Platelet Serotonin Uptake Research Articles

Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets

Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets

Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets

The human serotonin transporter (5-HTT), encoded by a single gene on chromosome 17q11.2, is expressed in brain and blood cells. 5-HTT is implicated in mood and anxiety regulation, and is where antidepressant and antianxiety drugs initially act in the brain. A 5-HTT-linked promoter region (5-HTTLPR) insertion/deletion polymorphism with long (l) and short (s) forms affects transporter expression and function. The s variant reduced 5-HTT gene transcription in a reporter gene construct and human lymphoblasts, resulting in reduced transporter levels and 5-HT uptake, acting as a dominant allele. In this study, we investigated the expression and function of 5-HTT in platelets from healthy male volunteers. The l variant was associated with more rapid initial platelet 5-HT uptake (Vmax), the index of platelet 5-HTT function most clearly heritable, while the s allele was dominant. The 5-HTTLPR genotype had no effect on platelet [3H]paroxetine binding (Bmax), affinity for [3H]5-HT or [3H]paroxetine, or 5-HT content. The 5-HT uptake findings support a functional difference in the two 5-HTTLPR variants, reinforcing their attractiveness as candidate genes in neuropsychiatric research.

Serotonin transporter on rat platelets: levels of mRNA underlie inherited differences in uptake kinetics

By the breeding selection for the extreme values of platelet serotonin transporter activity, two sublines of Wistar-derived rats, with constitutionally high or low platelet serotonin uptake (PSU), were previously developed. In order to study the genetic background of these inherited differences, comparative Northern blot analysis of the platelet serotonin transporter messenger RNA levels of the animals from the two sublines was performed. If the values of animals from the high-PSU subline are taken as 100%, animals from the low-PSU subline demonstrated lower values of both platelet serotonin uptake and transporter mRNA levels (amounting to 62 and 76% respectively). Correlation between platelet serotonin uptake and the respective levels of messenger RNA for the serotonin transporter ( r = 0.829, P < 0.01, N = 8) points to the same direction, indicating that the process of breeding selection for the extreme values of transporter kinetics has influenced transcription mechanisms of the serotonin transporter gene.

The effect of treatment with a new antidepressant: INN 00835 on platelet serotonin uptake in depressed patients

The effect of chronic administration of platelet-activating factor (PAF) on airway reactivity, cell recruitment and lung morphology in the guinea-pig has been investigated. Alzet osmotic minipumps delivering either PAF (7.2 mg/kg/14 days) in 0.25% (w/v) bovine serum albumin in saline (saline-BSA), acetylcholine or saline-BSA alone were implanted s.c. in the neck region of guinea-pigs and connected to the jugular vein. In some experiments, implanted and non-implanted animals were treated daily with the PAF antagonist, BN 52021 (15 mg/kg, twice a day, p.o.). On day 15 after minipump implantation, the animals were anesthetized with urethane (1.2 g/kg, i.p.) and tracheal cannula was inserted for mechanical ventilation. Pulmonary inflation pressure (PIP) was monitored and airway responsiveness was assessed by administration of increasing doses of histamine (0.2–100 μg/kg, i.v.). As compared to saline-BSA-treated or non-implanted guinea-pigs, chronic treatment of the animals with PAF induced a significant (p<0.01) increase in airway response. No significant change in airway responsiveness was observed following chronic acetylcholine administration. In contrast, regardless of the treatment of the animals, no change in the threshold dose of histamine inducing alteration in PIP was noted, suggesting that PAF induces bronchopulmonary hyperreactivity rather than hyperresponsiveness. In addition, no significant difference was observed in the in vitro responsiveness to histamine of lung parenchymal strips from animals having received PAF or saline-BSA. Histological evaluation of the lung from guinea-pigs receiving PAF exhibited moderate hyperplasia of airway smooth muscle cells, marked eosinophil infiltration and increase in mast cell number in the peribronchial zone as compared to those from control, acetylcholine- or solvent-treated animals. These alterations were markedly reduced or absent in guinea-pigs implanted with PAF-containing minipumps and concomitantly treated with BN 52021. In conclusion, chronic administration of PAF to guinea-pigs results in airway hyperreactivity to histamine in vivo, associated with structural changes in airway smooth muscle cell mass, but which is unlikely to be secondary to protracted bronchoconstriction.

