Platelet 5-HT2 Receptor Research Articles

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.

Platelet 3H ketanserin binding in migraine.

Platelet 3H ketanserin binding was studied in 33 patients of migraine and 30 healthy controls. The binding characteristics: equilibrium dissociation constant (Kd) and maximal number of binding sites (Bmax) determined by Scatchard analysis revealed a significant decrease in Kd and no change in Bmax in migraine cases. No correlation was observed between the Kd and Bmax with the clinical features of migraine. The findings of the present study show that there is a decreased affinity of platelet 5-HT2 receptors in migraine.

Binding affinity of a newly synthesized 5-HT2 antagonist, AT-1015 (N-[2-[4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate), in the rabbit platelet membrane.

The object of this study was to investigate the binding affinity of a newly synthesized 5-HT2 antagonist, (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate) (AT-1015), in the rabbit platelet membrane using [3H]-ketanserin by radioligand binding assay method and to compare the results with other selective 5-HT2 antagonists. The results showed that AT-1015 displayed high affinity to 5-HT2 receptors in rabbit platelet membranes. The pKi value of AT-1015 was 7.40, which is slightly lower than that of ketanserin, but higher than that of cyproheptadine. On the other hand, the displacement potency of AT-1015 for 5-HT2 receptors in rabbit platelets was similar to those of sarpogrelate and ritanserin. This is the first report of the high affinity of AT-1015 in rabbit platelets.

Correlations for serotonin levels and measures of mood in a nonclinical sample.

The Beck Depression Inventory is frequently used to detect depression and its severity because depression is a prevalent mood disorder and is commonly treated by prescription of selective serotonin-reuptake inhibitors such as Prozac. The importance of serotonin (5-HT) in the treatment of major depression is evident but the nature of this involvement is unclear. In this study, the characteristics of platelets are employed as a peripheral model of the neuron to estimate central serotonergic activity, which is a consequence of numerous factors including 5-HT2 receptor sensitivity. The greater the sensitivity of the platelet serotonin receptors, the lower the concentration of serotonin required to mobilise a particular amount of calcium from internal stores through serotonin stimulation. Hence, Platelet 5-HT2 receptor sensitivity is inferred from the concentration of serotonin that is required to produce half maximal intracellular calcium mobilisation (EC50). In the present study, the correlation of -.422 between scores on the Beck Depression Inventory and EC50 in a sample of 49 university students was significant, implying that mood is significantly related to 5-HT2 receptor sensitivity, such that increases in depressed mood are accompanied by increases in 5-HT2 receptor sensitivity.

A PET study of brain 5-HT2 receptors and their correlation with platelet 5-HT2 receptors in healthy humans.

Platelets share many properties with brain serotonergic neurons such as active 5-hydroxytryptamine (5-HT) transport, 5-HT2 receptors, and mitochondrial monoamine oxidase. We measured brain 5-HT2 receptors and platelet 5-HT2 receptors in healthy volunteers to determine if there was any correlation between the two measures. Ten healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. 5-HT2 receptor binding was determined for each subject with positron emission tomography and [18F]setoperone scan in the brain and with 3H-LSD binding in platelets. We found no significant correlation between 5-HT2 binding potential (BP) in platelets (Bmax/Kd) and a semiquantitative estimate of 5-HT2 BP in frontal, parietal, and temporal cortical regions. SPM voxel based analysis also showed no significant correlation between the 5-HT2 BP in platelets and in the brains of the study subjects. Brain 5-HT2 receptor binding was not significantly correlated to platelet 3H-LSD binding in healthy subjects. This raises questions about the validity of generalizing findings from platelet studies to 5-HT neurons in the brain.

317. A PET study of brain 5-HT2 receptors and their correlation with platelet 5-HT2 receptors

We measured brain 5-HT2 receptors and platelet 5-HT2 receptors in healthy volunteers to determine if there was any correlation between the two measures in living humans. Ten healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. 5-HT2 receptor binding was determined for each subject with Positron Emission Tomography (PET) and fluorine-18 labeled setoperone scan in the brain and with 3H-LSD binding in platelets. We found no significant correlation between 5-HT2BP in platelets (Bmax/Kd) and a semiquantitative estimate of 5-HT2BP in frontal, parietal, and temporal cortical regions of the 10 healthy subjects. SPM voxel based analysis also showed no significant correlation between the 5-HT2BP in platelets and in the brains of the study subjects. Brain 5-HT2 receptor binding was not significantly correlated to platelet 3H-LSD binding in healthy subjects. This raises questions about the validity of generalizing findings from platelet studies to 5-HT neurons in the brain.

