Serotonin Transporter Availability Research Articles

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-[18F]-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-[18F]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

Back to table of contents Previous article Next article Journal DigestFull AccessJournal Digest: CBT With Cardiac Rehab, PMDD Neurochemistry, and MoreNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:24 Mar 2023https://doi.org/10.1176/appi.pn.2023.04.3.14Antidepressants May Induce Resistance to AntibioticsiStock/SproetniekAntidepressants can induce bacterial resistance to antibiotics, according to a report in PNAS.“While antibiotics are acknowledged as the major driver of increasing antibiotic resistance, little attention is paid to the contribution of antidepressants in this process,” wrote the study authors from the University of Queensland and colleagues.For the study, the researchers exposed E. coli bacteria to five commonly prescribed antidepressants: agomelatine, bupropion, duloxetine, escitalopram, and sertraline—each at five different concentrations (0.1, 1, 10, 50 and 100 mg/ml) for 60 days.After 60 days, exposure to all antidepressants was associated with increased growth of antibiotic-resistant bacteria at significantly faster rates compared with no exposure to antidepressants. Additionally, antibiotic resistance developed faster at higher doses.“Strikingly, the antidepressants sertraline and duloxetine at clinically relevant concentrations in colon (e.g., 50 mg/L) caused an effect after only 1 [day] of exposure,” the authors noted.After examining expression of genes and proteins in these bacteria, the researchers concluded that enhanced production of reactive oxygen molecules following exposure to antidepressants was associated with increased antibiotic resistance.“[O]ur findings highlight the need to re-evaluate the antibiotic-like side effects of antidepressants,” the researchers wrote.Wang Y, Yu Z, Ding P, et al. Antidepressants Can Induce Mutation and Enhance Persistence Toward Multiple Antibiotics. Proc Natl Acad Sci USA. 2023; 120(5): e2208344120. Poor Insight May Increase Risk of Relapse for Psychotic DepressioniStock/FG TradeSome research has shown that people with psychotic depression who have poor insight about their delusions are less likely to achieve depression remission. A report in the Journal of Affective Disorders now suggests such poor insight does not increase the risk of relapse if remission is achieved.Investigators at the University of Toronto and colleagues reviewed data from the STOP-PD II trial, which evaluated the efficacy of a combination of sertraline and olanzapine versus sertraline only for treating psychotic depression in adults. STOP-PD II had three phases: acute, stabilization, and randomized continuation.For the acute phase, adults with psychotic depression received a combination of sertraline (150-200 mg/d) and olanzapine (15-20 mg/d) for up to 12 weeks. Participants who achieved remission (absence of delusions and hallucinations) were then eligible to enroll in an eight-week stabilization phase, where they continued on the same medication regimen. Participants who remained in remission during the stabilization phase were then randomized to continue taking the sertraline-olanzapine combination or switch to sertraline plus placebo; these participants were followed for up to 36 weeks. Patient insight into delusions was assessed at the beginning and end of the stabilization phase.A total of 126 participants entered the final phase of the trial; after 36 weeks, 67 remained in remission, 47 relapsed, and 12 left the study. The investigators found that neither the degree of insight at the start of follow-up nor the change in insight score during the stabilization phase of the trial was associated with relapse risk.“Although unanticipated, this finding can provide reassurance to clinicians that residual or reemergent insight impairment following acute treatment does not preclude patients from sustaining remission of psychotic depression,” the investigators wrote.Song J, Mulsant BH, Sanches M, et al. Residual or Re-emergent Impaired Insight Into Delusions Following Remission is Unrelated to Later Relapse During a Randomized Clinical Trial of Continuation Pharmacotherapy for Psychotic Depression - The STOP-PD II Study. J Affect Disord. 2023; 325: 29-34. Adjunct CBT Can Boost Cardiac Rehabilitation OutcomesiStock/bojanstoryAdding a few sessions of cognitive-behavioral therapy (CBT) to regular cardiac rehabilitation may reduce depression and anxiety symptoms in patients with heart disease. These findings come from a clinical study published in European Heart Journal.For the study, researchers at Bispebjerg and Frederiksberg Hospital in Copenhagen enrolled 147 adults (average age 54) who were recently diagnosed with coronary artery disease or valvular heart disease and were experiencing psychological distress (defined as a score of 8 or higher on the Hospital Anxiety and Depression Scale, or HADS). All participants received eight weeks of cardiac rehabilitation, which consisted of twice weekly exercise sessions along with education about heart disease, managing risk factors, dietary counseling, and more. Half of the participants also received five, two-hour sessions of group CBT delivered by a trained cardiac nurse.After three months, HADS scores (which averaged 17 at baseline) dropped by eight points among the participants who received CBT in combination with cardiac rehabilitation; in the group receiving cardiac rehabilitation only, these scores dropped by four points. The differences between the two groups remained after six months.The adults who received CBT also reported greater improvement in emotional quality of life at six months compared with those receiving cardiac rehabilitation alone. The adults in both groups reported similar physical quality of life.After 12 months, fewer adults receiving CBT were readmitted to a hospital for a cardiovascular issue than those receiving rehabilitation alone (25% vs. 49%, respectively).