Circannual variations in the binding of [ 3H]lysergic acid diethylamide to serotonin 2A receptors and of [ 3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers

Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.

Inhibition of platelet serotonin uptake by cytochrome P450 inhibitors miconazole and econazole

Serotonin uptake in human platelets was inhibited by cytochrome P450 inhibitors such as miconazole and econazole but not clotrimazole. There was a correlation between inhibition of serotonin uptake and inhibition of imipramine binding, suggesting that these P450 inhibitors may inhibit serotonin uptake via direct binding to the transporter. P450 inhibitor effects on serotonin uptake did not seem to be related to the effects of these compounds on intracellular calcium mobilization. Additionally, nitric oxide pathway stimulation does not appear to be involved.

Serotonin: Ubiquitous Neuromodulator in the Failing Heart

Serotonin exhibits various cardiovascular effects and evidence of its role in various cardiovascular disorders is emerging. Serotonin levels in whole blood and the platelet serotonin uptake were significantly increased in patients with heart failure compared to control subjects. However, the intraplatelet serotonin content was not significantly different in the two groups. We conclude that serotonin is involved in the syndrome of heart failure both directly and indirectly through its action on cardiac contractility, heart rate, preload, and afterload.

Plasma and platelet concentration and platelet uptake of serotonin in normal and pre-eclamptic pregnancies

Pharmacologic and methodologic advances over the last decade have resulted in a body of information implicating serotonin as a mediator in the genesis of preeclamptic hypertension. Platelets contain the largest storage of serotonin in peripheral blood and have the ability to take up this amine from sourroundings, store and release it by several mechanisms. Plasma and platelet serotonin concentrations and platelet serotonin uptake have been measured in 8 non-pregnant women, 12 normal pregnant women and 8 women with severe pre-eclampsia. Plasma serotonin concentration was significantly higher in severely preeclamptic women, compared with age and gestation matched normal pregnant women. In addition, plasma serotonin concentration was directly related to systolic and diastolic blood pressure with severity of the syndrome. Furthermore, platelet serotonin concentration in women with pre-eclampsia was significantly higher than in non-pregnant controls, but it was not significantly different from the normal pregnant women. Moreover, serotonin is effectively taken up by platelets through a saturable transport process. The calculated apparent Km for serotonin uptake process did not differ significantly among non-pregnant women, normal pregnant women and women with pre-eclampsia. However, Vmax values were significantly higher in women with pre-eclampsia than in the normotensi ve pregnant women. As the actions of serotonin in the periphery could be terminated primarily by active uptake system by platelets and placenta, significant alterations in the rate of transport could result in physiologically significant changes in serotonin levels. These data raise the possibility that abnormal regulation of transporter function is involved in the etiology of pre-eclampsia.

Altered serotonin function in suicide. Evidence from platelet and neuroendocrine studies.

Significant progress has been made in understanding psychosocial, psychological, and environmental factors associated with suicide; however, it is only recently that attention has been paid to the understanding of the neurobiology of suicide. There are several studies that implicate the serotonin (5-HT) system in suicide. Initial evidence was obtained from observations of low 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of depressed patients with a previous history of suicide attempts. Several strategies have been used to examine the serotonergic system in suicidal behavior, which include the determination of serotonin and its metabolites in CSF and postmortem brain tissues as well as serotonin receptor subtypes in postmortem brain tissues, and in platelets of suicidal patients. The neuroendocrine strategy, often termed the "window to the brain," has been extensively used for studying the serotonergic system in suicide. This chapter will review the results obtained from neuroendocrine and serotonin studies in platelets. Initial studies in platelets focussed on determining serotonin uptake and serotonin transporter binding sites in platelets of depressed and suicidal patients. Whereas several studies have found decreased imipramine binding sites of platelets of depressed patients, imipramine binding sites in platelets of suicidal patients showed inconsistent results. Similarly, no consistent changes in 5-HT uptake have been observed in platelets obtained from suicidal patients compared to nonsuicidal patients. On the other hand, studies of platelet 5-HT2A receptors appear to be quite encouraging. Initially, several investigators indicated that they found an increase in platelet 5-HT2A receptors in depressed patients. Subsequently, it was shown that platelet 5-HT2A receptors in suicidally depressed patients were significantly higher compared to nonsuicidally depressed patients and normal control subjects. It has also been shown that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis, similar to platelets. 5-HT2A receptors have also been shown to be increased in the postmortem brain of suicide victims by several investigators, although some investigators do not find such an increase. The neuroendocrine strategy provides an important method for studying serotonin function in the central nervous system of depressed and suicidal patents. Using a serotonergic probe of 5-HT1A receptors, several investigators examined ipsapirone-induced prolactin release in suicidal patients and did not find it different that that of control subjects. On the other hand, fenfluramine, which causes release of serotonin and blocks serotonin uptake, causes a decreased release of prolactin in depressed patients compared to normal control subjects. Furthermore it has been shown by some investigators that fenfluramine-induced prolactin release is also decreased in suicidal patients compared to normal control subjects. In summary, platelet and neuroendocrine studies have provided initial evidence sufficient to suggest serotonergic abnormalities in suicidal patients. Most earlier evidence is based on CSF 5-HIAA studies, but it appears that 5-HT2A receptors in both platelet and postmortem brain samples are increased in suicidal patients. The observation that platelet 5-HT2A receptors are increased in suicidal patients independent of diagnosis provides a very useful potential biological marker for identifying suicidal patients.

