Platelet serotonin in infantile autism. Cross-over effects of a dopamine agonist and an antagonist]

In infantile autism, the serotoninergic (5-HT) hypothesis is corroborated by biological dosages and therapeutic effects of fenfluramine which decrease blood serotonin. However other drugs, such as dopaminergic agonists or antagonists, have therapeutic effects. Therefore, we tested the hypothesis that two dopaminergic (DA) drugs have a similar 5-HT effect underlying the therapeutic efficiency. We evaluated in a randomized, double-blind and cross-over study, the effects of a DA agonist (bromocriptine) and a DA antagonist (amisulpride) on platelet 5-HT in infantile autism. The prolactinemia, reflecting the DA action, has been also measured. Nine children, aged from 4 to 13 years, according to the DSM III for infantile autism, received either drug in a random order during four weeks with an in-between placebo period of six weeks. The dosages of platelet 5-HT and serum prolactin were carried out at the beginning and at the end of every phase of treatment (active or placebo) with radioenzymology and radioimmunoassay methods respectively. The principal results on serum prolactin show neither order x treatment interaction, nor order effect but a significant treatment effect (p < 0.01): amisulpride increases serum prolactin whereas bromocriptine decreases according to the usual data. About platelet 5-HT, there is neither order x treatment interaction, nor treatment effect but a significant order effect (p < 0.01). Both drugs increase platelet 5-HT in the first phase of treatment. This order effect could be explained by a remanent effect of amisulpride after 6 wash-out weeks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma serotonin in autism

Serotonin is necessary for normal fetal brain development. Administration of serotonin inhibitors to pregnant rats results in offspring with abnormal behaviors, brain morphology, and serotonin receptor numbers. Low maternal plasma serotonin may contribute to abnormal brain development in autism. In this study, plasma serotonin levels in autism mothers and control mothers of typically developing children were compared, and plasma serotonin levels in children with autism (n = 17) and their family members were measured. Plasma serotonin levels in autism mothers were significantly lower than in mothers of normal children (P = 0.002). Plasma serotonin levels correlated between autism mothers and their children, but differed between autistic children and their fathers (P = 0.028) and siblings (P = 0.063). Low maternal plasma serotonin may be a risk factor for autism through effects on fetal brain development.     

Deficient inhibition as a marker for familial ADHD.

OBJECTIVE: The authors investigated whether deficient inhibitory control, as measured by the stop-signal paradigm, delineates a familial subgroup of attention deficit hyperactivity disorder (ADHD). METHOD: Subjects were 54 ADHD children defined as having poor or good inhibition (on the basis of stop-signal paradigm performance) and 26 healthy comparison children. Family history of ADHD and measures of neurobiological and psychosocial risk were compared among the three groups. RESULTS: ADHD was significantly more prevalent in the families of the children with ADHD who exhibited poor inhibition (48.1%) than in the families of those exhibiting good inhibition (18.5%) or in the families of healthy comparison children (7.7%). No differences in neurobiological or psychosocial risk were found for the three groups. CONCLUSIONS: Deficient inhibition delineates a familial subtype of ADHD. Psychosocial and neurobiological factors did not account for inclusion in the good inhibition group and did not act conjointly with inhibition to increase the risk for ADHD in the poor inhibition group. This study demonstrates that cognitive measures such as a laboratory measure of inhibition can serve as phenotype markers for genetic analyses.     

Salivary prolactin as a marker for central serotonin turnover.

Central nervous system (CNS) serotonin deficits have been linked to many pathological behaviors in both human and nonhuman primates. The plasma prolactin response to fenfluramine has been widely used to assess CNS serotonin functioning in humans. Prolactin is also found as an integrated measure in saliva. We hypothesized that salivary prolactin concentrations would correlate positively with cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) in rhesus monkeys. Twenty-seven adult male and female rhesus macaques (Macaca mulatta) were sampled for concurrent saliva, blood, and CSF. Saliva and blood serum were assayed for prolactin concentrations, and CSF was assayed for 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). Salivary prolactin concentrations were positively correlated with CSF 5-HIAA concentrations. No other relationships between any of the measures, including that between salivary prolactin and serum prolactin, were found to be statistically significant. These findings suggest the possibility of using salivary prolactin concentrations as an index of CNS serotonin turnover in humans.     

Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin

Tracking serotonergic pathways in the brain through immunodetection of serotonin has widely been used for the anatomical characterization of the serotonergic system. Immunostaining for serotonin is also frequently applied for the visualization of individual serotonin containing fibers and quantification of serotonin positive fibers has been widely used to detect changes in the serotonergic innervation. However, particularly in conditions with enhanced serotonin metabolism the detection level of serotonin may lead to an underestimation of the true number of serotonergic fibers. The serotonin transporter (SERT) protein, on the other hand, is less liable to metabolism and for that reason we hypothetized that SERT immunostaining is a more stable marker of serotonergic fibers. Rats were pretreated with monoamine oxidase (MAO) inhibitor and compared with placebo treated rats. Brains were double immunostained for serotonin and SERT protein and colocalization was quantified in several brain areas by confocal microscopy. In comparison with untreated rats, MAO inhibitor treated rats had a significantly higher number (almost 200% increase) of serotonin immunopositive fibers whereas no difference was observed in the number of the SERT positive fibers. Colocalization between serotonin and SERT positive fibers was close to 100% in MAO inhibitor treated animals but only 30% in untreated rats. We conclude that the rapid metabolism of serotonin leads to an underestimation of immunodetected serotonergic fibers and that in many instances, SERT immunostaining may be a better indicator of serotonergic fibers.     

儿童孤独症血浆5-羟色胺的测定

目的 比较孤独症儿童和正常儿童血浆5-羟色胺(5-HT)的浓度,探索5-HT浓度增高和5-HT浓度正常的孤独症儿童各自的临床特点。方法 采用孤独症行为评定量表(ABC)、儿童期孤独症评定量表(CARS)和适应行为评定量表对33例孤独症儿童进行评定,并进行了血浆5-HT检测,以高出正常儿童平均5-HT浓度1.67个标准差的孤独症儿童为5-HT增高组,其他孤独症儿童为5-HT正常组,比较两组孤独症儿童的临床特征。结果 孤独症儿童的ABC得分为72.30±29.91、CARS的得分为41.83±4.05、适应行为评定量表的得分为66.55±12.52。孤独症儿童5-HT浓度为0.77±0.33μmol/L;正常儿童5-HT浓度为0.62±0.18μmol/L,两组经t检验有显著性差异(t=2.23;P=0.03)。5-HT增高的孤独症儿童有9例,5-HT正常的孤独症儿童有24例,两组临床特征比较未发现明显差异。结论 27.3％的孤独症儿童5-HI浓度增高,5-HT增高与5-HT正常的儿童孤独症临床特征相同。孤独症的病因可能是异质性的。     

Platelet serotonin levels in panic disorder

Platelet serotonin levels were examined in 18 patients with panic disorder and compared to platelet serotonin levels of eight healthy controls. There was no statistically significant difference in the platelet serotonin levels between the two groups.     

Platelet serotonin transporter in stroke patients

OBJECTIVES: Post-stroke depression can be treated with serotonin transport inhibitors suggesting a role for the serotonin system in these patients. The number of platelet serotonin transporters in stroke patients and in control subjects have been measured in this study. MATERIAL AND METHODS: Newly admitted stroke patients who did develop or who did not develop a post-stroke depression, non-acute patients who previously had had a stroke and control subjects were compared. The number of platelet serotonin transporters was analysed by ligand binding methodology. RESULTS: The number of platelet serotonin transporters was low shortly after a stroke compared with normal subjects; no difference was found between the stroke patients who developed a post-stroke depression and those who did not. CONCLUSION: A low number of platelet serotonin transporters may be a non-specific state marker for a condition as acute stroke.     

Platelet serotonin concentration in schizophrenic patients

Platelet serotonin (5-HT) concentration did not significantly differ between control subjects (N = 45) and schizophrenic (N = 62) or chronic schizophrenic (N = 39) patients. No clinical feature was associated with hyperserotonemia, but the subgroup receiving benzodiazepines had a significantly higher 5-HT level than other patients.     

Platelet serotonin decrease in alcoholic patients

This study investigated the platelet 5-HT levels and their changes according to different physiological and pathological factors in 30 young alcoholic patients (16 alcohol abusers and 14 alcohol-dependent subjects) and 26 healthy controls. Platelet 5-HT levels were determined by a fluorescent-ortho-phthalaldehyde assay. The mean platelet 5-HT levels obtained in patients during withdrawal and after 2 weeks of abstinence were significantly lower than in controls. Presence of positive history of impulse control disorders (ICD) influenced the mean platelet 5-HT levels in patients. These preliminary results suggest that the platelet 5-HT level decrease observed in alcohol-dependent patients mostly free from ICD and in alcohol abusers mostly affected by ICD might result from comparable neurobiological mechanisms. However, the age of onset of alcohol dependence might depend on psychological functioning features.     

