Serotonin 5-HT2A receptor polymorphisms are associated with irritability and aggression in conduct disorder.

In childhood and adolescence, overt antisocial and aggressive manifestations are typically diagnosed as conduct disorder (CD). Given that the emerging research has pointed to the influence of 5-HT2A receptors in the ontogeny of aggression, we aimed to analyze the association of its genetic polymorphisms with CD. The study included 228 male adolescent subjects (120 with and 108 without CD). CD was diagnosed according to Structured Clinical Interview for DSM-IV criteria, while evaluations of aggressive/dissociative behaviors were performed using psychometric questionnaires including the PCL-YV, OAS-M, KADS, and CBCL. Platelet 5-HT concentration was determined by spectrophotofluorometry. Genotyping of 5-HT2A receptor polymorphisms rs2070040, rs9534511, rs4142900, rs9534512 was performed using TaqMan SNP Genotyping Assays. Subjective irritability, physical aggression toward others, and antisocial behavior were strongly associated with the G allele of rs2070040 and rs4142900, and the C allele of rs9534511 and rs9534512. A significantly increased platelet 5-HT concentration in CD subjects, compared to controls, was lost after the correction according to the smoking status. Our results indicate an association of the studied HTR2A polymorphisms and their haplotypes with irritability and impulsivity traits, which may contribute to the aggressive and antisocial behavior in male adolescents with CD.

Whole Blood Serotonin Levels and Platelet 5-HT2A Binding in Autism Spectrum Disorder.

Elevated whole blood serotonin (WB5-HT) is a well-replicated biomarker in autism spectrum disorder (ASD). Decreased platelet serotonin receptor 5-HT2A binding has been reported in ASD. WB5-HT levels and platelet 5-HT2A specific binding were obtained from 110 individuals with ASD and 18 controls. Individuals with ASD had significantly higher WB5-HT levels than controls. There was no difference in the platelet 5-HT2A specific binding between groups. Multiple regression analyses revealed that platelet 5-HT2A binding significantly predicted WB5-HT in the control sample but not in the ASD sample. These results indicate that the relationship between WB5-HT and platelet 5-HT2A binding differs depending on ASD diagnosis, suggesting differences in platelet 5-HT system regulation in ASD.

Extract of Yokukansan improves anxiety-like behavior and increases serum brain-derived neurotrophic factor in rats with cerebral ischemia combined with amyloid-42 peptide.

OBJECTIVE: To examine the effects of Yokukansan (YKS) extract on two endogenous modulators of anxiety, brain-derived neurotrophic factor (BDNF) and serotonin (5-HT)2A receptors pharmacologically, in the ischemic rat model of dementia. METHODS: The cerebral ischemia (CI) was induced by bilateral occlusion of the vertebral and common carotid arteries (4-vessel occlusion ischemia). The CI was combined with the amyloid-ß42 peptide (Aß42) injected intracerebroventricularly, and referred to as CI+Aß. Anxiety-like behaviors were assessed by elevated plus maze (enclosed arm), light/dark transition test (dark chamber), and open-field test. Wet-dog shakes were induced by the 5-HT2A receptor agonist 2, 5-dimethoxy-4-iodoamphetamine (DOI). The concentration of BDNF in serum was determined by enzyme-linked immuno sorbent assay. RESULTS: CI + Aß increased anxiety, as demonstrated by the increase of time spent in the enclosed arms and dark chambers, and locomotion in the outer zone of the open field (thigmotaxis). CI + Aß decreased the serum concentration of BDNF. YKS reduced the anxiety-like behaviors, suppressed the DOI-induced wet-dog shakes and increased serum BDNF concentrations. CONCLUSION: Our findings suggest that YKS extract improves CI + Aß-induced anxiety by antagonizing 5-HT2A receptors and increasing BDNF.

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines.

BACKGROUND: Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. METHODS: This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. RESULTS: The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. CONCLUSIONS: The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.

Multiple tissue methylation analysis of HTR2A exon I in suicidal behavior.