Platelet studies in panic disorder: A review

AbstractObjective: The blood platelet has been proposed as a model of central neurons and may therefore be used as a peripheral marker of psychiatric illness. One method of investigating serotonin function in panic disorder has relied on the use of the platelet as a model of serotonergic neurons. This article reviews the studies of platelet function in panic disorder.Method: A literature search and review of relevant papers was undertaken.Result: Studies examining platelet serotonin uptake and concentration in panic disorder patients have to date yielded conflicting results, with some investigators reporting increased serotonin uptake, others reduced uptake. Similarly studies of platelet 3H-imipramine binding have also yielded conflicting results. Two studies of platelet 3H-paroxetine binding have shown a reduction in the density of binding sites (Bmax) in patients with panic disorder. Platelet monoamine oxidase activity in anxiety disorders has been reported to be increased by some investigators but decreased by others. Methodological considerations may have been responsible for these differences. Finally, studies of α2 adrenoceptor density have also produced contrasting findings.Conclusion: The findings of these studies indicate that platelet function is altered in panic disorder. Such changes may allow an insight into the biochemical aetiology of the illness. Further studies are required to delineate the role of serotonin and non-adrenaline in panic disorder.

P.3.040 The effect of citalopram treatment on platelet serotonin uptake and 3H-paroxetine- and 3H-LSD-binding in panic disorder

P.3.040 The effect of citalopram treatment on platelet serotonin uptake and 3H-paroxetine- and 3H-LSD-binding in panic disorder

S.19.03 Is there a specific psychopharmacology for eating disorders?

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

P.1.048 - The effect of antidepressants on platelet serotonin level and serotonin uptake in rats genetically selected for these traits

La psicoeducazione, strategia di intervento non farmacologico raccomandata dalle attuali linee guida sul trattamento della schizofrenia, integrando elementi appartenenti a diversi approcci psicoterapeutici, favorisce il miglioramento delle conoscenze relative alla malattia e delle abilità di coping. Obiettivo della presente rassegna è descrivere le principali evidenze di efficacia sulla psicoeducazione nella schizofrenia sulla base di importanti revisioni e metanalisi condotte nell’ultimo decennio e di singoli studi relativi alle peculiarità di intervento sui pazienti e sui familiari.La psicoeducazione risulta efficace, sia nelle fasi acute sia nelle fasi stabili, nel ridurre le ricadute e i ricoveri dei pazienti, oltre a favorire l’aderenza al trattamento, diminuire il carico soggettivo e migliorare il benessere del nucleo familiare. Singoli studi condotti nell’ultimo decennio hanno considerato aspetti specifici di intervento che contribuiscono a determinare l’efficacia della psicoeducazione nella schizofrenia, tra i quali l’attenzione alle variabili culturali, sia dei pazienti sia dei familiari, che risulterebbe particolarmente importante per la programmazione di interventi terapeutici in contesti multietnici. Risultano pertanto necessari ulteriori studi finalizzati alla standardizzazione dei programmi di intervento per specifiche categorie di pazienti e nelle differenti fasi del decorso clinico del disturbo, così come le procedure di valutazione degli esiti, con riferimento sia al miglioramento dell’outcome dei pazienti sia al benessere globale del nucleo familiare, e dei relativi periodi di follow-up.Psychoeducation, a non-pharmacological strategy recommended by current guidelines for the treatment of schizophrenia, integrates elements from different psychotherapeutic approaches and promotes improvement of knowledge regarding the disease and coping skills. The aim of this review is to describe the main evidence of efficacy on psychoeducation in schizophrenia on the basis of recent reviews and meta-analyses, and recently published studies on new approaches in the field.Psychoeducation can reduce rates of relapse and rehospitalization, improve adherence to treatment and have other positive effects on patients and their families, such as reduction of burden. Single studies have considered culturally sensitive and other new psychoeducational approaches that would be important for therapeutic interventions especially in multiethnic contexts. Future research should therefore focus patients and their families participate in psychoeducational interventions, but also on the minimum effective psychoeducation dose, on those patients with schizophrenia who do not have supporting families willing to partecipate in family psychoeducation, on standardized outcomes and follow-up periods.