“Brief group cognitive-behavioral therapy delivered by cardiac nurses may reduce psychological distress and morbidity in the short term, and may be integrated with existing [cardiac rehabilitation] programmes,” the authors concluded.Holdgaard A, Eckhardt-Hansen C, Lassen CF, et al. Cognitive-Behavioural Therapy Reduces Psychological Distress in Younger Patients With Cardiac Disease: A Randomized Trial. Eur Heart J. 2023; 44(11):986-996. Autism Does Not Appear to Accelerate Cognitive AgingiStock/Yaraslau SaulevichGiven the cognitive symptoms associated with autism spectrum disorder (ASD), some researchers have hypothesized that adults with ASD may be prone to accelerated cognitive aging. A longitudinal study appearing in Psychiatry Research now questions this theory.“Even on cognitive domains where autistic adults generally seem to experience more difficulties compared to non-autistic adults (fluency, theory of mind), and on tasks where longitudinal changes were most prominent across groups (response speed, fluency, inhibition, verbal memory) no significant differences in cognitive change between those with and without an autism diagnosis were observed,” wrote the authors from the University of Amsterdam.The study involved adults aged 25 to 85 years, including 128 with ASD and 112 without ASD. These participants received a cognitive test battery multiple times over an average of 3.5 years. The tests assessed 15 different cognitive variables.Although the adults with ASD self-reported more cognitive difficulties at baseline, the researchers found age-related changes in cognition appeared similar in adults with and without ASD.“[D]ifferences in development in various cognitive domains observed in the first stages of life of autistic individuals do not seem to persist or retrace in later stages of life,” the authors wrote. Still, they cautioned that “careful interpretation of the current conclusions is essential, and more longitudinal research is key to understand cognitive decline in older autistic adults precisely, and more generally throughout the autistic population.”Torenvliet C, Groenman AP, Radhoe TA, et al. A Longitudinal Study on Cognitive Aging in Autism. Psychiatry Research. 2023; 321: 115063. PMDD Symptoms May Be Tied to Serotonin UptakeiStock/AndreusA brain imaging study suggests that women with premenstrual dysphoric disorder (PMDD) have more unused serotonin transporters during their premenstrual cycle than women without the disorder. This study, which was published in Biological Psychiatry, also showed that the number of available transporters correlated with the severity of depressive symptoms in the women with PMDD.Investigators at the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig, Germany, and colleagues conducted PET scans of 30 women with PMDD and 29 matched women without this disorder. All participants were scanned during both their premenstrual phase and preceding periovulatory phase and they completed mood and irritability assessments shortly before each scan.During periovulation, both groups of women showed similar levels of occupied versus available serotonin transporters in the midbrain. During the premenstrual phase, however, the number of available serotonin transporters increased by 18% in women with PMDD (indicating less serotonin movement across neural synapses) while it decreased by 10% in women without PMDD. Women with PMDD who experienced the greatest changes in serotonin transporter availability between the premenstrual and periovulatory phases also reported the greatest increases in depressive symptoms. There was no association between transporter availability and irritability scores.“These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients,” the authors wrote. “These neurochemical findings argue for systematic testing of presymptom-onset dosing of selective serotonin reuptake inhibitors or non-pharmacological strategies to augment extracellular serotonin in PMDD.”Sacher J, Zsido RG, Barth C, et al. Increase in Serotonin Transporter Binding in Patients with Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand PET Imaging Study. Biol Psychiatry. January 18, 2023. Online ahead of print. Psychotrauma Screen Trauma Screen Adapted for Use in IraniStock/FatCameraTrauma is a global issue and a public health concern. A multinational team led by investigators at Iran’s Kermanshah University of Medical Sciences has created and tested a Persian version of the Global Psychotrauma Screen (GPS)—a brief self-report instrument that screens for a range of trauma-related psychological symptoms.The GPS is a 22-item yes/no screen that assesses symptoms of posttraumatic stress disorder (PTSD), depression, anxiety, sleep problems, and dissociation, as well as risk and protective factors.“Kermanshah city, located in the western part of Iran, has experienced multiple wars over the past eight years, involving both airstrikes and ground battles. The area is also one of the most earthquake-prone areas of the world,” the investigators wrote in BMC Psychiatry. “Although several [PTSD] instruments exist in Iran, there is no brief screening tool available that assesses the wide range of psychological reactions to a potentially traumatic event.”The team first constructed a Persian-language version of the GPS with the aid of psychotrauma experts and 30 lay volunteers. The proposed screen was then tested alongside the PTSD Checklist for DSM-5 (PCL-5) and the General Health Questionnaire (GHQ) in 800 adults who had lived through the 2017 Kermanshah earthquake.A comparison of the three assessments suggested that the Persian GPS was consistent and reliable at measuring participants’ trauma symptoms, and that a score above nine suggests a possible PTSD diagnosis. They also found that 52% of the respondents scored above nine, highlighting the high degree of trauma in the region. ■Salimi Y, Hoeboer C, Motevalli Haghi SA, et al. Trauma and its Consequences in Iran: Cross-Cultural Adaption and Validation of the Global Psychotrauma Screen in a Representative Sample. BMC Psychiatry. 2023; 23(1): 65. ISSUES NewArchived