Platelet response to shear stress: Changes in serotonin uptake, serotonin release, and ADP induced aggregation

A rotational viscometer was used to study the effects of shear stress and solid surface interaction on human platelets in platelet-rich plasma. For 5 min. exposure times to the shear field, the post-shear ¹⁴C-serotonin uptake rate was reduced by 40% at a stress level of 100 dynes/cm². Serotonin release under shear and changes in post-shear aggregation response to ADP were also found for stress levels above 100 dynes/cm². For 30 sec exposure times the results were similar to those at 5 min., but considerably higher stresses were required to induce changes in the parameters measured. In all cases marked changes in serotonin uptake and release, and in aggregation response were found at stress levels well below those which cause significant platelet lysis. Experiments were carried out with three different viscometer configurations so that the shear stress level and solid surface access were varied independently. Surface access was not found to be a significant variable under the conditions of the experiments.     

Metabolism of serotonin in autism in children

In this controlled study of 22 autistic children and 22 normal controls matched for age and sex, the frequency of hyperserotonemia in infantile autism was confirmed. Platelet serotonin was elevated in patients. Comparative to controls, serotonin was also high in urine of autistic patients, while, on the contrary there was no difference for the urinary excretion of 5-HIAA. No difference was observed either for serotonin uptake and efflux or for MAO activity, in isolated platelets. The elevation of plasma free tryptophan - significant only with the Kolmogorov Smirnov test - suggests that 5-HT biosynthesis might be enhanced. In the group of patient reported in this study, disorders of serotonin metabolism are associated with disturbances of platelet catecholamines, and also with elevated immunoglobulins and enhanced cellular immunity reactions.     

Platelet serotonin metabolism and ultrastructure in migraine

Biochemical and ultrastructural techniques were used to study the nature of platelet serotonin involvement in migraine. Serotonin levels were increased to a moderate degree in classic migraine, but not in common migraine. The platelet content of 5-hydroxyindoleacetic acid was equally reduced in both classic and common migraine. Platelet-dense bodies, the storage organelles for serotonin, were increased in both migraine groups, particularly in classic migraine. The results were interpreted as evidence for reduced platelet serotonin turnover combined with dense body hyposecretion in migraine sufferers. These findings are further supportive evidence for altered serotonergic function between attacks of migraine, and argue in favor of a role for serotonin in the mechanisms of a migraine attack.     

Early, non-psychotic deviant behavior in schizophrenia: a possible endophenotypic marker for genetic studies

Early non-psychotic deviance occurs in some, but not all, pre-schizophrenic patients and has been linked to the later course of the disorder, suggesting its relationship with the schizophrenia syndrome. However, early deviance has rarely been explored as an endophenotypic marker in large samples of schizophrenic patients. We characterized the early childhood behavior and syndrome history of 205 adults with DSM-IV schizophrenia. Sixty percent of our sample had poor socialization, extreme fears/chronic sadness, and/or attention impairment/learning disabilities beginning before age 10. The remaining 40% were without behavioral difficulties until the onset of schizophrenia. Logistic regression analyses suggested that the risk of syndrome onset before age 17 was 2.5 times more likely among patients with poor socialization beginning before age 10. Schizoaffective disorder was 3.75 times greater among patients with extreme fears/chronic sadness in childhood, and schizophrenic patients with early attention impairment/learning disabilities were 2 times more likely to have a 1 degrees, 2 degrees or 3 degrees relative with schizophrenia. We concluded that early deviant behavior indicated a distinct subgroup of patients, and was linked to syndrome characteristics specifically relevant to genetic studies, in particular age at onset and family history of schizophrenia. Since early syndrome onset has been associated with specific genetic anomalies in other complex neuropathologic disorders, it may prove valuable to regard these early deviant behaviors as an indicator of early syndrome onset for future genetic studies of schizophrenia.     

Platelet serotonin uptake in panic disorder patients: a replication study

Platelet serotonin uptake was measured in 29 patients with DSM-III panic disorder or agoraphobia with panic attacks and compared to values obtained in 23 controls. Both the affinity constant (Km) and the maximal rate of uptake (Vmax) were determined in a buffered medium using 14C-serotonin. Patients and controls did not differ significantly with respect to age or Km values. A statistically significant difference was observed for Vmax (mean +/- SD = 65 +/- 22 pmol/10(8) platelet/min in patients vs. 44 +/- 13 pmol/10(8) platelets/min in controls). This finding suggests an overactivity of peripheral serotonergic function in panic disorder, which may also imply a similar dysfunction centrally.