5-HIAA Concentrations Research Articles

Behavioral characterization of adult male and female rhesus monkeys exposed to cocaine throughout gestation.

In utero cocaine exposure has been associated with alterations in the dopamine (DA) system in monkeys. However, the behavioral outcomes of prenatal cocaine exposure in adulthood are poorly understood. To assess several behavioral measures in 14-year-old rhesus monkeys exposed to cocaine in utero and controls (n = 10 per group). For these studies, two unconditioned behavioral tasks, novel object reactivity and locomotor activity, and two conditioned behavioral tasks, response extinction and delay discounting, were examined. In addition, cerebrospinal fluid (CSF) samples were analyzed for concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA). No differences in CSF concentrations of 5-HIAA and HVA, latencies to touch a novel object or locomotor activity measures were observed between groups or sexes. However, prenatally cocaine-exposed monkeys required a significantly greater number of sessions to reach criteria for extinction of food-reinforced behavior than control monkeys. On the delay-discounting task, male prenatally cocaine-exposed monkeys switched preference from the larger reinforcer to the smaller one at shorter delay values than male control monkeys; no differences were observed in females. These findings suggest that prenatal cocaine exposure results in long-term neurobehavioral deficits that are influenced by sex of the individual.

Enhanced nociceptive responding in two rat models of depression is associated with alterations in monoamine levels in discrete brain regions

Altered pain responding in depression is a widely recognized but poorly understood phenomenon. The present study investigated nociceptive responding to acute (thermal and mechanical) and persistent (inflammatory) noxious stimuli in two animal models of depression, the olfactory bulbectomized (OB) and the Wistar-Kyoto (WKY) rat. In addition, this study examined if altered nociceptive behaviour was associated with changes in monoamine levels in discrete brain regions. OB rats exhibited mechanical allodynia (von Frey test) but not thermal hyperalgesia (hot plate and tail-flick tests) when compared to sham-operated counterparts. Formalin-induced nociceptive behaviour was both heightened and prolonged in OB versus sham-operated controls. An inverse correlation was observed between 5-hydroxyindoleacetic acid (5-HIAA) concentration in the hippocampus and amygdaloid cortex and nociceptive behaviour in the formalin test. In comparison, WKY rats exhibited thermal hyperalgesia in the hot plate test, while behaviour in the tail-flick and von Frey tests did not differ between WKY and Sprague–Dawley rats. Furthermore, WKY rats exhibited enhanced formalin-evoked nociceptive responding up to 40 min post administration, an effect inversely correlated with serotonin and 5-HIAA levels in the hypothalamus. In conclusion, these findings demonstrate that altered pain responding observed in clinically depressed patients can be modelled pre-clinically, providing a means of investigating the neurochemical basis of, and possible treatments for, this phenomenon.

Platelet serotonin level predicts survival in amyotrophic lateral sclerosis.

BackgroundAmyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown.MethodologyPlatelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects.Principal FindingsPlatelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters.Conclusions/SignificanceThe positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease.

Quetiapine and Norquetiapine in Plasma and Cerebrospinal Fluid of Schizophrenic Patients Treated With Quetiapine

This study investigated concentrations of quetiapine and norquetiapine in plasma and cerebrospinal fluid (CSF) in 22 schizophrenic patients after 4-week treatment with quetiapine (600 mg/d), which was preceded by a 3-week washout period. Blood and CSF samples were obtained on days 1 and 28, and CSF levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured at baseline and after 4 weeks of quetiapine, allowing calculations of differences in HVA (ΔHVA), 5-HIAA (Δ5-HIAA), and MHPG (ΔMHPG) concentrations. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Scale at baseline and then at weekly intervals. Plasma levels of quetiapine and norquetiapine were 1110 ± 608 and 444 ± 226 ng/mL, and the corresponding CSF levels were 29 ± 18 and 5 ± 2 ng/mL, respectively. After the treatment, the levels of HVA, 5-HIAA, and MHPG were increased by 33%, 35%, and 33%, respectively (P < 0.001). A negative correlation was found between the decrease in PANSS positive subscale scores and CSF ΔHVA (r(rho) = -0.690, P < 0.01), and the decrease in PANSS negative subscale scores both with CSF Δ5-HIAA (r(rho) = -0.619, P = 0.02) and ΔMHPG (r(rho) = -0.484, P = 0.038). Because, unfortunately, schizophrenic patients experience relapses even with the best available treatments, monitoring of CSF drug and metabolite levels might prove to be useful in tailoring individually adjusted treatments.

