High-dose fenfluramine administration decreases serotonin transporter binding, but not serotonin transporter protein levels, in rat forebrain

Administration of D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) can produce long-lasting decreases in serotonin transporter (SERT) binding and tissue levels of serotonin (5-HT) in rat forebrain. These changes have been viewed as evidence for 5-HT neurotoxicity, but no studies have measured SERT protein levels. In the present study, we determined the effect of high-dose D-FEN or PCA, administered according to a "neurotoxic" dosing regimen, on the density of SERT sites using ligand binding methods and on SERT protein levels using Western blots. Rats were sacrificed 2 days and 2 weeks after administration of drug or saline. The density of SERT was determined in homogenates of caudate and whole brain minus caudate. D-FEN and PCA decreased SERT binding by 30-60% in both tissues and at both time points. Similarly, D-FEN and PCA administration profoundly decreased tissue 5-HT and 5-HIAA in frontal cortex. Despite the large decreases in SERT binding and depletion of tissue 5-HT that occurred with D-FEN administration, SERT protein expression, as determined by Western blot analysis, did not change in either tissue or time point. PCA administration decreased SERT protein by about 20% only at the 2-day point in the caudate. Drug treatments did not change expression of glial fibrillary acidic protein (GFAP), a hallmark indicator of neuronal damage, in whole brain minus caudate in the 2-week group. These results support the hypothesis that decreases in tissue 5-HT and SERT binding sites induced by D-FEN and PCA reflect neuroadaptive changes, rather than neurotoxic effects.     

Amygdala serotonin transporters in alcoholics measured by whole hemisphere autoradiography

BACKGROUND: A dysfunction in brain serotonin turnover is a well-established factor associated with the impulsive and sociopathic behavior in alcoholics. The conjuncted alterations in functioning of serotonin transporter (SERT) may play a role in the regulation of emotional balance, judgement, and the adverse behavioral effects of ethanol misuse. These traits may be related to serotonergic regulation in the amygdala and prefrontal cortex. METHODS: The binding of [(3)H]citalopram to SERT was evaluated in the amygdala of Cloninger type 1 and 2 alcoholics (n = 17), and nonalcoholic control subjects (n = 10) by postmortem whole-hemisphere autoradiography. RESULTS: The SERT binding was substantially lower in the dorsal amygdala in alcoholic subjects when compared with the controls (-28%, effect size 1.26, P = 0.016). In secondary analysis, this reduction was observed in both alcoholic subgroups (-26% in type 1 alcoholics, and -33% in type 2 alcoholics). In ventral amygdala, no alteration was observed. There were significant correlations between the SERT binding in dorsal amygdala and in previous results from frontal cortical areas in alcoholics, depending on the type of alcoholic. CONCLUSIONS: These results suggest that SERT binding in the amygdala, as well as the differential regulation of the SERT in amygdala and frontal cortex in alcoholics may help to explain the dysfunctional regulation of emotions in alcoholics.     

Elevated serotonin transporter binding in depressed patients with Parkinson's disease: A preliminary PET study with [11C]DASB

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early‐stage PD patients and in seven healthy matched‐control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [¹¹C]DASB. Depressed PD patients displayed a wide‐spread increase (8–68%) in [¹¹C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices. Elevated [¹¹C]DASB binding was positively correlated with depressive symptoms but not with disease severity or duration. Compatible with recent PET/[¹¹C]DASB findings in major depression, the present preliminary data suggest that increased [¹¹C]DASB binding, possibly reflecting greater serotonin transporter density (up‐regulation), might be a pathological feature of depression in Parkinson's disease—and possibly a characteristic of depressive illness in general. © 2008 Movement Disorder Society     

Preserved serotonin transporter binding in de novo Parkinson’s disease: negative correlation with the dopamine transporter

Recent imaging and neuropathological studies indicate reduced serotonin transporter (SERT) in advanced Parkinson’s disease (PD). However, data on SERT in early PD patients are sparse. Following the hypothesis that the serotonergic system is damaged early in PD, the aim of our study was to investigate SERT availability by means of PET imaging. Since the loss of dopaminergic neurons is the pathologic hallmark of PD and SERT might be associated with psychiatric co-morbidity, we further sought to correlate SERT availability with the availability of dopamine transporter (DAT) and depressive or motor symptoms in early PD. We prospectively recruited nine early PD patients (4 female, 5 male; 42–76 years) and nine age matched healthy volunteers (5 female, 4 male; 42–72 years). Diagnosis of PD was confirmed by the UK brain bank criteria and DAT imaging. SERT availability was measured by means of [¹¹C]DASB PET. For neuropsychiatric assessment done on the day of PET we applied UPDRS parts I, II and III, Beck’s Depression Inventory, Hamilton Rating Scale for Depression, Mini-Mental State Examination and Demtect. SERT was not reduced in any of 14 investigated regions of interest in the nine PD patients compared to healthy controls (p > 0.13). SERT was negatively associated with DAT in the striatum (r = −0.69; p = 0.04) but not within the midbrain. There was no correlation of SERT availability with depressive symptoms. No alteration of SERT binding in our patients suggests that the serotonergic system is remarkably preserved in early PD. Correlation with DAT might point to a compensatory regulation of the serotonergic system in early stages of PD.     

