RESUMEN
Bulimia Nervosa (BN) is a serious eating disorder, which affects 0.8-2.9% of the young population. The etiology is unknown and biomarkers would support in understanding the pathophysiology of BN, and in identifying BN patients that may benefit from medical treatment. This systematic review aims to answer whether (a) BN deviate from healthy controls in terms of serotonin (5-HT) biomarkers in blood, and whether (b) blood-based 5-HT biomarkers could be used to tailor psychopharmacological treatment in BN. A literature search using PubMed, PsycINFO and Embase was done using the following search terms: "Bulimia Nervosa" AND "serotonin" AND "blood" OR "plasma" OR "serum". 32 studies were included in this systematic review. Several biomarkers and challenge tests were identified and all studies described an association with BN and dysregulation of the 5-HT system compared to healthy controls. Several studies pointed to an association also to borderline symptoms in BN. BN deviate from healthy controls in terms of 5-HT biomarkers in blood supporting an abnormal 5-HT system in BN. 5-HT biomarkers and associated methods could be used to tailor treatment in BN although as yet, most tests described are unpractical for bedside use.
Asunto(s)
Bulimia Nerviosa/sangre , Bulimia Nerviosa/diagnóstico , Serotonina/sangre , Biomarcadores/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/sangre , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Humanos , Receptores de Serotonina/sangre , Triptófano/sangreRESUMEN
PURPOSE: To determine platelet serotonin (5-HT) concentrations and genotype and allele frequencies of serotonergic type 2A receptor gene (HTR2A) and 5-HT transporter gene (SLC6A4) in women with pre-eclampsia, gestational hypertension without proteinuria (PIH) and in control normotensive pregnant women. METHODS: The study included 96 control women, 131 women with PIH and 84 women with pre-eclampsia (ICD-10 criteria) in the last trimester of pregnancy. Variants of the HTR2A T102C (rs6313) and SLC6A4 (5-HTTLPR and rs25531) were determined by the PCR and real-time PCR procedures. Platelet 5-HT concentrations were analyzed by the spectrofluorimetric method. RESULTS: The frequency of the 5HTTLPR and of HTR2A T102C genotypes or alleles was similar between three groups of pregnant women and was not associated with low platelet 5-HT concentrations observed in pregnant women with PIH or pre-eclampsia. CONCLUSIONS: The results confirm alterations in the peripheral 5-HT system in pregnancy-induced hypertension. Low platelet 5-HT concentration is a common feature of both PIH and pre-eclampsia. The results did not support the hypothesis that hypertension in pregnancy is a trait associated with polymorphic variants of the HTR2A and SLC6A4 or that they have a role in the predisposition to hypertensive disorders in pregnancy. The further studies are necessary to elucidate the role of 5-HT and genetic factors in the development of hypertensive disorders in pregnancy.
Asunto(s)
Plaquetas/metabolismo , Hipertensión Inducida en el Embarazo/sangre , Preeclampsia/sangre , Receptor de Serotonina 5-HT2A/genética , Receptores de Serotonina/sangre , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Alelos , Presión Sanguínea/fisiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Hipertensión/complicaciones , Hipertensión Inducida en el Embarazo/etiología , Preeclampsia/etiología , Embarazo , Tercer Trimestre del Embarazo , Proteinuria , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Serotonina/genética , Factores de RiesgoRESUMEN
We investigated whether platelet-tritiated paroxetine binding, a measure of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity, and aggression--though not craving--among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.