5-HT 2 receptor levels in women suffering from premenstrual dysphoric disorder (PMDD) before and after treatment with sertraline

Premenstrual Dysphoric Disorder (PMDD) affects 3-8% of women of reproductive age It has been demonstrated to be closely associated with Major Depressive Disorder (MDD) and might indicate vulnerability to develop MDD Serotonergrc functions have been shown to be abnormal in MDD, and some serotonial receptor functions were shown to be decreased in PMDD, as state or trait abnormalities. Here we report on platelet 5-HT2 receptor levels in women with prospectively confirmed PMDD, as compared to women with no PMS Platelet 5-HTL receptors were determined (with LSD) in women during the non-symptomatic mid-follicular phase, and the symptomatic late-luteal phase of the menstrual cycle, and following treatment with sertraline at a dose of up to 150mgiday AfIinity (IQ) of 5-HTz receptors of women with PMDD decreased uniformly from the follicular (1 65+0.86) to the luteal phase (1.17+0 37). Compared to control subjects, 5-HTz receptor affinity for serotonin was unaffected by sertraline administration However, binding (B,,,) of the 5-HTz receptors was shown to have increased (I 1 2+6 0) in subjects who responded well to treatment with SSRI, but not in women who did not improve (-4 7+2 6)

A study of platelet serotonin receptor in mania

Background: Serotonergic (5-HT) dysfunction has been hypothesized in mania; however platelet studies on the 5-HT uptake rate and the 5-HT transporter have revealed inconsistent results. To the best of our knowledge no studies have been conducted on the 5-HT2 receptor status in mania.Methods: We determined density (Bmax) and dissociation constant (Kd) of 5-HT2 receptors in the platelets of 29 normal control and 29 manic subjects using 125I-ketanserin as the binding radioligand. The manic patients were assessed for the same after 14 days of treatment with lithium (n = 14) and after return to premorbid levels of functioning (n = 5).Results: There were no significant differences in the Bmax (3.51 ± 3.04 vs. 3.14 ± 3.44 fmol/mg protein, p = ms) values between normal control and manic subjects. In comparison to the baseline values Bmax at day 14 (3.49 ± 3.68 vs. 2.18 ± 1.90 fmol/mg protein, p = ns) and following recovery (1.17 ± 0.85 vs. 1.29 ± 1.13 fmol/mg protein, p = ns) did not show any significant difference.Conclusions: Our findings preliminarily suggest that the platelet 5-HT2 receptor is neither a state marker nor a trait marker in mania; however studies on the 5-HT2 receptor using positron-emission tomography ligands will help in conclusively ruling out the involvement of this receptor in mania.

Increased Platelet 5-HT2 Receptor Binding After Electroconvulsive Therapy in Depression

We investigated the effect of electroconvulsive treatment (ECT) on platelet 14C-serotonin uptake, 3H-paroxetine binding and 5-HT2 receptors in 12 patients (10 women and 2 men) unresponsive to pharmacological treatment. The mean numbers of ECTs given was 6.1 +/- 1.5. Mean treatment days was 14.6 +/- 3.8. Mean percent reduction in MADRS scores was 80.7 +/- 19.7 (p < 0.002). The number of 5-HT2 receptors increased significantly and uniformly after ECT (p = 0.011). There was no correlation between the degree of increase in 5-HT2 receptor densities and the reduction in MADRS scores after ECT. There was no difference in mean Bmax for platelet 3H-paroxetine binding before and after ECT. Bmax increased in six patients and decreased in six patients. The study shows an increase in platelet 5-HT2-receptor densities in depression after repeated ECT. Recognizing the similarities between 5-HT2 receptors in platelets and cerebral cortex, it seems reasonable to assume that a similar upregulation of cortical 5-HT2 receptors occurs after ECT.

