Serotonin Transporter Density Research Articles

Substituted Amphetamines That Produce Long‐Term Serotonin Depletion in Rat Brain (“Neurotoxicity”) Do Not Decrease Serotonin Transporter Protein Expression

Administration of high-dose D-fenfluramine (D-FEN) or parachloroamphetamine (PCA) produces 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 few studies have measured SERT protein levels. Thus, 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 to 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 D-FEN- and PCA-induced decreases in tissue 5-HT and SERT binding sites reflect neuroadaptive changes rather than neurotoxic effects.

P.3.026 Tiagabine as an efficacious augmentation therapy to selective serotonin reuptake inhibitors in patients with generalized anxiety disorder

The serotonergic system and the orbitofrontal cortex have been consistently implicated in the pathophysiology of obsessive compulsive disorder. Yet, the relations between these two systems and the ways they interact in producing obsessions and compulsions are poorly understood. The present study tested the hypothesis that pathology of the orbitofrontal cortex leads to a dysregulation of the serotonergic system which is manifested in compulsive behavior, using a new rat model of this disorder. In the model, ‘compulsive’ behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We found that lesion to the rat orbital cortex led to a selective increase in compulsive lever-pressing that was prevented by the serotonin re-uptake inhibitor, paroxetine, and was paralleled by an increase in the density of the striatal serotonin transporter, assessed using high affinity [3H]imipramine binding. These results suggest that the serotonergic system is involved in orbital lesion-induced compulsivity, and provide a possible account for the observed association between obsessions and compulsions and dysfunction of the orbitofrontal cortex and of the serotonergic system in obsessive compulsive disorder.

Neurochemical alterations produced by daily nicotine exposure in periadolescent vs. adult male rats

Chronic treatment with nicotine differentially alters behavior in adolescent rats compared to adult rats. It is not known, however, whether the effects of nicotine on the neurochemical pathways with which it interacts differ in adolescents vs. adults. In the current study, the effects of a 7-day treatment with nicotine on nicotinic, dopaminergic, and serotonergic neurochemistry were examined in the caudate putamen and nucleus accumbens in periadolescent vs. adult male rats. Nicotine treatment increased dopamine transporter densities and decreased serotonin transporter densities in periadolescent rats. There was no change in nicotinic acetylcholine receptor densities or dopamine D1 or D2 receptor densities in nicotine-pretreated periadolescent rats. In adult rats pretreated with nicotine, there was an increase in nicotinic acetylcholine densities, but no change in dopamine transporter, dopamine D1 or D2 receptor, or serotonin transporter densities. Overall, these findings show that periadolescent rats have neurochemical adaptations to nicotine different from adult rats. These alterations may explain, at least in part, the differential behavioral effects of chronic nicotine in adult and adolescent male rats.

2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine: an improved serotonin transporter imaging agent.

Imaging serotonin transporters (SERT) is an emerging research tool potentially useful to cast light on the mechanisms of drug action as well as to monitor the treatment of depressed patients. We have prepared two new derivatives of 3, 2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine (4) and 2-(2-(dimethylaminomethyl)benzyl)-5-iodophenylamine (5) (K(i) for SERT = 0.37 and 48.6 nM, respectively). Both [(125)I]4 and [(125)I]5 displayed excellent brain uptakes in rats, and they showed a highest uptake in hypothalamus (between 60 and 240 min), a region populated with the highest density of SERT. The specific uptake of [(125)I]4 in the hypothalamus resulted in a target to nontarget ratio ([hypothalamus-cerebellum]/cerebellum) of 4.3 at 2 h. Autoradiography of rat brain sections (ex vivo at 2 h) of [(125)I]4 showed an excellent regional distribution pattern consistent with known SERT localization. These data suggest that [(123)I]4 may be useful for imaging SERT binding sites in the brain by single photon emission computed tomography (SPECT).