Asunto(s)
Agresión/fisiología , Población Negra , Plaquetas/metabolismo , Trastornos Relacionados con Cocaína/sangre , Impulso (Psicología) , Conducta Impulsiva/sangre , Receptores de Serotonina/sangre , Población Urbana , Adulto , Agresión/psicología , Atención Ambulatoria , Proteínas Portadoras/metabolismo , Trastornos Relacionados con Cocaína/diagnóstico , Trastornos Relacionados con Cocaína/rehabilitación , Femenino , Humanos , Conducta Impulsiva/diagnóstico , Masculino , Paroxetina/farmacocinética , Determinación de la Personalidad , Philadelphia , Ensayo de Unión Radioligante , Receptores de Droga/metabolismo , Valores de Referencia , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Síndrome de Abstinencia a Sustancias/sangre , Síndrome de Abstinencia a Sustancias/diagnóstico , Síndrome de Abstinencia a Sustancias/rehabilitaciónRESUMEN
The 5-HT2A receptor binding parameters using [3H]ketanserine and its intracellular signal inositol 1,4,5 trisphosphate (IP3) concentrations were determined in platelets from schizophrenic patients so as to assess differences with respect to a control group and to a standardized antipsychotic drug treatment. Seventy-five antipsychotic-free patients with a DSM-IV diagnosis of paranoid schizophrenia were included in the study. Blood samples were collected before the onset of antipsychotic treatment (baseline values) and after 3 weeks of treatment. Antipsychotic-free schizophrenic patients showed significantly increased basal 5-HT2A densities in comparison to the control group, together with a significantly increase (23%) in the 5-HT2A binding density in those patients treated with risperidone. These changes could be attributed to an up-regulation of 5-HT2A receptors caused by previous treatment with antipsychotic drugs, which is consistent with the chronic effect of 5-HT2A antagonists to up-regulate the number of binding sites. With regard to second messenger IP3 concentrations, basal concentrations in schizophrenic patients were not significantly different from control values, nor was there any significant difference between basal vs. posttreatment values. These results are possibly related to failure of second messenger systems of 'translating' extracellular messages generated presynaptically into effective neurotransmitter signals in schizophrenic patients.
Asunto(s)
Plaquetas/metabolismo , Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Serotonina/sangre , Esquizofrenia/sangre , Adulto , Antipsicóticos/administración & dosificación , Plaquetas/efectos de los fármacos , Estudios de Casos y Controles , Femenino , Humanos , Ketanserina/metabolismo , Masculino , Receptor de Serotonina 5-HT2A , Receptores de Serotonina/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Factores de Tiempo , TritioRESUMEN
Serotonin 5-HT(1A) receptors were characterized in rat resting lymphocytes obtained by cardiac puncture with the use of the ligand [3H]8-hydroxy-2-(di-n-propylamino)tetralin. Selectivity of the specific binding was demonstrated by inhibition experiments with various serotonergic and nonserotonergic drugs. The rank order of potency for inhibition was WAY-100478>pindobind>NAN-190>buspirone>imipramine>serotonin. While pimozide, desipramine, nomifensine, haloperidol and sulpiride did not inhibit the binding. Kinetic parameters calculated from saturation experiments indicated one site of interaction, with an equilibrium dissociation constant of 2.50 nM and maximum binding capacity of 487.21 nmol/10(6) cells. Complete dissociation was obtained with serotonin as the displacement agent, and equilibrium dissociation constant calculated by association and dissociation experiments was 2.03 nM. Thus, serotonin 5-HT(1A) receptors are present in resting lymphocytes. The in vivo administration of the mitogens lipopolysacharide (0.1 mg/kg, 18 h) or concanavalin A (0.2 mg/kg, 18 h) increased the number of sites. The elevation produced by the latter was of higher magnitude than that of lipopolysacharide, and two sites of the binding were determined by isotopic dilution. Immobilization stress (1 h daily for 7 days) also resulted in a significant increase of binding capacity, but was smaller than that produced by the mitogens. The affinity of binding was not affect by the treatments. The results indicate that serotonin 5-HT(1A) receptors are modulated by unspecific and specific immune system activation, as well as by a potent stress condition, which might result in relevant functional modifications in the response of rat lymphocytes.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/sangre , Concanavalina A/farmacología , Inmovilización/fisiología , Linfocitos/metabolismo , Agonistas de Receptores de Serotonina/sangre , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Buspirona/metabolismo , Buspirona/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cinética , Lipopolisacáridos/metabolismo , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Masculino , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/sangre , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Estrés Fisiológico/sangre , Estrés Fisiológico/inmunologíaRESUMEN
BACKGROUND: Studies of the 5-HT(2A) receptor subtype in major depression have focused on the density of these receptors in neuronal cells and platelets, showing an up-regulation secondary to a deficit in serotonergic activity in major depression. However, their functional state has often been disregarded. The aim of the study was to investigate whether depressed patients show abnormalities in the function of the 5-HT(2A) receptor pathway in platelets. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was assessed in 30 untreated patients with major depressive disorder and in 15 controls. Since 5-HT(2A) platelet receptors mediate the serotonin-induced platelet aggregation response, this index was used as a measure of the functional status of the platelet 5-HT(2A) receptor pathway. RESULTS: There was no significant difference in the percentage of serotonin-amplified platelet aggregation to ADP between depressed patients and controls. No correlation with the severity of depression, as assessed by the Hamilton scale, was found. CONCLUSION: The results showed no consistent changes in the platelet aggregating responses to serotonin in the depressed patients. Therefore this study does not support the hypothesis of an alteration of the functional status of platelet 5-HT(2A) receptors in major depression.