ADAM is an effective tool for in vivo study of serotonergic function: validation in rat models

ADAM, 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine, is a recently described SPECT tracer for exploration of the serotonin transporter. We evaluated its potential to detect abnormalities in serotonergic function in the rat using 1) a model of serotonergic neuron lesion induced with 5,7-dihydroxytryptamine (5,7-DHT), and 2) experimental induction of acute decrease in endogenous brain serotonin levels. Cerebral biodistribution studies of [125I]ADAM were performed in normal conditions, in 5,7-DHT-lesioned rats, and after acute serotonin depletion obtained with p-chlorophenylalanine (pCPA). Around 50% reduction in accumulation of ADAM was observed in the hypothalamus and hippocampus 3 weeks after lesion of serotonergic neurons, whereas a more modest decrease of 15-30% occurred in the thalamus, frontal cortex, and striatum. This demonstrated the ability of the tracer to detect serotonergic neuron loss in vivo. After inducing acute 5-HT depletion with pCPA, we observed an increase in in vivo [125I]ADAM binding in all brain areas studied. The higher in vivo binding of [125I]ADAM in pCPA-treated rats than in controls was mainly due to an increase in specific binding to the SERT, as demonstrated by greatly reduced binding in the presence of a saturating dose of paroxetine. This may indicate in vivo competition between ADAM and 5-HT for binding to the SERT. The present findings thus demonstrate that ADAM is a specific SERT radioligand which can be used for in vivo study of central serotonin systems, and supports its use as a tracer for SPECT studies in human disorders involving dysfunction of serotonergic neurotransmission.     

Excess of serotonin affects neocortical pyramidal neuron migration

The serotonin transporter (SERT) is a key molecule involved in the homeostasis of extracellular levels of serotonin and is regulated developmentally. Genetic deletion of SERT in rodents increases extracellular levels of serotonin and affects cellular processes involved in neocortical circuit assembly such as barrel cortex wiring and cortical interneuron migration. Importantly, pharmacological blockade of SERT during brain development leads to phenotypes relevant to psychiatry in rodents and to an increased risk for autism spectrum disorders in humans. Furthermore, developmental adversity interacts with genetically-driven variations of serotonin function in humans and nonhuman primates to increase the risk for a variety of stress-related phenotypes. In this study, we investigate whether an excess of serotonin affects the migration of neocortical pyramidal neurons during development. Using in utero electroporation combined with time-lapse imaging to specifically monitor pyramidal neurons during late mouse embryogenesis, we show that an excess of serotonin reversibly affects the radial migration of pyramidal neurons. We further identify that the serotonin receptor 5-HT₆ is expressed in pyramidal neuron progenitors and that 5-HT₆ receptor activation replicates the effects of serotonin stimulation. Finally, we show that the positioning of superficial layer pyramidal neurons is altered in vivo in SERT knockout mice. Taken together, these results indicate that a developmental excess of serotonin decreases the migration speed of cortical pyramidal neurons, affecting a fundamental step in the assembly of neural circuits. These findings support the hypothesis that developmental dysregulation of serotonin homeostasis has detrimental effects on neocortical circuit formation and contributes to increased vulnerability to psychiatric disorders.     

Non‐amines,drugs without an amine nitrogen,potently block serotonin transport: Novel antidepressant candidates?