Neurobiologie et pharmacothérapie de la phobie sociale

Resume Bien que Marks ait propose des 1970 une classification des phobies comprenant la phobie sociale, l’apparition de l’entite diagnostique phobie sociale est encore plus recente. Elle a lieu en 1980 avec le DSM III, 3e edition de la nomenclature de l’American Psychiatric Association, qui etablit des criteres operationnels pour son diagnostic. De ce fait, les recherches visant a identifier les facteurs genetiques, familiaux et temperamentaux, les correlats neurochimiques et neuroendocriniens ainsi que les structures cerebrales s’inscrivant dans la pathogenie de ce trouble en sont a leur debut. Neanmoins, elles ont permis d’apprecier l’intervention des influences genetiques, du milieu familial, et de traits temperamentaux, comme l’inhibition comportementale face a l’inconnu, dans le risque d’apparition d’une phobie sociale. Elles ont egalement contribue a mettre en evidence des perturbations du fonctionnement des systemes de neurotransmission monoaminergique dans la phobie sociale. Parallelement, les progres realises dans l’analyse des relations structure-fonction, et notamment l’apport recent de la neuro-imagerie, ont souligne l’importance des voies cortico-limbiques dans la physiopathologie de la phobie sociale, avec la participation de regions et structures cerebrales comme le cortex prefrontal, l’hippocampe, l’amygdale et le striatum. Ceci n’a rien de surprenant si l’on considere leur role essentiel dans la signification attribuee aux informations emanant de l’environnement, les processus emotionnels, mnesiques et de conditionnement contextuel, ainsi que dans la programmation des comportements dont on peut supposer l’alteration a la lumiere des symptomes caracteristiques de la maladie. La demarche pharmacotherapique aujourd’hui proposee repose sur l’efficacite demontree d’agents medicamenteux, au premier rang desquels figurent les inhibiteurs selectifs de la recapture de la serotonine dont l’emploi peut aujourd’hui prevaloir sur celui d’autres produits egalement actifs, comme les inhibiteurs de la monoamine oxydase non selectifs et irreversibles ou les benzodiazepines, de par la simplicite de leur utilisation et leur tres bonne tolerance.

Mood disorders and serotonin transporter density in ecstasy users--the influence of long-term abstention, dose, and gender.

Neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") on the serotonin (5-HT) system have been described in animals and humans, but little is known about long-term effects of ecstasy use on mood. To investigate short-term and long-term effects of ecstasy use on mood and its association with 5-HT neurotoxicity, dose, and gender in humans. Fifteen moderate ecstasy users, 23 heavy ecstasy users, 16 former heavy ecstasy users and 15 drug-using, but ecstasy-naive controls were included. Mood was assessed using the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory (BDI). Outcomes were correlated with 5-HT transporter (SERT) density, assessed with [123I]beta-CIT single photon emission computed tomography (SPECT). The prevalence of mood disorders assessed by CIDI did not differ between all groups. The overall test for differences in BDI scores between groups was near significance (P=0.056), with BDI scores higher in former heavy ecstasy users than in ecstasy-naive controls (P=0.045). BDI scores were correlated with the total number of ecstasy tablets used (r=0.310; P=0.021). No associations between CIDI or BDI outcomes and SERT density or gender were observed. These results suggest that ecstasy use is not associated with clinical depression (CIDI). However, the number of ecstasy tablets taken lifetime was associated with higher BDI scores for depressive mood, and this relationship seemed to persist after ecstasy use had stopped. We did not find that depressed mood in ecstasy users was associated with decrease in SERT density. Prospective studies are needed to establish the causal relationship between ecstasy use and depressed mood.

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

BackgroundSerotonergic 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 [11C]McN 5652. MethodsEleven OCD subjects, free of psychiatric medications and comorbid depression, and 11 matched healthy control subjects underwent PET scans following injection of [11C]McN 5652 and magnetic resonance imaging (MRI) scans. Total distribution volumes (VT) 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 (V3″). 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. ResultsNo significant group differences were observed in [11C]McN 5652 BP or V3″ in the ROIs. No significant group differences were detected in the voxelwise analysis of BP or V3″ maps. ConclusionsOCD without comorbid depression, may not be associated with major changes in SERT availability in subcortical and limbic regions.

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.

Acute and chronic effects of nicotine on serotonin uptake in prefrontal cortex and hippocampus of rats

We sought to investigate the effect of nicotine exposure (chronic and acute) on serotonin transporter (SERT) activity in two regions of the brain important for behavioral effects of nicotine. We first looked at the effects of chronic nicotine exposure (0.7 mg/kg nicotine, twice a day for 10 days) on [(3)H]5-HT uptake in prefrontal cortex (PFC) and hippocampus of rats. A significant increase in [(3)H]5-HT uptake was observed in synaptosomes prepared from both regions. To rule out the possibility that the increases were due to the last injection given, in a separate set of experiments a single injection of nicotine was administered the evening before sacrifice. No change in uptake occurred in either region, suggesting that the increases in uptake caused by nicotine was an effect of chronic exposure and not to an acute treatment. SERT binding studies, using prefrontocortical or hippocampal membrane preparations, revealed that chronic nicotine exposure significantly increased B(max) which correlated to an increase in SERT density. Lastly, we looked at the short-term effect of nicotine on [(3)H]5-HT uptake. Rats received a single nicotine injection 15-75 min before sacrifice. PFC synaptosomes displayed a time-dependent increase in uptake, whereas hippocampal synaptosomes showed an increase at only one time point.