P-423 - The relationship between ketanserin binding sites and 5-HT2 receptors in platelets (human and rabbits) and rabbit vascular smooth muscle

P-423 - The relationship between ketanserin binding sites and 5-HT2 receptors in platelets (human and rabbits) and rabbit vascular smooth muscle

76-9 - Increased platelet 5-HT 2 receptor binding after electroconvulsive therapy in depression

We investigated the effect of electroconvulsive treatment (ECT) on platelet 14C-serotonin uptake, 3H-paroxetine binding and 5-HT2 receptors in 12 patients (10 women and 2 men) unresponsive to pharmacological treatment. The mean numbers of ECTs given was 6.1 +/- 1.5. Mean treatment days was 14.6 +/- 3.8. Mean percent reduction in MADRS scores was 80.7 +/- 19.7 (p < 0.002). The number of 5-HT2 receptors increased significantly and uniformly after ECT (p = 0.011). There was no correlation between the degree of increase in 5-HT2 receptor densities and the reduction in MADRS scores after ECT. There was no difference in mean Bmax for platelet 3H-paroxetine binding before and after ECT. Bmax increased in six patients and decreased in six patients. The study shows an increase in platelet 5-HT2-receptor densities in depression after repeated ECT. Recognizing the similarities between 5-HT2 receptors in platelets and cerebral cortex, it seems reasonable to assume that a similar upregulation of cortical 5-HT2 receptors occurs after ECT.

An investigation into the psychobiology of social phobia: personality domains and serotonergic function.

The aim of the present study was to explore a psychobiological perspective in the aetiology of social phobia. The emphasis was on serotonergic function and personality. A total of 20 social phobics according to ICD-10 DCR criteria were assessed with the Schedule for Clinical Assessment in Neuropsychiatry and the International Personality Disorder Examination. They were compared with an age-matched normal population with regard to scores on the Fear of Negative Evaluation Scale, the Social Avoidance and Distress Scale, the Temperament and Character Inventory, and platelet 5HT2 receptor function. Other Axis-I disorders and cluster C personality disorders were frequently encountered. The social phobia group was characterized by high levels of harm avoidance, and low levels of novelty seeking, co-operativeness and self-directedness. Platelet 5HT2 receptor density did not differentiate between the groups, but was associated with severity of social phobia. An integrated psychobiological model is presented.

Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression. Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls. Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [3H]paroxetine, or 5-HT2 receptors, labelled with [3H]LSD. However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline. A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls. Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively. These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation. Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients.

Platelet serotonin aggregation in depression

AbstractSerotonin aggregation is a measure of function of platelet 5-HT2 receptors. The test has been proposed as a valid peripheral model of central 5-HT2 receptor function. Receptors of this subtype are implicated in theories of the aetiology of depressive states.This pilot study proposes a normal range for the test for both males and females. Untreated depressed subjects had results which grouped at the lower end of the range. The test proved reproducible with a correlation coefficient of r = 0.939 with an interval of at least six weeks between sampling. A small number of successfully treated patients were retested with no empirical difference in their results, which are included in the reproducibility studies.Our provisional results indicate the reliability of serotonin aggregation scores for an individual. The difference in scores noted in depressed subjects is more likely to be a trait rather than a state marker.

Platelet Binding Characteristics Distinguish Placebo Responders from Nonresponders in Depression

To determine whether there are characteristics distinguishing placebo responders from nonresponders, we studied 37 outpatients meeting DSM-III-R criteria for depression who were enrolled in controlled drug trials and 14 control subjects. Clinical data and blood samples were collected on admission and after a 7- to 10-day placebo washout. All patients experiencing a 40% drop in the Hamilton Rating Scale for Depression (HRSD) at the time of the second evaluation were considered placebo responders. There were no statistically significant differences between the two groups in clinical variables. Platelet markers distinguished the groups: Most notably, placebo nonresponders had the lowest 5-HT uptake site density values, placebo responders had intermediate values, and normal controls had the highest values. Placebo responders and placebo nonresponders had higher 5-HT uptake affinity values. No significant differences were observed among the groups in platelet 5-HT2 receptor site density or affinity values. These results suggest that platelet serotonin characteristics, but not common clinical characteristics, may distinguish depressed patients who do and do not respond to placebo.