Asunto(s)
Plaquetas/metabolismo , Trastorno Depresivo Mayor/sangre , Agregación Plaquetaria/efectos de los fármacos , Receptores de Serotonina/sangre , Adenosina Difosfato/farmacología , Adulto , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Nefelometría y Turbidimetría , Escalas de Valoración Psiquiátrica , Receptor de Serotonina 5-HT2A , Serotonina/farmacología , Caracteres SexualesRESUMEN
BACKGROUND: Several studies support the notion that disturbances in the central serotonergic function are related to impulsive aggression. There is recent evidence from studies on 5-HT(1B) knock-out mice that this specific receptor is involved in impulsive aggressive behavior. The aim of the present study was to investigate 5-HT(1B/1D) receptor functioning in normal intelligent hospitalized children with oppositional defiant disorder (ODD). METHODS: The growth hormone (GH) response to a challenge with the 5-HT(1B/1D) agonist sumatriptan was examined in 20 children with an ODD, of whom 13 had an attention-deficit/hyperactivity disorder comorbidity, and 15 normal control subjects (NC). Blood samples for growth hormone were collected repeatedly between 8:30 and 12:00 AM. Sumatriptan was administered at 10 AM. The effect of stress due to this procedure was assessed by measuring salivary cortisol. RESULTS: The GH response was significantly stronger in the children with ODD. After sumatriptan injection NC children showed a significant increase in cortisol; no such pattern was present in the ODD group. CONCLUSIONS: The results suggest that the postsynaptic 5-HT(1B/1D) receptor is functionally more sensitive in children with ODD.
Asunto(s)
Déficit de la Atención y Trastornos de Conducta Disruptiva/tratamiento farmacológico , Déficit de la Atención y Trastornos de Conducta Disruptiva/fisiopatología , Receptores de Serotonina/sangre , Agonistas de Receptores de Serotonina/uso terapéutico , Serotonina/sangre , Sumatriptán/uso terapéutico , Agresión/efectos de los fármacos , Análisis de Varianza , Niño , Femenino , Hormona del Crecimiento/sangre , Hospitalización , Humanos , Conducta Impulsiva/terapia , Masculino , Receptores de Serotonina/fisiología , Serotonina/fisiologíaRESUMEN
Recent evidence from our laboratory and others have suggested that the mechanism for a decrease in resting blood pressure after an acute bout of exercise is a centrally mediated decrease in total peripheral resistance. This study examined the effect of the central serotonergic system on post exercise hypotension (PEH) in 11 borderline hypertensive individuals (nine male, two female) aged 24.5 +/- 5.1 years. Each subject completed two, 30-min cycling bouts at 70% of VO2peak while under placebo or a selective serotonin re-uptake inhibitor (SSRI) treatment. Blood pressure was recorded directly from the radial artery, and treatments were randomised, double blinded and separated by at least 14 days. Baseline blood pressure was 145/72 mm Hg for systolic (SBP) and diastolic (DBP) respectively. Peripheral measures of serotonin (5-HT) were lower under SSRI treatment, whereas the major 5-HT metabolite, 5-hydroxyindoleacetic acid, was not significantly changed, indicating elevated central 5-HT levels. There was no difference in any of the haemodynamic variables between trials. Despite an increased heart rate for the initial 75 min post exercise, SBP was decreased as much as 23 mm Hg during the initial 60 min post exercise, after which it had returned to normal. DBP was unchanged after exercise. Circulating adrenaline (0.60 +/- 0.14 ng/mL to 1.3 +/- 1.6 ng/ml) and noradrenaline (0.27 +/- 0.31 ng/ml to 4.5 +/- 2.1 ng/ml) were significantly elevated during exercise. Both returned to pre-exercise levels within 15 min post exercise. Unexpectedly, oxygen uptake was slightly (5%), but significantly increased over the entire duration of the SSRI trial. We conclude that the central serotonergic system is not responsible for PEH in our borderline hypertensive population.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Ejercicio Físico/fisiología , Hipertensión/fisiopatología , Hipotensión/fisiopatología , Paroxetina/farmacología , Receptores de Serotonina/efectos de los fármacos , Receptores de Serotonina/fisiología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/fisiología , Adulto , Prueba de Esfuerzo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Ácido Hidroxiindolacético/sangre , Hipertensión/sangre , Hipotensión/sangre , Masculino , Receptores de Serotonina/sangre , Serotonina/sangreRESUMEN