Positron emission tomography of striatal serotonin transporters in Parkinson disease.

Little is known about serotonin neurons in Parkinson disease (PD). To study the serotonin system in PD with positron emission tomography, using the serotonin transporter radioligand [11C](+)McN5652. We measured the density of the serotonin transporter and the density of [11C]WIN35,428-labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To assess the effects of possible differences in blood flow or brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the caudate nucleus and putamen. Patients with PD showed reductions in the specific distribution volumes of [11C](+)McN5652 in the caudate (P<.01) and putamen (P<.01), along with the expected reductions in striatal [11C]WIN35,428 binding (P<.01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mitigating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging. These results suggest that the density of serotonin transporters, like that of dopamine transporters, is reduced in the striatum of patients with PD and that these changes are related to disease stage.

Strain differences in the distribution of dopamine transporter sites in rat brain

The Wistar Kyoto (WKY) rat has long been proposed as an animal model of depressive behavior. Exposure to stress produces symptoms such as anhedonia, psychomotor retardation, ambivalence, and negative memory bias. Autoradiographic studies have revealed significant differences in the density of norepinephrine transporter (NET) and serotonin transporter (5-HTT) sites in several brain regions in WKY rats compared to Sprague–Dawley (S-D) rats. Since the mesolimbic dopamine (DA) system is involved in cognitive, emotional, and motivational behaviors, this study examined the distribution of dopamine transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and S-D rats. DAT sites were labeled with [ 3H]-GBR12935 (1 nM), and mazindol (50 μM) was used to define nonspecific binding. Quantitative analysis of the specific binding indicated that WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas in comparison to WIS and S-D rats. While the binding of [ 3H]-GBR to DAT sites was significantly decreased in the nucleus accumbens (NAc), the amygdala, the ventral tegmental area (VTA), and the reticular part of the substantia nigra ( P<.05), the binding was significantly increased in the hippocampal subregions and the hypothalamus ( P<.05) in WKY rats compared to the other two strains. In contrast, no strain differences were found in the caudate–putamen. The observed differences in the density and distribution of DAT sites in WKY rats may lead to altered modulation of synaptic DA levels in the cell body and mesolimbic regions, thereby contributing to the noted depression-like behaviors reported in this rat strain.

Autoradiographic imaging of the serotonin transporter in the brain of rats and pigs using S-([ 18F]fluoromethyl)-(+)-McN5652

The [ 18F]fluoromethyl analogue of (+)-McN5652 ([ 18F]FMe-McN) has recently been developed as a radioligand for imaging the neuronal serotonin transporter (SERT) with positron emission tomography (PET). We describe here the autoradiographic evaluation of [ 18F]FMe-McN in the brain of rats and pigs. Autoradiographic studies of [ 18F]FMe-McN performed on rat and pig brain in vitro showed a high accumulation of radioactivity in the regions rich in SERT, such as amygdala, hypothalamus, superficial gray layer of the superior colliculus, various nuclei of thalamus and substantia nigra. The binding of [ 18F]FMe-McN was reduced by citalopram, a highly selective inhibitor for SERT. Similar regional specific binding densities of [ 18F]FMe-McN were observed in both species. The regional distribution and specific binding of this radiotracer correlates well with the distribution and regional brain binding of [ 3H]citalopram. Region-to-cerebellum ratios of [ 18F]FMe-McN in vitro reached a maximum value of 20.6 in the rat and 14.5 in the pig. In addition, ex vivo autoradiography of the rat brain was performed 90 min after i.v. administration of [ 18F]FMe-McN. The highest regional uptake of [ 18F]FMe-McN was observed in the hypothalamic area, substantia nigra and amygdaloid area. There is a high correlation between the in vitro and in vivo binding. The region-to-cerebellum ratio in vivo reached a maximum value of 5.1 in the substantia nigra, the highest yet reported for an 18F-labelled SERT tracer in vivo in this region. Furthermore, the distribution volume of [ 18F]FMe-McN calculated from the PET data in various regions of the porcine brain is highly correlated with the SERT density as determined by in vitro autoradiography with [ 3H]citalopram. Thus, [ 18F]FMe-McN has a clear potential as a radiotracer for studies of the SERT distribution in man with PET.