Desensitization and resensitization of human platelets to 5-hydroxytryptamine at the level of signal transduction

Desensitization of platelets to 5-hydroxytryptamine (5HT) (1 microM), during active removal of the agonist by the platelet 5HT-uptake system, was studied at the level of signal transduction. Desensitization to 5HT was dose-dependent and homologous. Without occupation of the 5HT2 receptor, neither an increase in cytosolic [Ca2+] (30 nM ionomycin), nor a separate or simultaneous activation of protein kinase C (by 10 microM 1-oleoyl-2-acetylglycerol), could induce desensitization to 5HT (1 microM). During the early phase of desensitization, the 5HT2 receptor was coupled to phospholipase C, whereas during the late phase of desensitization this coupling was disconnected. However, after disappearance of the agonist, the coupling in the resting platelet recovered quickly, and was nearly complete (82%) after 30 min. During this resensitization, the 5HT-inducibility of activation of phospholipase C, of the increase in cytosolic [Ca2+] and of stimulation of protein kinase C were restored in parallel. The time course for resensitization of the 5HT-induced increase in cytosolic [Ca2+] was independent of the presence of extracellular Ca2+. It is concluded that, after dissociation of 5HT from the platelet 5HT2-receptor, 5HT-induced responses rapidly resensitize. Because of its short duration and the parallelism in recovery between the different 'down-stream phospholipase C' intracellular transduction signals, it is considered that desensitization arises from a reversible change in the transduction mechanism at a step up to or including the activation of phospholipase C. Neither desensitization nor resensitization to 5HT is dependent on the presence of extracellular Ca2+.

The platelet intracellular calcium response to serotonin is augmented in bipolar manic and depressed patients

AbstractThe serotinergic system is widely implicated in the pathophysiology of affective disorder. In this study, basal levels of intracellular calcium as well as the effects of serotonin on intracellular calcium were studied in bipolar manic (N = 21), bipolar depressed (N = 19), bipolar euthymic (N = 20) and normal control (N = 20) subjects. At a serotonin concentration of 100 nm, there was an elevation in intracellular calcium readings, with the highest mean levels in the manic group (158·6, SD = 105·1) followed by the depressed (140·6, SD = 76·4), controls (122·8, SD = 61·6) and the euthymics (96·2, SD = 31·0). The difference between manics and euthymics reached statistcal significance (P = 0·0181) using pooled variance, as did the difference between depressives and euthymics (P = 0·0238). Similar results were found at the 500 nm and 1 μm levels of serotonin. This suggests that an enhanced serotonin mediated mobilization of intracellular calcium occurs in patients in both the manic and depressive phases of bipolar disorder, and may be an index of second messenger dysregulation secondary to hypersensitivity of the platelet 5HT2 receptor. In addition, the results suggest that this is a state marker of bipolar disorder.

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.

Use of selective serotonin reuptake inhibitors and other serotonergic drugs in the biological dissection of affective disorders.

The need to subtype patients with affective disorders on the basis of biological characteristics is well recognized, and much of the research in this area has focused on the serotonergic system. Biological subtyping can be approached using both peripheral and central markers. Peripheral markers include platelet serotonin concentrations, the density and affinity of platelet serotonin reuptake and platelet 5-HT2 receptors, and plasma serotonin concentrations. Central markers include cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations, and endocrine, psychological and body temperature responses to challenge tests with a number of serotonergic drugs. More recently, the role of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic drugs in sleep, and in the control of cardiovascular homeostasis, has been studied. This may provide a greater understanding of the mechanisms of serotonin dysregulation in affective disorders, and may ultimately improve treatment of these conditions.

Human platelet 5-HT2 receptor binding sites re-evaluated: a criticism of current techniques [corrected

The human platelet 5-HT2 receptor may resemble a peripheral model of central 5-HT2 binding sites and has been linked to changes in 5-HT2 receptor function in depression. Therefore, evaluation of the human platelet 5-HT2 binding characteristics is important. Comparing [3H]ketanserin and [3H]LSD as ligands clearly indicated [3H]LSD as ligand of choice for binding studies dealing with the human platelet 5-HT2 receptor. [3H]LSD binding was specific, saturable, and depended upon incubation time, protein concentration and previous handling of tissue, i.e., use of fresh or frozen tissue. In contrast, studies with [3H]ketanserin were unsatisfactory. Although mean receptor densities and affinities have been relatively constant between individuals and over time in healthy subjects with [3H]LSD, examination of the individual data showed considerable variations within single subjects. Thus, KD ranged between 0.50 and 0.68 nM, and Bmax was in the range of 64.9 to 97.1 fmol/mg protein in healthy individual subjects. Therefore, we recommend [3H]LSD as ligand of choice to study platelet 5-HT2 receptor binding in humans. Furthermore, repeated measurement of individual data over time should be interpreted cautiously, especially when data from depressed patients are under examination.