The serotonin transporter (SERT) is a principal site of action of therapeutic antidepressants in the brain. Without exception, these inhibitors of serotonin transport contain an amine nitrogen in their structure. We previously demonstrated that novel compounds without an amine nitrogen in their structure (non-amines), blocked dopamine transport in cells transfected with the human dopamine transporter. The present study investigated whether, in the absence of an amine nitrogen, certain non-amines bind selectively to the SERT and block the transport of serotonin. At 10 microM concentration, select non-amines displayed no, or little, affinity for 9 serotonin, 5 dopamine, 7 adrenergic, 5 muscarinic cholinergic, 3 opiate and histamine receptors. The affinities of non-amines for [(3)H]citalopram binding sites on the SERT and their potencies for blocking [(3)H]serotonin transport were measured in cloned human SERT stably or transiently expressed in HEK-293. Whether oxa- or carba-based, non-amines bound to [(3)H]citalopram-labeled sites and blocked [(3)H]serotonin transport in the low nanomolar range, at values equal to or higher than those of some conventional antidepressants. A non-amine, O-1809, was 99-fold more selective for the serotonin over the dopamine transporter. As substituents on the aromatic ring of non-amines confer high affinity for the SERT, we investigated the hypothesis that aromatic-aromatic interactions may contribute significantly to non-amine/transporter association. A SERT mutant was produced in which a highly conserved aromatic amino acid, phenylalanine 548, was replaced by an alanine (F548A). Although the affinities of several non-amines were unchanged in the mutant SERT, the affinity of imipramine was decreased, revealing possible differences in amine and non-amine binding domains on the SERT. The similar affinities of non-amines and conventional antidepressant drugs for the SERT support the view that an amine nitrogen is not essential for drugs to block serotonin transport with high affinity. Non-amines open avenues for developing a new generation of antidepressants.     

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.     

Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors.

BACKGROUND: Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations. METHODS: Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment). RESULTS: In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response. CONCLUSIONS: Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.     

Serotonin‐transporter‐linked promoter region polymorphism and serotonin transporter binding in drug‐naïve patients with major depression

Aims: Both the serotonin transporter and its genetic regulation by the serotonin‐transporter‐linked polymorphic region have a role in the pathophysiology of depression. Most of the previous studies have found no influence of serotonin‐transporter‐linked polymorphic region allelic variation on serotonin transporter binding in healthy controls or patients with major depression. Due to the inconsistency of the previous findings, we compared single photon emission computed tomography imaging with the serotonin‐transporter‐linked polymorphic region genotype in patients with major depressive disorder. Methods: A total of 23 drug‐naïve patients with major depressive disorder were genotyped and brain imaged with ^[123I]nor‐β‐CIT single photon emission computed tomography. The severity of depression was evaluated with the 17‐item Hamilton depression rating scale. Results: Depressed patients homozygous for the short allele had lower ^[123I]nor‐β‐CIT binding in the medial prefrontal cortex, but not in the midbrain, compared with the other genotypes. Conclusion: The decreased medial prefrontal cortical serotonin transporter binding in the patients homozygous for the short allele may be linked to altered function of the serotonin‐transporter‐linked polymorphic region gene expressed in these patients, especially in the medial prefrontal cortex.     

Serotonin transporter in Parkinson's disease: A meta‐analysis of positron emission tomography studies

Positron emission tomography (PET) is a powerful analytical tool for in vivo molecular imaging of the human brain. Over the past years, a number of PET studies imaging the serotonin transporter (SERT) have been used and provided evidence for the key role of serotonergic pathology in patients with Parkinson's disease (PD). Here, we review the role of SERT in the development of motor and nonmotor complications in patients with PD, and we performed a meta‐analysis to identify the patterns of SERT pathology and the relevance to symptoms. Consistent SERT pathology in raphe nuclei, striatum, thalamus, and hypothalamus and associations with aging, PD progression, development of dyskinesias, and cognitive decline were observed. Ann Neurol 2017;81:171–180     

A study of the serotonin transporter in the prefrontal cortex in late-life depression and Alzheimer's disease with and without depression

Previous studies investigating the serotonin transporter (SERT) in depression have been inconsistent and included a large proportion of subjects who had committed suicide. In Alzheimer's disease studies have generally reported a reduction in SERT density but have not compared Alzheimer's disease subjects with and without comorbid major depression. We conducted a post mortem study of SERT density in the prefrontal cortex in normal elderly, a group of elderly depressed subjects and in Alzheimer's disease subjects with and without major depression. A post mortem study comparing SERT density in the prefrontal cortex in elderly controls (n = 10), subjects with major depression (n = 8) and subjects with Alzheimer's disease with (n = 9) and without (n = 5) comorbid major depression. We used autoradiography to measure the density of [3H]CN-IMI binding (non-specific binding determined with citalopram) to the SERT in the prefrontal cortex. We found a marked reduction in specific SERT binding in the prefrontal cortex in Alzheimer's disease subjects compared with both control (P = 0.002) and depressed subjects (P = 0.004) but no difference in SERT binding between depressed and control subjects or between Alzheimer's disease subjects with and without depression. Our study confirms previous reports of a reduction in SERT binding in Alzheimer's disease but indicates this reduction is not greater in Alzheimer's disease subjects who also have had major depression. In a group of subjects more typical of late-life depression we did not identify any alterations in SERT density.     