Neuroimaging of serotonin transporters in post-stroke pathological crying

Pathological crying (PC) is a neuropsychiatric disorder characterized by an excessive tendency towards crying after brain damage. To elucidate the role of serotonin neurotransmission for PC, a pilot study was performed using single photon emission computed tomography with [ 123I]β-CIT to estimate central (midbrain/pons and thalamus/hypothalamus) serotonin transporter (SERT) densities in 15 stroke patients who did or did not have PC. SERT binding ratios in midbrain/pons were significantly lower in the PC subgroup.

The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease.

One of the most frequent psychiatric symptoms in patients with Wilson's disease (WD) is depression. It has been suggested that depression is associated with deficits in serotonergic neurotransmission, but, hitherto, no measurements have been performed in WD. We prospectively examined 23 adult patients (12 women, 11 men, mean age 40 years) with WD for symptoms of depression using the Hamilton rating scale for depression (HAMD). We correlated the data with the presynaptic serotonin transporter density (SERT density) in the thalamus-hypothalamus and the midbrain-pons regions measured with high resolution single-photon emission computed tomography (SPECT) 24 hours after the application of 180 MBq 2beta-carbomethoxy-3beta-(4 [(123)I]iodophenyl)tropane ( [(123)I]b-CIT). The regions of interest were determined by coregistration with a standard MRI dataset. A significant negative correlation was found between HAMD and SERT density in the thalamus-hypothalamus region (r = -0.49, p = 0.02), but not in the midbrain-pons (r = -0.31, p = 0.15). We conclude that depression in patients with Wilson's disease is correlated with alterations of serotonergic neurotransmission in the thalamus-hypothalamus region.

Jealousy and Subthreshold Psychopathology: A Serotonergic Link

Background: A few studies suggest that different neurotransmitters may play a role in the expression of jealousy. Our study aimed to explore the serotonergic system by means of the specific binding of ³H-paroxetine (³H-Par) to platelet membranes of healthy subjects with and without excessive jealousy concerns, according to a specific self-administered questionnaire [Questionnaire for affective relationships (QAR)]. Subjects and Methods: The study sample includes 21 subjects concerned by jealousy thoughts and 21 control subjects without jealousy concerns, as shown by their QAR scores. Subjects of the first group were administered a battery of self-report instruments designed to detect the presence of typical, atypical and subthreshold psychopathology. Platelet membranes and ³H-Par binding were carried out according to standardized protocols. Results: Subjects with excessive jealousy concerns had a reduced density of ³H-Par binding as compared with control subjects without jealousy concerns and had one or more psychiatric spectrum conditions. Conclusions: Our findings suggest that excessive jealousy is associated with various forms of psychopathology and may be underlain by alteration of the serotonergic system, as reflected by the lower density of the platelet serotonin transporter.

Differential in vivo clearance of serotonin in rat dorsal raphe nucleus and CA3 region

In vivo chronoamperometric recordings were used to determine if the majority of serotonin transporters (SERTs) in the dorsal raphe nucleus (DRN) are functionally active. This was achieved by comparing the clearance of exogenously applied serotonin (5-HT) from the extracellular fluid (ECF) of the DRN to that in the CA3 region of the hippocampus, an area with lower SERT density. Serotonin was pressure ejected into these regions in anesthetized rats and reproducible electrochemical signals measured by carbon fiber microelectrodes were recorded. Consistent with SERT density as measured by [ 3H]cyanoimipramine binding in these brain regions (DRN>>CA3), clearance of 5-HT was significantly faster in DRN compared to that in the CA3 region. The selective serotonin reuptake inhibitor, fluvoxamine, prolonged 5-HT clearance in both CA3 and DRN. It is known that the norepinephrine transporter (NET) contributes to clearance of 5-HT in the dentate gyrus (DG) but not in CA3. Given that the DRN receives noradrenergic innervation, it was also determined if the NET contributes to 5-HT clearance in the DRN. Destruction of the NET with the neurotoxin 6-hydroxydopamine failed to alter 5-HT clearance parameters in the DRN. These data support the hypothesis that serotonin transporters are functionally active in the DRN, that serotonin clearance is mediated primarily by the SERT in the DRN and that the faster clearance of 5-HT from this region is related to its greater density of functional SERTs.