OBJECTIVE: The main aim of the current study was to investigate epigenetic alterations in serotonin 2A receptor (HTR2A) exon I CpG sites as possible risk factors for suicidal behavior. We also aimed to analyze the epigenetic alterations in two different tissues as epigenetic mechanisms are tissue specific. These epigenetic changes may lead to a better prediction of suicidal behavior. METHODS: Direct CpG methylation analysis was carried out on genomic DNA from the saliva of 20 schizophrenia suicide attempters and 27 non-attempters, and from post-mortem brain tissues of nine suicide victims and 11 controls. We used bisulfite pyrosequencing to assess the contributions of six CpG sites including the rs6313 (C102T) site in the first exon of HTR2A in suicide attempters and suicide victims. RESULTS: DNA methylation analysis did not find a significant difference in CpG methylation between suicide attempters and non-attempters (P=0.759) or between suicide victims and controls (P=0.189). We found a strong positive correlation between CpG methylation levels in blood and saliva (r=0.547, P<0.001). DISCUSSION: DNA methylation analysis confirmed that the overall methylation level of HTR2A exon I was around 80% for DNA extracted from saliva and almost 30% in the frontal cortex DNA. The results of this investigation do not support the evidence that methylation analysis of the HTR2A may be useful for investigating the epigenetic factors involved in suicidal behavior.

Serotonin 2A receptor clustering in peripheral lymphocytes is altered in major depression and may be a biomarker of therapeutic efficacy.

BACKGROUND: In a previous report, we showed that the clustering of serotonin (5HT) transporter (SERT) protein on cell membranes of peripheral lymphocytes predicts responsivity to antidepressant medication in two subpopulations of naïve depression patients (Rivera-Baltanas et al., J Affect Disord, 2012, 137, 46-55). In this study, we extended this idea to 5-HT2A receptor clusters in a similar patient population. METHODS: We collected blood samples from a subset of patients from our previous study on SERT clustering (20 untreated and newly diagnosed depression patients, and 20 matched control subjects). Blood samples were collected at the time of diagnosis and after 8 weeks of pharmacological treatment and at analogous times in control subjects. We used the Hamilton scale to quantify the level of depression in patients both before and after treatment. We then used immunocytochemistry to assess 5-HT2A receptor clusters in lymphocytes at the same time points. RESULTS: We found that both the size and number of 5-HT2A receptor clusters were increased in naïve depression patients compared to control subjects. Interestingly, there were individual differences in the distribution of 5-HT2A receptor cluster size that allowed us to differentiate the depression patients into two subgroups: a D-I group and a D-II group. After 8 weeks of pharmacological treatment, patients in both groups showed an improvement of symptoms, but patients in the D-II group had a much better outcome with many of them showing remission of symptoms. Furthermore, although treatment decreased cluster number and size in both D-I and D-II groups, only the D-II patients showed an increase in the number of clusters within the modal peak. Importantly, the same patients that belonged in the D-I or D-II groups in the present report were also assigned to the same groups in our previous study on SERT clustering. LIMITATIONS: The data should be replicated within a proper clinical trial. CONCLUSIONS: 5-HT2A receptor clusters in peripheral lymphocytes are altered in major depression, partially reversed by antidepressant treatment, and may be considered a putative biomarker of therapeutic efficacy in major depression.

Platelet serotonin transporter and 5-HT2A receptor binding in adolescents with eating disorders.

The pathogenetic involvement of the serotonergic system in eating disorders is an established finding. Conclusions from platelet studies are based on results from investigations of subjects with a mean age of 20 years or more. The aim was to investigate whether previous findings in adults are valid also for adolescents who are examined within a relatively short interval after the onset of the eating disorder. [(3)H]paroxetine binding to the platelet serotonin transporter and [(3)H]lysergic acid diethylamide ([(3)H]LSD) binding to the 5-HT2A receptor was studied in 15 female adolescents with eating disorders (11 with anorexia nervosa and 4 with clearly anorectic eating behaviour not fulfilling the criteria for anorexia nervosa) and 32 controls. The patients revealed a higher density of serotonin transporters and a lower density of 5-HT2A receptors compared with healthy controls of the same age (775 ± 165 vs. 614 ± 111 fmol/mg protein (p = 0.003) for [(3)H]paroxetine binding and 215 ± 59 vs. 314 ± 151 fmol/mg protein (p = 0.005) for [(3)H]LSD binding). The findings of increased density of platelet serotonin transporters and reduced density of 5-HT2A receptors differ from previous results in older patients. The lower patient age and the short duration of disease in the present study, possibly in conjunction with variations in stress-related psychological and biological factors, may have caused these differences. Although the present findings contradict prevailing evidence, they add further information concerning the nature of serotonergic involvement in eating disorders and indicate that demographic and course-related factors might influence the regulation of the serotonin system in these disorders.

The CC genotype in the T102C HTR2A polymorphism predicts relapse in individuals after alcohol treatment.