It has been reported that platelet intracellular calcium (Ca) response stimulated by serotonin (5-HT) is enhanced in unmedicated patients with some types of mood disorders compared to normal subjects. However, the mechanism of this enhancement has not been elucidated. In this study, at first, I examined whether the enhanced 5-HT-induced Ca response was specific to some types of mental disorder. Then, the relationship between the 5-HT-induced platelet intracellular Ca rise and the density of 5-HT2A receptors on the platelets of normal subjects was investigated. Furthermore, effects of modulators of two main signal transduction systems, protein kinase C (PKC) and calmodulin (CaM), on 5-HT-induced platelet intracellular Ca response in the platelets of normal subjects were examined. As a result, the specificity to bipolar disorder among several psychiatric disorders was observed in enhanced 5-HT-induced Ca mobilization. There was no correlation between Ca response to 5-HT and the Bmax of 5-HT2A receptors. Pretreatment with PKC activator (PMA) dose-dependently reduced the Ca response induced by 5-HT, while pretreatment with CaM antagonist (10-30 microM W-7), myosin light chain kinase inhibitor (30 microM ML-9) or Ca/CaM-dependent protein kinase II inhibitor (10 microM KN-93) increased the Ca response with no remarkable changes in basal Ca level. But PKC inhibitors (bisindolylmaleimide II and staurosporine) failed to increase the Ca response at every dose. Pre-incubation with 10 mM lithium reduced the enhanced Ca response to 5-HT induced by 30 microM W-7. These findings suggest the possibility that calmodulin dysfunction might be involved in the mechanism of enhanced intracellular Ca response to 5-HT in bipolar disorder.
Asunto(s)
Plaquetas/metabolismo , Calcio/sangre , Trastornos del Humor/etiología , Serotonina/farmacología , Adulto , Antidepresivos/farmacología , Calcio/fisiología , Calmodulina/fisiología , Femenino , Humanos , Litio/farmacología , Masculino , Proteína Quinasa C/fisiología , Receptor de Serotonina 5-HT2A , Receptores de Serotonina/sangre , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: To examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide (LSD) to the platelet 5-HT(2A) receptor are influenced by postmenopausal estrogen/progestogen treatment. METHODS: Twenty-three postmenopausal women with climacteric symptoms completed this double-blind, randomized, crossover study. The women received 2 mg of estradiol continuously during four 28-day cycles. In the last 14 days of each cycle, 10 mg of medroxyprogesterone acetate, 1 mg of norethindrone acetate, or placebo was given. Before treatment, as well as once during the last week of each treatment, blood samples were collected for analysis of [3H]LSD and [3H]paroxetine binding. The power of the study setup was 81%. The study had an effect size of 0.36, corresponding to the ability to detect a 15% difference in [3H]paroxetine and [3H]LSD binding between treatments with alpha =.05 and beta =.20, based on a previously reported standard deviation within cells of 20% of the mean binding values. RESULTS: The number of platelet receptors (B(max)), or the affinity of the radioligand to the receptor (K(d)), for [3H]paroxetine binding did not change during estrogen or estrogen-progestogen treatment, nor did B(max) or K(d) for [3H]LSD binding change during the different treatments. However, in a subgroup of depressed patients, the decrease in B(max) for [3H]LSD binding during treatment was significantly more pronounced than in the nondepressed subgroup (P <.05). CONCLUSION: Estrogen treatment with or without the addition of progestogen does not affect binding to the serotonin transporter or to the serotonergic 5-HT(2A) receptor in healthy postmenopausal women.