NANETS Consensus Guidelines for the Diagnosis of Neuroendocrine Tumor

Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines. 1 Some of these substances cause specific clinical syndromes, 2 whereas other may have elevated plasma or urine levels that are not associated with specific syndromes or symptom complexes Unfortunately, there is no Bideal neuroendocrine tumor marker,[ 3 but according to the presentation, the sensitivity and specificity of each marker vary, and it is generally possible to choose those of greatest value for each clinical syndrome. The biochemical markers are those hormones or amines secreted by the neuroendocrine cells from which these tumors are derived. Some of these are not specific to any tumor, but are produced and secreted by most NETs, whereas other biochemical markers are more specific to the type of tumor and where their quantification can lead to the suspicion or confirmation of the presence of such a tumor. The annual incidence of NETs has risen to 40 to 50 cases per million, perhaps because of better diagnosis and the availability of highly specific and sensitive ways to measure these tumors’ products, improved immunohistochemistry, and enhanced techniques for tumor detection. Thus, the perceived increase in incidence may not be a real change in the incidence of the disease. There are a number of impediments to the diagnosis of these tumors. They are rare, comprising less than 2% of gastrointestinal (GI) malignancies, and are therefore not high on the list of causes of specific symptom complexes. Symptoms themselves are often nonspecific and do not lend themselves readily to identifying the specific underlying tumor. In addition, the manifestations are protean and mimic a variety of disorders. Tumors may be found incidentally on laparoscopy for abdominal pain or during the surgical removal of an appendix or even during a computerized tomographic scan of the abdomen for unexplained symptoms. Lung carcinoids may present with hemoptysis or asthma-like symptoms, and midgut carcinoids may be confused with irritable bowel syndrome (IBS). The natural history of this disease is invariably attended by a long history of vague abdominal symptoms, a series of visits to a primary care practitioner, and referral to a gastroenterologist, often with a misdiagnosis of IBS. These symptoms persist with a median latency to correct diagnosis of 9.2 years by which time the tumor has metastasized, causing symptoms such as flushing and diarrhea and progressing on its slow but relentless course until the patient dies. Clearly, a greater index of suspicion and a carcinoid tumor profile screen are warranted for all patients presenting with Btraditional IBS symptoms.[ Midgut carcinoids are associated with mesenteric fibrosis, which can compress mesenteric vessels and cause bowel ischemia and malabsorption, which may be found in the absence of an abdominal mass. The diagnosis of metastases to the liver is generally more obvious but often still takes place only after a delay of many years. Even then, an incorrect diagnosis is not uncommon. Unless biopsy material is examined for the secretory peptides chromogranin, synaptophysin, or neuron-specific enolase (NSE), tumors may be labeled erroneously as adenocarcinoma, with a negative impact on physician’s attitudes regarding management and underestimation of prospects for survival. 4 The common symptomatic manifestations of patients with carcinoid tumors are illustrated in Tables 1 and 2. Flushing