Tyrosine kinase inhibitors regulate serotonin uptake in platelets

Uptake of tritiated serotonin into human platelets was found to be rapidly inhibited by the tyrosine kinase inhibitors, genistein and methyl 2,5-dihydroxycinnamatc. Binding studies indicated that uptake inhibition did not correlte with direct binding of these inhibitors to the transporter. Chelation of mobilizable intracellular Ca 2+ did not inhibit the effects of genistein on uptake. These results suggest a more direct, non-Ca 2+ mediated effect of tyrosine kinase inhibitors on uptake.

Acute effect of exercise on human blood platelet serotonin uptake and monoamine oxidase activity

Blood platelet serotonin (5-HT) uptake and monoamine oxidase (MAO) activity have been widely used as peripheral markers for presynaptic 5-HT reuptake and central monoamine metabolism (Lingj~erde 1990; Oreland et al 1980). This has led to interest in studying factors that might affect these parameters. Such studies have shown that both 5-HT uptake and MAO activity depend on the size of the blood platelets (Demet et al 1990; Murphy et al 1978; Gawel et al 1981). Since exercise tends to increase the concentration and the mean volume of circulating blood platelets (Jensen et al 1984), we reasoned that physical activity might influence measurements of 5-HT uptake and MAO activity. Moreover, depression and mania are associated with characteristic changes in the level of physical activity, so we reasoned that these changes might be responsible for differences in blood platelet 5-HT uptake and MAO activity observed in relation to various affective disorders (Meltzer and Arora 199l; Oreland et al 1980). The aim of this study was to determine whether light exercise immediately prior to blood sampling influences blood platelet 5-HT uptake and MAO activity.

Effect of melatonin on active transport of serotonin into blood platelets

Previous research has demonstrated that the circadian rhythm of melatonin negatively correlates with that of the sensitivity of platelet serotonin uptake sites. Moreover, serotonin has been found to be a competitive inhibitor of melatonin binding to platelets. The goal of the present study was to investigate whether melatonin directly affects platelet serotonin transport. Blood samples from 12 healthy subjects were assayed for serotonin transport into platelets. Active transport of serotonin (at a concentration of 10 −6 M) into blood platelets was measured in the presence of melatonin at physiological concentrations (10 −12M to 2 × 10 −9M) and at high nonphysiological concentrations (2 × 10 −8M to 2 × 10 −3M). Melatonin inhibited serotonin uptake by blood platelets at the high concentrations only (|> 10 −5M with IC 50 value of 1.1 × 10 −3M) and had no effect at physiological concentrations.

Hypodensity of platelet serotonin uptake sites in posttraumatic stress disorder: Associated clinical features

We have previously reported that binding to blood platelets of paroxetine, a selective serotonin (5-HT) reuptake inhibitor which binds to 5-HT uptake sites, is decreased in patients with posttraumatic stress disorder (PTSD). Specifically, we found a lower number of platelet 3H-paroxetine binding sites (B max) and a lower dissociation constant (K d) for 3H-paroxetine binding in combat veterans with PTSD compared to normal control subjects. In the current study we assessed the relationship of platelet 3H-paroxetine binding to clinical features in 41 Vietnam combat veterans with SCID-diagnosed PTSD. The results indicated that B max of platelet 3H-paroxetine binding was negatively correlated with both state and trait anxiety, as well as with depressive and overall PTSD symptoms. However, there was no evidence that platelet 3H-paroxetine binding differed as a function of comorbid psychiatric diagnoses including major depression, other anxiety disorders and substance abuse in these patients.