Asunto(s)
Plaquetas/metabolismo , Terapia de Reemplazo de Estrógeno , Síndrome Premenstrual/sangre , Receptores de Serotonina/sangre , Proteínas Portadoras/fisiología , Estudios Cruzados , Método Doble Ciego , Estradiol/farmacología , Estradiol/uso terapéutico , Femenino , Humanos , Dietilamida del Ácido Lisérgico/metabolismo , Acetato de Medroxiprogesterona/farmacología , Acetato de Medroxiprogesterona/uso terapéutico , Persona de Mediana Edad , Paroxetina/metabolismo , Congéneres de la Progesterona/farmacología , Congéneres de la Progesterona/uso terapéutico , Ensayo de Unión RadioliganteRESUMEN
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.
Asunto(s)
Plaquetas/metabolismo , Ketanserina/metabolismo , Trastornos Migrañosos/sangre , Receptores de Serotonina/sangre , Antagonistas de la Serotonina/metabolismo , Adulto , Femenino , Humanos , Cinética , Masculino , Unión Proteica , Receptores de Serotonina/fisiología , Serotonina/fisiologíaRESUMEN
Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.
Asunto(s)
Plaquetas/metabolismo , Buserelina/administración & dosificación , Síndrome Premenstrual/sangre , Receptores de Serotonina/sangre , Serotonina/sangre , Adulto , Buserelina/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Femenino , Fase Folicular , Humanos , Fase Luteínica , Dietilamida del Ácido Lisérgico/sangre , Paroxetina/sangre , Placebos , Síndrome Premenstrual/tratamiento farmacológico , Receptor de Serotonina 5-HT2A , Antagonistas de la Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , TritioRESUMEN
BACKGROUND: Several studies on serotonin 1A (5-HT(1A)) receptor knockout mice in different genetic backgrounds indicate that such mice display a more anxious phenotype than their corresponding wild types. We hypothesized that the 5-HT(1A) receptor knockout mice would show a different phenotype than the wild type mice in the stress-induced hyperthermia (SIH) paradigm, which tests putative anxiolytic effects of drugs. Moreover, on pharmacologic challenges with the 5-HT(1A) receptor agonist flesinoxan we expected an absence of the functional response in knockout mice relative to wild type mice. METHODS: Effects of the 5-HT(1A) receptor agonist flesinoxan, alone or in combination with the 5-HT(1A) receptor antagonist WAY-100635, and the gamma-aminobutyric acid A (GABA(A))-benzodiazepine receptor agonist diazepam were studied in the SIH paradigm in male 129/Sv 5-HT(1A) receptor knockout and wild type mice. In addition, the effects of flesinoxan on plasma corticosterone concentrations were determined. RESULTS: Plasma corticosterone concentrations were dose dependently elevated by flesinoxan in wild type mice but not in knockout mice. Flesinoxan dose dependently decreased SIH in wild type mice but not in knockout mice. The flesinoxan effect in wild type mice was blocked by WAY-100635. Furthermore, diazepam decreased SIH in both genotypes. There were no differences in basic SIH responses between wild type and knockout mice. CONCLUSIONS: 5 -HT(1A) receptor knockout mice display a normal SIH response, and results indicate, based on the SIH, that the GABA(A)-benzodiazepine receptor complex functions normally.
Asunto(s)
Fiebre/metabolismo , Receptores de Serotonina/efectos de los fármacos , Serotoninérgicos/farmacología , Estrés Psicológico/metabolismo , Animales , Corticosterona/sangre , Diazepam/farmacología , Fiebre/sangre , Fiebre/genética , Moduladores del GABA/farmacología , Masculino , Ratones , Ratones Noqueados , Análisis Multivariante , Piperazinas/farmacología , Piridinas/farmacología , Receptores de Serotonina/sangre , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Estrés Psicológico/sangreAsunto(s)
Plaquetas/metabolismo , Citalopram/efectos adversos , Receptores de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Sodio/sangre , Sodio/deficiencia , Anciano , Anciano de 80 o más Años , Plaquetas/efectos de los fármacos , Citalopram/sangre , Demencia/sangre , Demencia/complicaciones , Electrólitos/sangre , Femenino , Humanos , Masculino , Receptor de Serotonina 5-HT2A , Inhibidores Selectivos de la Recaptación de Serotonina/sangreRESUMEN
Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0.55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.