RETRACTED: MDMA- and p-chlorophenylalanine-induced reduction in 5-HT concentrations: effects on serotonin transporter densities

Low levels of serotonin may reduce the density of the serotonin transporter (SERT) by either increasing trafficking or reducing synthesis; a "neuroadaptive response". To determine whether 3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in SERT density could be related to such a mechanism, p-chlorophenylalanine or MDMA was administered to rats, and brain serotonin and SERT density were measured. As expected, both treatments led to serotonin depletion 1, 7 and 14 days later. However, only MDMA reduced SERT density. This observation suggests that MDMA-induced reductions in SERT density do not represent neuroadaptive responses to decreased levels of brain serotonin, but may occur in response to some other stimulus or to the neurotoxic effects of MDMA.

Cocaine differentially alters behavior and neurochemistry in periadolescent versus adult rats

This study examined whether there are differences in the behavioral and neurochemical effects of cocaine in periadolescent rats compared to adult rats. Periadolescent (postnatal days 28–35) and adult rats were injected with cocaine or vehicle for 7 days. Ten days later (day 17), rats either were challenged with cocaine, or dopamine transporter and receptor and serotonin transporter binding were examined. Adult rats became sensitized to the locomotor-activating effects of cocaine and there were increases in dopamine transporter density in the caudate putamen compared to vehicle-treated adult rats. In addition, serotonin transporter densities were increased in the ventromedial caudate putamen, nucleus accumbens shell, and the olfactory tubercle in cocaine-treated adult rats compared to vehicle-treated adult rats. In contrast, periadolescent rats did not show sensitization to cocaine and there was no effect of cocaine on either dopamine or serotonin transporter densities. These findings suggest that there are different neurochemical and behavioral adaptations to repeated cocaine administration in periadolescent versus adult rats.

In vitro and in vivo characterisation of [ 11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography

3-Amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, labeled with carbon-11 ([ 11C]-DASB), is a recently introduced radiotracer for imaging the serotonin transporter (SERT) by positron emission tomography (PET). A series of in vitro and in vivo experiments were performed to further characterise the properties of [ 11C]-DASB as an in vivo imaging agent for SERT. In vitro binding assays confirmed that DASB binds specifically to SERT with nanomolar affinity and high selectivity over a large number of other receptors, ion-channels and enzymes in the central nervous system. Ex vivo, [ 11C]-DASB binding in rat brain was shown to be saturable (ED 50 of 56 nmoles/kg), and sensitive to both the number of available SERT binding sites and the number of viable serotonin neurons. Estimates of the radiation dose in man were extrapolated from rat biodistribution data (effective dose 5.5 E-03 mSv/MBq; critical organ -urinary bladder wall). Together with previous studies, the present findings indicate that [ 11C]-DASB is a very useful radiopharmaceutical for probing changes in SERT densities using PET imaging in the living human brain.

Serotonin transporter gene polymorphisms and platelet [ 3H] paroxetine binding in premenstrual dysphoria

The purpose of this study was to investigate if women with premenstrual dysphoria differ from controls with respect to the number of platelet serotonin transporters, and with respect to three polymorphisms in the gene coding for the serotonin transporter: a 44 base pair insertion/deletion in the promoter region, a variable number of tandem repeats in the second intron, and a single nucleotide polymorphism in the 3′ untranslated region. Also, the possible relationship between the three polymorphisms and platelet serotonin transporter density was analyzed. The density of platelet [ 3H]paroxetine binding sites was significantly lower in women with premenstrual dysphoria than in controls, but patients and controls did not differ with respect to allele or genotype frequency for any of the three polymorphisms examined. A significant association between the number of platelet serotonin transporters and the promoter polymorphism was observed, subjects being homozygous for the short (deletion) variant having higher platelet serotonin transporter density than subjects carrying the long (insertion) allele. The results support the assumption that serotonin-related psychiatric disorders—such as premenstrual dysphoria—may be associated with a reduction in platelet [ 3H]paroxetine binding, but argue against the notion that this reduction is due to certain variants of the serotonin transporter gene being more common in patients than in controls.