Distinct effects of sleep deprivation on binding to norepinephrine and serotonin transporters in rat brain

There is evidence to suggest that the antidepressant activity of sleep deprivation may be due to an enhancement of serotonergic and/or noradrenergic neurotransmission in brain. In the present study we examined the possibility that such changes may occur at the level of the norepinephrine (NET) and serotonin (SERT) and transporters. Rats were deprived of sleep for 96 h using the modified multiple platform method and then sacrificed for autoradiographic assessments of NET and SERT binding throughout the brain. [3H]Nisoxetine binding to the NE transporter was generally decreased in 44 of 45 areas examined, with significant reductions occurring in the anterior cingulate cortex (-16%), endopiriform n. (-18%), anterior olfactory n. (-19%), glomerular layer of olfactory bulb (-18%), ventral pallidum (-14%), medial preoptic area (-16%), retrochiasmatic/arcuate hypothalamus (-18%), anteromedial thalamic n. (-15%), and rostral raphe (-17%). In contrast, SERT binding measured with [11C]DASB showed no clear directional trends in 61 brain areas examined, but was significantly reduced in subdivisions of the anterior olfactory nucleus (-22%) and substantia nigra (-18%). Thus, sleep deprivation induced widespread decreases in NET binding, and fewer and well-localized decreases in SERT binding. Significant down-regulation in one brain region, the anterior olfactory nucleus, was observed in the case of both transporters. These results suggest that mechanisms involved in the antidepressant action of sleep deprivation may involve generalized NET down-regulation as well as decreased SERT binding in specific areas. Insofar as these changes may be associated with increased levels of serotonin (5-HT) and norepinephrine (NE) in the synapse, they suggest that sleep deprivation may share some basic mechanisms of action with several current antidepressant medications.     

Lower serotonin transporter binding in caudate in alcoholics

Dorsal striatum is regulated by the serotonergic system, and it is a brain area with a role in the development of obsessive thought patterns, which may be related to addiction. In this study, possible alterations of [(3)H]citalopram binding to serotonin transporter (SERT) were evaluated in the dorsal striatum of Cloninger type 1 and 2 alcoholics, and nonalcoholic control subjects by postmortem whole-hemisphere autoradiography in humans. The SERT binding was significantly lower (-26%, effect size 1.74) in the caudate body of alcoholics. The SERT binding tended to be lower also in the other parts of the dorsal striatum in alcoholics, but the results did not reach significance. In addition, there was a significant positive correlation, especially in type 1 alcoholics, between the SERT binding in the body of the caudate and in the perigenual anterior cingulate cortex, an area in which the SERT binding has been shown to be lower among alcoholics. These results give preliminary evidence to suggest that the SERT binding in the dorsal striatum may be lower in alcoholics, and that the serotonergic system may be affected in cortical and striatal areas simultaneously. The cortico-striatal-thalamic axis may have an important role in fully developed addictions and the characterization of these correlations within the serotonergic system may lead to a better understanding of the anatomical dynamics underlying the neurochemistry of alcoholism.     

Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(11)C]McN 5652.

BACKGROUND: Serotonergic abnormalities have been hypothesized to contribute to obsessive-compulsive disorder (OCD). This study examined whether brain serotonin transporter (SERT) availability is altered in OCD using positron emission tomography (PET) and the SERT PET radiotracer [(11)C]McN 5652. METHODS: Eleven OCD subjects, free of psychiatric medications and comorbid depression, and 11 matched healthy control subjects underwent PET scans following injection of [(11)C]McN 5652 and magnetic resonance imaging (MRI) scans. Total distribution volumes (V(T)) were derived by kinetic analysis (one tissue compartment model) using the arterial input function. Two measures of SERT availability were computed: binding potential (BP) and specific to nonspecific partition coefficient (V(3)"). Groups were compared using region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps; ROIs were selected based on their relatively high SERT density and included subcortical (dorsal caudate, dorsal putamen, ventral striatum, midbrain, thalamus) and limbic (hippocampus, amygdala, anterior cingulate cortex) regions. RESULTS: No significant group differences were observed in [(11)C]McN 5652 BP or V(3)" in the ROIs. No significant group differences were detected in the voxelwise analysis of BP or V(3)" maps. CONCLUSIONS: OCD without comorbid depression, may not be associated with major changes in SERT availability in subcortical and limbic regions.     

