance imaging scans. To assess SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. Patients’ level of insight was assessed using the Insight and Treatment Attitude Questionnaire (ITAQ). The relationship between ITAQ scores and [11C]DASB BPND values was examined using the region-of-interest (ROI)- and voxel-based analyses with relevant variables as covariates. The prefrontal cortex and its four subregions were selected as a priori ROIs since the prefrontal cortex has been implicated as the critical neuroanatomical substrate of impaired insight in schizophrenia.ResultsThe ROI-based analysis revealed that the ITAQ illness insight dimension had significant negative correlations with the [11C]DASB BPND in the left dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ treatment insight dimension had significant negative correlations with the [11C]DASB BPND in the bilateral dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ total score showed significant negative correlations with the [11C]DASB BPND in the bilateral prefrontal cortex and three subregions (dorsolateral, ventrolateral, and orbitofrontal cortices). A supplementary voxel-based analysis corroborated a significant negative association between the ITAQ score and the [11C]DASB BPND in the prefrontal cortices.ConclusionOur study provides in vivo evidence of significant negative correlations between insight deficits and prefrontal SERT availability in patients with schizophrenia, suggesting significant involvement of prefrontal serotonergic signaling in impaired insight, one of the core symptoms of schizophrenia.

Positron emission tomography imaging of serotonin degeneration and beta-amyloid deposition in late-life depression evaluated with multi-modal partial least squares

Depression in late-life is associated with increased risk of cognitive decline and development of all-cause dementia. The neurobiology of late-life depression (LLD) may involve both neurochemical and neurodegenerative mechanisms that are common to depression and dementia. Transgenic amyloid mouse models show evidence of early degeneration of monoamine systems. Informed by these preclinical data, the hypotheses were tested that a spatial covariance pattern of higher beta-amyloid (Aβ) and lower serotonin transporter availability (5-HTT) in frontal, temporal, and parietal cortical regions would distinguish LLD patients from healthy controls and the expression of this pattern would be associated with greater depressive symptoms. Twenty un-medicated LLD patients who met DSM-V criteria for major depression and 20 healthy controls underwent PET imaging with radiotracers for Aβ ([11C]-PiB) and 5-HTT ([11C]-DASB). A voxel-based multi-modal partial least squares (mmPLS) algorithm was applied to the parametric PET images to determine the spatial covariance pattern between the two radiotracers. A spatial covariance pattern was identified, including higher Aβ in temporal, parietal and occipital cortices associated with lower 5-HTT in putamen, thalamus, amygdala, hippocampus and raphe nuclei (dorsal, medial and pontine), which distinguished LLD patients from controls. Greater expression of this pattern, reflected in summary 5-HTT/Aβ mmPLS subject scores, was associated with higher levels of depressive symptoms. The mmPLS method is a powerful approach to evaluate the synaptic changes associated with AD pathology. This spatial covariance pattern should be evaluated further to determine whether it represents a biological marker of antidepressant treatment response and/or cognitive decline in LLD patients.