Early death and CSF monoamine metabolites in schizophrenia spectrum psychosis

Introduction: Patients with schizophrenia have higher rates of mortality than the general population. Lower concentrations of the cerebrospinal fluid (CSF) monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been associated with suicidal, aggressive and impulsive behavior. Mortality has been suggested as a measure of impulsivity and a relationship between early death and lower concentrations of CSF monoamine metabolites has been reported but the studies are few with short periods of follow-up and small numbers. Aim: The objective of this study was to investigate a relationship between early death and concentrations of CSF 5-HIAA and HVA. Methods: Three hundred and eighty-five inpatients with schizophrenia spectrum psychosis were lumbar punctured in a standardized manner and followed for a median of 26 years. Patients were searched to identify those who had died. Causes of death were obtained from the Causes of Death Register. Results: During the time of follow-up, 97 patients died. Schizophrenia spectrum psychosis patients died at an earlier age from both natural and unnatural causes of death. No significant associations were found between CSF 5-HIAA and HVA concentrations and non-suicidal death. Attempted suicide was not a risk factor for non-suicidal death at younger age. Conclusion: Patients with schizophrenia spectrum psychosis die at an earlier age from both natural and unnatural causes of death. Attempted suicide is not a risk factor for non-suicidal death at younger age. Low concentrations of CSF HVA and 5-HIAA were not a risk factor for non-suicidal death at younger age in schizophrenia spectrum psychosis.

Tryptophan hydroxylase gene 1 ( TPH1) variants associated with cerebrospinal fluid 5-hydroxyindole acetic acid and homovanillic acid concentrations in healthy volunteers

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. We investigated possible relationships between five TPH1 gene polymorphisms and cerebrospinal fluid (CSF) concentrations of the major serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the major dopamine metabolite homovanillic acid (HVA), and the major norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in healthy volunteers ( n = 132). The G-allele of the TPH1 rs4537731 (A-6526G) polymorphism was associated with 5-HIAA and HVA, but not MHPG concentrations. None of the other four TPH1 polymorphisms (rs211105, rs1800532, rs1799913 and rs7933505) were significantly associated with any of the monoamine metabolite concentrations. Two (rs4537731G/rs211105T/rs1800532C/rs1799913C/rs7933505G and rs4537731A/rs211105T/rs1800532C/rs1799913C/rs7933505G) of five common TPH1 five-allele haplotypes were associated with 5-HIAA and HVA concentrations in opposite directions. None of the common haplotypes was associated with MHPG concentrations in the CSF. The results suggest that TPH1 gene variation participates in the regulation of serotonin and dopamine turnover rates in the central nervous system of healthy human subjects.

Aggressiveness and brain amine concentration in dominant and subordinate finishing pigs fed the β-adrenoreceptor agonist ractopamine12

Under farm conditions, aggression related to the formation of social hierarchy and competition for resources can be a major problem because of associated injuries, social stress, and carcass losses. Any factor that may affect the regulation and amount of aggression within a farmed system, for instance, feeding the beta-adrenoreceptor agonist ractopamine (RAC), is therefore worthy of investigation. The objectives of this study were to assess the effects of the widely used swine feed additive RAC, considering also the effects of sex and social rank on aggressiveness and concentrations of brain amines, neurotransmitters essential for controlling aggression, in finishing pigs. Thirty-two barrows and 32 gilts (4 pigs/pen by sex) were fed either a control diet or a diet with RAC (Paylean, Elanco Animal Health, Greenfield, IN) added (5 mg/kg for 2 wk, followed by 10 mg/kg for 2 wk). The top dominant and bottom subordinate pigs (16 pigs/sex) in each pen were determined after mixing by a 36-h period of continuous behavioral observation. These pigs were then subjected to resident-intruder tests (maximum 300 s) during the feeding trial to measure aggressiveness. At the end of wk 4, the amygdala, frontal cortex, hypothalamus, and raphe nuclei were dissected and analyzed for concentrations of dopamine (DA); serotonin (5-HT); their metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively; norepinephrine; and epinephrine using HPLC. Ractopamine-fed gilts performed more attacks during the first 30 s of testing than pigs in all other subgroups (P < 0.05). By the end of the resident-intruder test (300 s), the dominant control gilts and barrows, and both dominant and subordinate RAC-fed gilts performed the greatest percentage of attacks (P < 0.05). Gilts had decreased norepinephrine and DOPAC concentrations in the amygdala and frontal cortex, and when fed RAC, gilts also had the least 5-HIAA concentration and greatest DA turnover rate in the amygdala (P < 0.05). The 5-HT concentration was less in the frontal cortex of gilts compared with barrows and in the raphe nuclei (single site for brain 5-HT synthesis) of dominant gilts (P < 0.05). Ractopamine may be affecting aggressive behavior through indirect action on central regulatory mechanisms such as the DA system. The aggressive pattern observed in the tested pigs, especially in gilts, is likely linked to brain monoamine profiling of a deficient serotonergic system in the raphe nuclei, amygdala, and frontal cortex, and enhanced DA metabolism in the amygdala, brain areas vital for aggression regulation.