S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats

The [(18)F]fluoromethyl analog of (+)-McN5652 ([(18)F]FMe-McN) for imaging serotonin transporter (SERT) with positron emission tomography (PET) has recently been synthesized. We describe here the biological evaluation of [(18)F]FMe-McN in rats. Biodistribution studies of [(18)F]FMe-McN in rat brain ex vivo after an intravenous injection showed a high accumulation of radioactivity in the regions rich in SERT, such as raphe nuclei, hypothalamus, thalamus, substantia nigra, locus coeruleus, and amygdala. Region-to-cerebellum ratios reached a maximum value of 9 in raphe nuclei within 3.5 h after administration. The specificity and selectivity of [(18)F]FMe-McN binding to SERT was studied by preinjecting blocking doses of serotonin, norepinephrine, and dopamine transporter inhibitors. Fluoxetine, a specific inhibitor for SERT, decreased the specific binding of [(18)F]FMe-McN in raphe nuclei by 91 +/- 4%; in other regions rich in SERT, similar results were obtained. GBR12909 and nisoxetine, selective inhibitors for dopamine transporter (DAT) and norepinephrine transporter (NET), respectively, showed no significant effects on the uptake of [(18)F]FMe-McN. Our studies show that [(18)F]FMe-McN has a clear potential as a tracer for studies with PET of SERT function in humans.     

5HTTLPR polymorphism and enlargement of the pulvinar: unlocking the backdoor to the limbic system.

BACKGROUND: The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. METHODS: Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. RESULTS: Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. CONCLUSIONS: The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.     

High resolution micro-SPECT scanning in rats using 125I β-CIT: Effects of chronic treatment with carbamazepine

Purpose:  Carbamazepine (CBZ) is a first-line antiepileptic agent with mood-stabilizing effects in bipolar disorder. It has been reported to influence extracellular concentrations of serotonin and dopamine, suggesting an interaction with monoamine transporters. We have investigated this effect using in vivo single photon emission computed tomography (SPECT) in rats.
Methods:  Adult male rats received 3 mg/kg/h CBZ via mini-osmotic pump. After 14 days continuous treatment, animals underwent two consecutive SPECT scans, using ¹²⁵I β-CIT as a radiotracer to label serotonin transporter (SERT) and dopamine transporter (DAT) sites in the brain. Pharmacologic distinction was enabled by ¹²⁵I β-CIT SPECT imaging in rats acutely exposed to the serotonin and dopamine transporter inhibitors, fluoxetine and GBR12909. The interaction between CBZ and ¹²⁵I β-CIT binding to SERT and DAT was investigated using in vitro autoradiography.
Results:  Carbamazepine (10 μ m ) did not affect binding of ¹²⁵I β-CIT to isolated rat brain slices, thereby excluding a direct effect on ligand binding to SERT and DAT. SPECT studies with fluoxetine and GBR12909 highlighted SERT binding in thalamus, hippocampus, centromedial nuclei, and occipital cortex, and DAT binding in the caudate. Prolonged treatment with CBZ failed to influence ¹²⁵I β-CIT binding to either SERT or DAT in any of the brain regions examined.
Discussion:  This study employed the novel technique of small animal SPECT imaging to investigate the effects of CBZ on monoamine transporters in rat brain. Following prolonged treatment, the drug was without effect on SERT or DAT availability. The mechanism by which CBZ exerts its mood stabilizing effects remains elusive.     

Midbrain serotonin transporters in de novo and L‐DOPA‐treated patients with early Parkinson’s disease – a [123I]‐ADAM SPECT study

Background: Dopaminergic availability is known to linearly decline in Parkinson’s disease (PD). In contrast, temporal characteristics of serotonergic markers like the serotonin transporter (SERT) in relation to clinical staging of PD and dopaminergic cell loss are less clear. This study investigated SERT availability using [¹²³I]‐ADAM and single‐photon emission tomography (SPECT) in drug‐naive, de novo patients, i.e., in a PD stage where dopaminergic decline starts to lead to the occurence of the characteristic motor symptoms. Methods: Nine de novo patients with PD and 9 age‐matched healthy controls were studied. Measurements were repeated after 3 months of levodopa treatment in patients with PD, and dopaminergic transporter (DAT) binding was examined at baseline using [¹²³I]‐FP‐CIT SPECT. Results: No alterations of SERT availability were found between groups, and neither correlation between SERT and DAT nor effects of levodopa treatment on SERT was found in patients with PD. Conclusions: These preliminary findings indicate that midbrain SERT is preserved in unmedicated patients at this early stage of PD, supporting the view that serotonergic decline temporally follows dopaminergic cell loss.