M-CPP challenge response as predictor of reponse to clozapine in neuroleptic resistant schizophrenia patients

The diagnosis, treatment, and pathophysiology of obsessive-compulsive disorder (OCD) were examined in a series of studies utilizing psychobiological approaches. Putative biological markers previously reported in depression were studied in this disorder and revealed that on some measures [Dexamethasone Suppression Test and rapid eye movement (REM) latency on sleep electroencephalogram (EEG)], OCD patients resemble those with major depressive disorder (MDD), whereas on others [REM density, platelet serotonin uptake, probably platelet 3H-imipramine binding, and 5-hydroxy-indoleacetic acid (5-HIAA) in cerebral spinal fluid (CSF)] they do not. The relationship between OCD and MDD was further explored in a double-blind, randomized crossover study designed to compare the antiobsessional effects of two tricyclic antidepressants, clomipramine (CMI) and desipramine (DMI), in a nondepressed cohort of OCD patients. CMI was found to have significant antiobsessional effects in this group, whereas in the same patients, DMI lacked therapeutic effects. These results suggest that not all antidepressants are antiobsessive and that some property of CMI, such as its potent serotonergic effects, may be of pathophysiological relevance for OCD. The role of serotonin in this disorder was then tested using the pharmacological challenge strategy. A novel serotonin postsynaptic receptor (5HT-1) agonist, m-chlorophenylpiperazine (m-CPP), was administered orally (0.5 mg/kg) under double-blind, placebo-controlled conditions to OCD patients and controls. In addition, a serotonergic receptor antagonist, metergoline (4 mg), was given to a subset of OCD patients. Relative to healthy volunteers, the OCD patients became significantly more anxious, depressed, and dysphoric after m-CPP administration. Moreover, in the OCD patients, obsessive-compulsive symptoms increased markedly after m-CPP and decreased significantly following metergoline administration. These results demonstrate that agents that bind to the 5HT-1 receptor can acutely affect the symptoms of OCD patients. The striking behavioral effects of these direct postsynaptic receptor ligands and the relative specificity of clomipramine as an antiobsessional agent suggest

Platelet serotonin markers and depressive symptomatology

Dysfunction of brain serotonergic symptoms may be a factor in the mood and behavioral disturbances associated with depression. Platelet serotonin measures represent indirect but easily obtainable indices of brain serotonin function. To examine the specificity of relationships between cognitive and vegetative symptom groupings and platelet serotonin measures, we assessed 35 depressed outpatients using the Hamilton Rating Scale for Depression and collected platelets after a minimum 3-week drug-free period. Platelets were also collected from 14 controls. The results showed that depressed patients had lower platelet serotonin (5-HT) uptake site density values than controls and that 5-HT uptake site density values were inversely correlated with the severity of cognitive symptoms of depression. Platelet 5-HT2 receptor density values were higher in depressed patients than controls, and there was a trend toward a direct correlation between the cognitive symptoms of depression and 5-HT2 receptor density values. Neither platelet measure showed any relationship with the severity of the vegetative symptoms of depression.

Platelet serotonin transport is altered in streptozotocin-induced diabetic rats

The present work was conducted to examine whether experimental diabetes (streptozotocin-induced) promotes changes in mean platelet volume, and platelet serotonin (5HT) uptake and content. These variables were measured in from four experimental groups: control, diabetic, diabetic+insulin, and non-diabetic+insulin. Animals treated fifteen days before with streptozotocin had platelets with higher 5HT uptake affinity, 5HT content, and volume. The insulin therapy reestablished the control values of all of these three variables. Non-diabetic animals treated one week with insulin did not show any variations. The effects of in vitro application of insulin, hyperglycaemic incubation medium, and streptozotocin on platelet amine uptake and release were also examined. Only those platelets incubated with streptozotocin showed an altered platelet 5HT uptake. No changes were observed for spontaneous 5HT release. The results are consistent with: a) an increase of platelet uptake capacity, as a consequence of an increase in platelet turnover, for explaining alterations of intraplatelet 5HT contents in experimental diabetes; b) a non-direct effect of insulin and glucose levels on platelet 5HT uptake -for explaining its dysfunctions in experimental diabetes-; c) the contribution of alterations in platelet 5HT transport for explaining the higher incidence of vascular complications in diabetic patients; d) the suitability of platelet as a model for investigating neuronal 5HT reuptake.