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.

Serotonin transporter availability, neurocognitive function and their correlation in abstinent 3,4-methylenedioxymethamphetamine users.

MDMA or Ecstasy has made a resurgence in popularity and the majority of users consist of teenagers and adolescents. Therefore, it is important to determine whether MDMA causes long-term damage and what this damage entails. There is an ongoing debate about possible neurocognitive changes in 3,4-methylenedioxymethamphetamine (MDMA) users related to MDMA's neurotoxic potential. Multiple neuroimaging studies have shown that Ecstasy use leads to lower serotonin transporter (SERT) availability in multiple brain regions. This may express itself in a loss of cognitive functions like memory, attention and executive function. However, there is increasing evidence reporting that MDMA's induced serotonergic adaptations are reversible over time. The question we thus address is whether the recovery of SERT function predicts a recovery of cognitive function. This review aims to investigate MDMA's long-term effects on SERT availability and cognitive functioning. A literature search was performed in PubMed. Studies that investigated the effects of MDMA on both SERT availability and cognitive performance were eligible for inclusion. SERT availability positively correlated with time of abstinence, whereas memory performance did not show this correlation, but remained impaired in MDMA users. No significant correlation between SERT availability and memory function was found (r=0.232, p=0.581; r=0.176, p=0.677). The main findings of this review are that MDMA-use leads to an acute decrease in SERT availability and causes an impairment in cognitive functions, mostly memory. However, SERT availability recovers with sustained abstinence while memory function does not. This suggests that SERT availability is not a biomarker for MDMA-induced cognitive impairment and likely also not for MDMA-induced neurotoxicity.

Striatal and prefrontal D2R and SERT distributions contrastingly correlate with default-mode connectivity

Although brain research has taken important strides in recent decades, the interaction and coupling of its different physiological levels is still not elucidated. Specifically, the molecular substrates of resting-state functional connectivity (rs-FC) remain poorly understood. The aim of this study was elucidating interactions between dopamine D2 receptors (D2R) and serotonin transporter (SERT) availabilities in the striatum (CPu) and medial prefrontal cortex (mPFC), two of the main dopaminergic and serotonergic projection areas, and the default-mode network. Additionally, we delineated its interaction with two other prominent resting-state networks (RSNs), the salience network (SN) and the sensorimotor network (SMN).To this extent, we performed simultaneous PET/fMRI scans in a total of 59 healthy rats using [11C]raclopride and [11C]DASB, two tracers used to image quantify D2R and SERT respectively. Edge, node and network-level rs-FC metrics were calculated for each subject and potential correlations with binding potentials (BPND) in the CPu and mPFC were evaluated.We found widespread negative associations between CPu D2R availability and all the RSNs investigated, consistent with the postulated role of the indirect basal ganglia pathway. Correlations between D2Rs in the mPFC were weaker and largely restricted to DMN connectivity. Strikingly, medial prefrontal SERT correlated both positively with anterior DMN rs-FC and negatively with rs-FC between and within the SN, SMN and the posterior DMN, underlining the complex role of serotonergic neurotransmission in this region.Here we show direct relationships between rs-FC and molecular properties of the brain as assessed by simultaneous PET/fMRI in healthy rodents. The findings in the present study contribute to the basic understanding of rs-FC by revealing associations between inter-subject variances of rs-FC and receptor and transporter availabilities. Additionally, since current therapeutic strategies typically target neurotransmitter systems with the aim of normalizing brain function, delineating associations between molecular and network-level brain properties is essential and may enhance the understanding of neuropathologies and support future drug development.

The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity

Background and aimsSerotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. MethodsIn this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. ResultsAs compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. ConclusionLean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.