The serotonin system is hypothesized to contribute to predisposition and course of alcohol dependence. However, the potential association between the T102C polymorphism (rs6313) in the type 2A serotonin receptor (HTR2A) gene and treatment outcomes in alcohol dependence has not been investigated. The aim of the study was to assess the contribution of this genetic polymorphism as a predictor of relapse in relation to other previously identified predictors. A sample of 254 alcohol dependent subjects, were recruited in alcohol treatment centers in Warsaw, Poland and prospectively assessed at baseline and follow-up after 12 months. At baseline, information about demographics, psychopathological symptoms and alcohol problems was obtained. The stop-signal task was performed and blood samples for genetic analysis of HTR2A T102C (rs6313) were collected. Relapse was defined as any drinking during the follow-up period. The statistical analysis showed that the CC genotype was significantly associated with increased relapse. Other significant factors were baseline depressive symptoms, number of drinking days during the 3 months prior to the baseline assessment, severity of alcohol-related problems, and a lifetime history of impulsive suicide attempts. Logistic regression analysis with and without the genetic factor revealed that adding the genetic factor increased the R square value by about 4%, with the CC genotype in the T102C polymorphism being the strongest predictor of relapse (OR = 2.32). The significant influence on relapse of the CC genotype, which is associated with fewer 5-HT2A receptors in the central nervous system, suggests the possibility that this genetic polymorphism could influence response to serotonergic medications.

SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients.

Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)ß3, 5-HT2A, and 5-HT7 receptors, PKCß2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)ß3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCß2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCß2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis.

BACKGROUND: Release of serotonin and activation of serotonin 5HT2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier-generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT2A receptor subtype. OBJECTIVE: To assess whether targeted inhibition of the serotonin 5HT2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. METHODS: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury+stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. RESULTS: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow-time area (index of coronary patency; normalized to baseline coronary flow) averaged 58-59% (P<0.01) following administration of APD791 vs. 21-28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin-mediated platelet activation. CONCLUSION: 5HT2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.

APD791, 3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile, pharmacokinetics, platelet activity and vascular biology.

We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide] a novel 5-hydroxytryptamine 2A (5-HT(2A)) receptor antagonist. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT(2A) receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT(2A) receptor versus 5-HT(2C) and 5-HT(2B) receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC(50) = 8.7 and 23.1 nM, respectively). Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit aortic smooth muscle cells (IC(50) = 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT(2A) receptor antagonist with potent activity on platelets and vascular smooth muscle.

Hyperserotonemia in autism: activity of 5HT-associated platelet proteins.

Disturbances in serotonin (5HT) neurotransmission have been indicated as biological substrates in several neuropsychiatric disorders including autism. Blood 5HT concentrations, elevated in about one-third of autistic subjects, are regulated through the action of peripheral 5HT-associated proteins. We have measured the activity of two platelet 5HT-associated proteins: 5HT transporter (5HTT) and monoamine oxidase B (MAOB), and indirectly studied the activity of 5HT(2A) receptor (5HT(2A)r) in 15 hyperserotonemic (HS) and 17 normoserotonemic (NS) autistic subjects, and 15 healthy controls (C). While mean velocities of 5HTT kinetics did not significantly differ among the groups, significant elevation in the mean velocity of MAOB kinetics was observed in NS subjects and was even more pronounced in HS subjects in comparison to controls. Also, a decrease in adenosine 5'-diphosphate-induced platelet aggregation of borderline significance was observed in NS subjects, compared to C subjects. The results suggest a possibility of upregulation of monoaminergic synthesis/degradation and, probably consequential, downregulation of 5HT(2A)r in autistic subjects.

Clinical and serotonergic predictors of non-affective acute remitting psychosis in patients with a first-episode psychosis.

OBJECTIVE: The study aimed to establish clinical predictors of non-affective acute remitting psychosis (NARP) and assess whether these patients showed a distinct serotonergic profile. METHOD: First-episode never treated psychotic patients diagnosed of paranoid schizophrenia (n=35; 21 men and 14 women) or NARP (n=28; 15 men and 13 women) were included. RESULTS: NARP patients showed significantly lower negative symptomatology, better premorbid adjustment, shorter duration of untreated psychosis, more depressive symptomatology and a lower number of 5-HT2A receptors than the paranoid schizophrenia patients. In the logistic regression, the four variables associated with the presence of NARP were: low number of 5-HT2A receptors; good premorbid adjustment; low score in the item 'hallucinatory behaviour' and reduced duration of untreated psychosis. CONCLUSION: Our findings support the view that NARP is a highly distinctive condition different from either affective psychosis or other non-affective psychosis such as schizophrenia, and highlight the need for its validation.