Asunto(s)
Encéfalo/metabolismo , Receptores de Serotonina/metabolismo , Adulto , Encéfalo/diagnóstico por imagen , Cerebelo/metabolismo , Estudios de Evaluación como Asunto , Humanos , Cinética , Masculino , Modelos Biológicos , Piperazinas/farmacocinética , Piridinas/farmacocinética , Receptores de Serotonina/sangre , Receptores de Serotonina 5-HT1 , Reproducibilidad de los Resultados , Antagonistas de la Serotonina/farmacocinética , Tomografía Computarizada de EmisiónRESUMEN
The frequency distribution of platelet 5-HT(2A) receptor densities (measured as [3H]LSD B(max)) was analysed in 60 patients with major depression and 40 matched control subjects to determine whether the observed receptor densities come from a single distribution or whether there are more distributions that are represented differently in control subjects and in diagnostic subgroups of non-suicidal and suicidal patients. The distribution of B(max) values in all subjects was tested by using the NOCOM program. The analysis has shown a best fit for a trimodal distribution of values (low, intermediate and high binding). There were significant differences in average probabilities of control subjects and patients from the two diagnostic subgroups belonging to any of the three distributions. In the control and non-suicidal groups, a significantly higher (P=0.003) proportion of individuals had a probability of belonging to a low binding distribution. In contrast, the probability of belonging to the high distribution was significantly greater (P=0.007) in the suicidal group of patients than in the non-suicidal group or in control subjects. In all three groups, the proportion of cases in each distribution fit those expected under the Hardy-Weinberg equilibrium. The results support the notion that high 5-HT(2A) receptor density is a marker of suicidality, possibly genetically determined.
Asunto(s)
Trastorno Depresivo Mayor/metabolismo , Receptores de Serotonina/sangre , Intento de Suicidio/psicología , Unión Competitiva/fisiología , Plaquetas , Recuento de Células , Humanos , ProbabilidadRESUMEN
The author reviews the current status of the platelet serotonin (5-HT)(2A) receptor in depression. Considered are studies of receptor binding, and 5-HT-induced platelet activation and aggregation. 5-HT(2A) receptor density tends to increase in depression, although this more clearly relates to suicidality than depression per se. Indeed, data are consistent with the hypothesis that increased density of platelet 5-HT(2A) receptors may be a marker for increased risk of suicide. 5-HT-induced calcium mobilization is enhanced in unipolar depression; however, unlike in bipolar depression, baseline calcium levels are not. Despite inconsistencies, 5-HT-induced aggregation appears inhibited in depression. This may manifest as a relative inhibition, i.e. no change in aggregation response despite a higher density of 5-HT(2A) receptors. The inhibited aggregation response is state dependent, and acute phase proteins or components of the stress response may be factors. It is unclear if differences between depressed and normal subjects in disposition of 5-HT(2A) receptors are generally indicative of traits or states. Nonetheless, there is little evidence that the degree of departure from normal density or activity of platelet of 5-HT(2A) receptors reflects severity of depression.
Asunto(s)
Plaquetas/fisiología , Trastorno Depresivo/sangre , Receptores de Serotonina/sangre , Humanos , Activación Plaquetaria , Agregación Plaquetaria , Unión ProteicaRESUMEN
It is well known that abnormalities in the brain serotonin system exist in patients with dementia. The present study was performed in order to investigate whether a peripheral serotonin system marker, the platelet 5-HT2A receptor, is affected in dementia. Thirty-eight patients with Alzheimer's disease (AD), 13 patients with vascular dementia, and 40 healthy controls were included in the study. There were no significant differences in receptor density for 5-HT2A receptor binding between the groups. Affinity of the radioligand to the receptor was significantly lower in AD than in vascular dementia and in the controls (p = .006 and p = .003, respectively), whereas there was no significant difference between the vascular dementia group and the control group. In 12 patients, treatment with citalopram was started due to depression or agitation. This treatment significantly reduced the Behavioral Pathology in Alzheimer's Disease Rating Scale scores (p = .001), but did not affect the platelet 5-HT2A receptor status. There was no correlation between 5-HT2A receptor status before treatment and the therapeutic effect of citalopram. The study indicates that platelet 5-HT2A receptor status is of limited value as a peripheral marker in dementia.