Repeated intermittent methylenedioxymethamphetamine exposure protects against the behavioral and neurotoxic, but not hyperthermic, effects of an MDMA binge in adult rats

We have recently shown that chronic intermittent exposure of adolescent rats to 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) completely blocks the reduction in serotonin transporter (SERT) binding and the hypoactivity seen following a subsequent MDMA binge treatment. The present study determined whether a similar neuroprotective effect also occurs in rats given the same intermittent MDMA exposure in adulthood. Adult male Sprague-Dawley rats were given either MDMA (10 mg/kg x 2) or saline, every fifth day, from postnatal day (PD) 60 to PD 85. The MDMA-induced latency until seminal plug production was reduced over the course of intermittent treatments. After a 1-week wash-out period, animals received either a low- or high-dose MDMA binge (2.5 or 5.0 mg/kg x 4). Core body temperature was measured during and after the binge to determine the effects of MDMA pretreatment on MDMA-induced hyperthermia. Spontaneous motor activity was determined the next day, and cortical and hippocampal samples were collected at 1 week postbinge to measure serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations as well as [3H]citalopram binding to SERT. Hyperthermia occurred more rapidly and seminal discharge was more common in the MDMA-pretreated group compared to the MDMA-naïve group in animals given the low-dose binge. MDMA preexposure protected animals from the reductions in cortical 5-HT levels and SERT binding produced by the high-dose binge and blocked the postbinge hypoactivity. These findings indicate that chronic, intermittent MDMA exposure in adulthood induces neuroprotective effects similar to those seen with adolescent treatment. However, there was also evidence for drug-induced sensitization in adults that was not observed in adolescents. Thus, altered drug sensitivity in chronic Ecstasy users may depend not only on the frequency and pattern of use but also on the age of the user.

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.

Characterization of cerebrospinal fluid monoamine metabolites in peripubertal chimpanzees (Pan troglodytes)

Assessment of cerebrospinal (CSF) monoamine metabolites 5-hydroxyindoeacetic acid (5-HIAA) and homovanillic acid (HVA), and the serotonin precursor tryptophan (TRP), in chimpanzees may help in understanding the neurobiology underlying aggressive, impulsive behavior in humans and non-human primates. Two CSF samples were obtained from 11 peripubertal chimpanzees 8 months apart and were assayed for monoamine metabolite and TRP concentrations. Substantial inter-individual stability was observed for 5-HIAA (n = 11; r = 0.83, P < 0.001) and HVA (r = 0.91, P < 0.001). Females had significantly higher concentrations of 5-HIAA compared to males (F(1,8) = 7.31; P < 0.05). Levels of 5-HIAA (r = -0.62, P < 0.05), HVA (r = -0.86, P < 0.001) and TRP levels (r = -0.67; P < 0.05) decreased with age. Close parallels were observed between chimpanzees and humans with respect to absolute levels, sex effects, ontogeny, and 5-HIAA-HVA correlations, supporting the potential utility of the measures in understanding relationships between monoamine functioning and behavior in chimpanzees and humans.

A role for serotonin in the antidepressant activity of N G-Nitro-L-arginine, in the rat forced swimming test

The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N G-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20 mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100 mg/kg). L-NA (5–20 mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1 mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5 mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4 mg/kg), attenuated the L-NA (20 mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT 2A receptor antagonist ketanserin (5 mg/kg) and the 5-HT 2C receptor antagonist RO-430440 (5 mg/kg). Co-treatment with the 5-HT 1A receptor antagonist WAY 100635 (0.3 mg/kg) or the 5-HT 1B receptor antagonist GR 127935 (4 mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors.