[Investigation of association of the brain-derived neurotrophic factor (BDNF) and a serotonin receptor 2A (5-HTR2A) genes with voluntary and involuntary attention in schizophrenia].

To investigate the effect of Val66Met BDNF and 5-HTR2A T102C polymorphisms on the characteristics of voluntary and involuntary visual attention, 89 patients with schizophrenia, 91 their well relatives and 163 controls have been studied. Attention was assessed using a modified version of the Munsterberg test. The significant interaction effect of the BDNF, 5-HTR2A and diagnosis on attention characteristics was found (p=0,04). Carriers of the Val/Val genotype demonstrated higher scores of both voluntary and involuntary attention and those with the A1 (T) allele needed more time for the performance of the test. The combination of the A1 allele with a Met BDNF allele was associated with lower scores of voluntary attention and higher scores of involuntary attention. The study confirmed the impairment of selective attention in patients with schizophrenia and their relatives while any pathological changes in involuntary attention were not observed. The effect of genotypes was presented irrespective of diagnostic group studied. The data obtained suggest that carriers of the Val/Val genotype are able to allocate more attentional resources to process external stimuli. At the same time, the possibility that this polymorphism is likely associated with specific visual-spatial abilities than with attention as such or general cognitive resources can not be excluded.

Low baseline serotonin-2A receptors predict clinical response to olanzapine in first-episode schizophrenia patients.

The purpose of this study was to determine whether platelet serotonin-2A (5-HT2A) binding sites and inositol 1,4,5 trisphosphate (IP3) concentrations before treatment can identify olanzapine-responsive patients. The study included 21 never medicated, first-episode schizophrenia patients (antipsychotic-naïve) and 21 patients with a DSM-IV-TR diagnosis of paranoid schizophrenia who had not received depot antipsychotic treatment in the previous 6 months or oral antipsychotic or antidepressant treatment in the previous 2 months (antipsychotic-free). In the antipsychotic-naïve group, olanzapine responders had a significantly lower number of 5-HT2A receptors and lower IP3 concentrations at baseline than non-responders. The combination of baseline 5-HT2A and IP3 values significantly predicted an improvement in negative symptomatology after 6 weeks of treatment with olanzapine. In the antipsychotic-free group, responders had significantly higher positive and lower negative symptomatology at baseline, together with a reduced number of 5-HT2A receptors. However, basal 5-HT2A receptors or IP3 concentrations did not significantly predict positive, negative or general clinical response. The reported results suggest that platelet 5-HT2A binding might be a trait marker that could help to identify those patients likely to show greater improvement in negative symptomatology after olanzapine treatment.

Platelet 5-HT2A receptor subresponsivity and lethality of attempted suicide in depressed in-patients.

In depressed patients, high-lethality suicidal acts are accompanied by serotonin system abnormalities analogous to those seen in completed suicides. We have previously reported greater platelet 5-HT2A receptor density, and impaired serotonin enhancement of ADP-induced platelet aggregation, an indirect measure of signal transduction, in high-lethality suicide attempters. We hypothesized that serotonin-activated phosphoinositide (PI) hydrolysis, a direct measure of platelet serotonin 5-HT2A receptor responsivity would be lower in depressed high-lethality suicide attempters. Twenty-three depressed in-patients that had previously made suicide attempts (low-lethality, n=6; high-lethality, n=17) had platelet 5-HT2A-mediated serotonin-simulated PI hydrolysis assayed. Platelet 5-HT2A receptor responsivity in high-lethality suicide attempters was 41% that of low-lethality suicide attempters (p<0.05). A seasonal effect was also observed. High-lethality suicidal acts are associated with more 5-HT2A receptors but impaired signal transduction.

Platelet 5-HT2A receptor binding and tryptophan availability in depression are not associated with recent history of suicide attempts but with personality traits characteristic for suicidal behavior.