Asunto(s)
Enfermedad de Alzheimer/sangre , Plaquetas/metabolismo , Citalopram/uso terapéutico , Demencia Vascular/sangre , Receptores de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/tratamiento farmacológico , Biomarcadores/sangre , Estudios de Casos y Controles , Cognición/efectos de los fármacos , Demencia Vascular/tratamiento farmacológico , Femenino , Humanos , Masculino , Escalas de Valoración Psiquiátrica , Receptor de Serotonina 5-HT2A , Receptores de Serotonina/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: The central serotonergic system has been implicated in the pathophysiology of depression and in the mechanism of the action of antidepressant drugs. The human platelet has been proposed as a peripheral model of central serotonergic neurons. METHODS: Six peripheral serotonergic parameters were determined simultaneously in 27 patients with unipolar depression before and after 2, 4, and 12 weeks of clomipramine or fluoxetine treatment according to the psychiatrist. RESULTS: In patients with depression versus matched control subjects, platelet [3H]paroxetine binding sites were found to be significantly decreased (2.10 +/- 0.70 versus 3.88 +/- 0.77 fmol/10(9) platelets; P = .0001), platelet serotonin (5-HT) content was found to be significantly decreased (1.90 +/- 1.52 versus 2.74 +/- 1.12 nmol/10(9) platelets; P = .001), and platelet inositol triphosphate levels were found to be significantly increased (2.85 +/- 0.70 versus 1.85 +/- 0.77 fmol/10(9) platelets; P = .0001). No significant difference between patients and control subjects was found for platelet [3H]-lysergic acid diethylamide ([3H]LSD) binding sites, aggregation tests with 5-HT or adenosine diphosphate and plasma 5-HT levels. Treatment with both clomipramine and fluoxetine gradually further reduced the density of platelet [3H]paroxetine binding sites and induced a dramatic decrease in platelet and plasma 5-HT levels. With clomipramine, the decreased blood 5-HT levels are associated with increased platelet [3H]LSD binding sites and aggregation responses. After 12 weeks, nonresponders to both treatments had platelet inositol triphosphate levels that were still increased (2.81 +/- 0.75 fmol/10(9) platelets) when responders levels were not different from those of control subjects (1.41 +/- 0.45 versus 1.70 +/- 0.25 fmol/10(9) platelets). CONCLUSIONS: Drug-free patients with depression had simultaneously decreased 5-HT transporter (5-HTT) sites and overstimulated phosphoinositide signaling systems. Clomipramine and fluoxetine treatments, which further decreased the density of 5-HTT sites, allowed platelet inositol triphosphate levels to return to normal values only in responders.
Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Antidepresivos Tricíclicos/farmacología , Plaquetas/metabolismo , Clomipramina/farmacología , Trastorno Depresivo/sangre , Fluoxetina/farmacología , Inositol 1,4,5-Trifosfato/sangre , Receptores de Serotonina/sangre , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Adulto , Estudios de Casos y Controles , Trastorno Depresivo/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Paroxetina/farmacología , Agregación Plaquetaria/efectos de los fármacos , Factores de TiempoRESUMEN
Possible age effects on binding of [(3)H]lysergic acid diethylamide ([(3)H]LSD) to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites were studied in platelets from healthy children (11-12 years of age), adolescents (16-17 years of age) and adults. Significant overall age effects were found both for the number of binding sites (B(max)) for [(3)H]LSD binding (p < 0.001), the affinity constant (K(d)) for [(3)H]LSD binding (p < 0.001), B(max) for [(3)H]paroxetine binding (p < 0.001) and K(d) for [(3)H] paroxetine binding (p = 0.006). In general, there was a decrease in B(max) with increasing age, which predominantly occurred between the ages 11-12 years and 16-17 years for the 5-HT(2A) receptor, and after 16-17 years of age for the serotonin uptake site. These developmental changes might have an impact on the effect of treatment with serotonergic drugs in children and adolescents. When the platelet serotonin variables investigated are employed in studies in children or adolescents, age matching or, alternatively, introduction of age control in the statistical analysis should be performed.