BACKGROUND: Abnormalities in the serotonergic (5-HT) system have been implicated in the pathogenesis of suicidal behavior. Studies on peripheral serotonergic parameters as a measure for central serotonergic function in suicidal patients appear to be promising, yet failed to show a clear association with suicidality. The objective of this study was to elucidate the role of serotonergic blood parameters in depressed suicidal patients and to examine their usefulness as a potential biological marker for suicidality. A number of personality traits were assessed in order to provide a basis for a psychobiological model of suicidal behavior. METHODS: Depressed patients with a recent suicide attempt (SA; n = 59) were compared to those without history of suicide attempts (NSA; n = 28). 5-HT2A receptor binding in platelets and tryptophan/amino acid ratio in plasma were measured. Acute psychopathology and personality traits as well as characteristics of suicide attempts were assessed. RESULTS: There was no significant difference between SA and NSA in terms of peripheral serotonergic parameters as well as personality traits. However, the whole sample showed associations between certain personality traits and serotonergic platelet parameters. Furthermore, we observed a relation between suicidal ideation, lethality of suicide attempts and peripheral serotonergic markers. LIMITATIONS: The number of cases with data on peripheral markers is relatively low. The potential influence of antidepressant medication previous to study inclusion has to be taken into account. The study focussed on depressed patients only. CONCLUSIONS: Low serotonergic function is involved in the pathogenesis of suicidality, whereas the use of platelet 5-HT2A receptor activity and tryptophan availability as biological markers for suicidality in depressed patients could not be proven an appropriate tool. Alterations in the serotonergic system are associated with trait aggression and other character dimensions.

Dieting and weight loss do not affect on the platelet serotonin 5-HT2A receptor.

Alterations related to the serotonin 5-HT(2A) receptor have been reported in various psychiatric disorders, and the 5-HT(2A) receptor is also one of the receptors mediating the effects of serotonin on feeding and satiety. The present study was carried out in order to investigate the association between the serotonin 5-HT(2A) receptor and weight loss during dieting in overweight subjects. In nine women studied before, during and after a 6-month period of dieting, body weight loss was not found to affect the platelet 5-HT(2A) receptor status. This finding implies that although body weight decrease is a common feature in many psychiatric disorders, the reported alterations in serotonin 5-HT(2A) receptor status in these disorders do not seem to be caused by the weight loss per se.

Decrease of the platelet 5-HT2A receptor function by long-term imipramine treatment in endogenous depression.

BACKGROUND: Animal studies have found that many antidepressants induce decreases in both the density and the functional activity of the serotonin 2A (5-HT2A) receptor subtype. However, the extrapolation of findings to humans has been inconclusive. A physiological platelet response mediated by this receptor, the serotonin-amplified platelet aggregation, was measured to study whether long-term antidepressant treatment induces changes in 5-HT2A receptor functioning in endogenous depressed patients. METHOD: The percentage of serotonin-amplified platelet aggregation to adenosine diphosphate (ADP) was studied in 15 untreated patients with major depressive disorder (DSM-IV) with endogenous features (Newcastle scale). This index was used as an indirect measurement of the functional status of platelet 5-HT2A receptors. Aggregation studies were repeated once remission of the symptoms was achieved during treatment with imipramine (150-300 mg/day). A group of 15 concurrent normal subjects was used as a control. RESULTS: A statistically significant decrease (p = 0.038) in the percentage of serotonin-amplified platelet aggregation to ADP was observed when remission was achieved (after 145 +/- 27 days). CONCLUSIONS: The results showed a decrease in a platelet functional response mediated by 5-HT2A receptors following effective imipramine treatment, suggesting that desensitization or down-regulation of the 5-HT2A receptor function could be linked to the therapeutic effect of some antidepressants. The data also support the use of platelet aggregometry as a surrogate measurement of antidepressant action, particularly in intra-subject designs.

Platelet serotonin 5-HT2A receptor binding in patients with carcinoid tumor.

BACKGROUND: As carcinoid tumors produce and secrete serotonin, various serotonin markers in blood, plasma and urine have been used as diagnostic tools, and quantification of the urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) is the method most frequently used. METHODS: [3H]lysergic acid diethylamide ([3H]LSD) binding to the platelet serotonin 5-HT2A receptor was investigated in nine patients with carcinoid tumors. The possible effect of serotonin-rich food on the receptor binding was also investigated. RESULTS: B(max) for [3H]LSD binding was significantly lower in the carcinoid group than in the control group (mean +/- SD: 17.6 +/- 1.3 vs. 23.9 +/- 5.2 fmol/mg protein; p = 0.007). Kd for [3H]LSD binding was significantly higher in the carcinoid group than in the control group (median: 1.14 vs. 0.71 nmol/L; p = 0.03). B(max) was inversely related to the urinary 5-HIAA excretion, but the correlation did not reach statistical significance (r(s) = -0.57; p = 0.14). Intake of five bananas per day for one week had no effect on B(max) or Kd in healthy volunteers. CONCLUSIONS: The results are consistent with a down-regulation of the 5-HT2A receptor as a response to the high serotonin levels found in patients with carcinoid tumors. Intake of serotonin-rich food does not affect the receptor characteristics. Further studies are needed to determine whether the platelet 5-HT2A receptor status can be used as a supplement to urinary 5-HIAA and other biochemical variables in carcinoid tumors.