Postnatal changes in serotonergic innervation to the hippocampus of methyl-CpG-binding protein 2-null mice

Rett syndrome is a progressive neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Previous reports have revealed serotonergic function to be altered in the medullas of patients with Rett syndrome and in an animal model of the disease. However, it has remained unclear whether a genetic loss of MeCP2 disrupts serotonergic innervation to the forebrain. In this study, we measured levels of monoamines by high-performance liquid chromatography with electrochemical detection in selected regions of the forebrains of Mecp2-null mice (Mecp2−/y) and wild-type mice (Mecp2+/y) on postnatal day (P) 14, P28, P42 and P56. The levels of hippocampal serotonin (5-HT) and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were significantly lower in Mecp2-null mice than in age-matched wild-type mice on P28, P42 and P56. Immunohistochemical analysis revealed a loss of 5-HT-immunoreactive fibers in the Mecp2-null hippocampus on P56. By contrast, in the raphe region of Mecp2-null mice, there were significant decreases in 5-HT and noradrenaline levels, but these differences later disappeared and there was no change in the number of 5-HT-immunoreactive neuronal cell bodies. Furthermore, we conducted an experiment comparing HPLC measurements in presymptomatic heterozygous females (Mecp2+/−) and wild-type female littermates (Mecp2+/+) on P56. Significant decreases in hippocampal 5-HT and 5-HIAA contents in Mecp2-heterozygous mice were revealed, and these were not accompanied by changes in 5-HT or noradrenaline contents in the raphe region. Therefore, these results indicated decreases in serotonergic innervation to the hippocampus in Mecp2-null males and Mecp2 heterozygous females. We speculate that disturbances in serotonergic neurotransmission in the hippocampus may be linked to the behavioral abnormalities seen in Rett syndrome, such as increased anxiety-like behaviors and reduced exploratory locomotion. MeCP2 may be required for stable serotonergic homeostasis and serotonergic innervation to the hippocampus during postnatal development.

Effects of stress of postnatal development on corticosterone, serotonin and behavioral changes

Stressful events early in life are associated with later psychiatric disorders. We focused on developmental stage and evaluated changes in the corticosterone and serotonergic systems as well as in later anxiety-related behavioral tests. Stressed male Wistar rats were divided into two groups: stressed from postnatal day 11 (PND 11) to 15 and stressed from PND 16 to 20. The rats were exposed to an elevated open platform. Stress increased corticosterone in both experimental groups. In the hypothalamus, amygdala and hippocampus, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) increased in the rats stressed from PND 11 to 15, and decreased in the rats stressed from PND 16 to 20. In a later behavioral test, rats stressed from PND 11 to 15 traveled shorter distances and tended to spend less time in the center than control rats following restraint stress. There were no significant changes in 5-HT and 5-HIAA in hypothalamus, amygdala and hippocampus after restraint stress in adults. These findings indicate that stress reactions and later effects are different depending on the developmental stage during which the rats were stressed. Stress during the PND 11–15 period may enhance later anxiety-related behaviors without altering 5-HT and 5-HIAA content.

Lower CSF HVA and 5-HIAA in bipolar disorder type 1 with a history of childhood ADHD

Bipolar disorder with childhood attention-deficit hyperactivity disorder (ADHD) is a subphenotype characterized by earlier age of onset, more frequent mood episodes, more suicide attempts, and more interpersonal violence than pure bipolar patients. The aim of this study was to test the biological validity of using childhood ADHD to subgroup bipolar disorder. The monoamine metabolites, homovanillinic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined in the cerebrospinal fluid (CSF) of 53 euthymic patients with bipolar disorder type 1, with (N = 17) and without (N = 36) a history of childhood ADHD. In addition to structured clinical interviews, childhood ADHD was assessed by a next of kin using the Autism-Tics, ADHD and other comorbidities questionnaire (A-TAC), and by patients themselves using the Wender Utah rating scale (WURS-25). Current ADHD symptoms were assessed by the Brown attention-deficit disorder scale (Brown ADD). Bipolar patients with childhood ADHD had significantly lower CSF concentration (mean +/- SD nmol/l) of HVA (89.0 +/- 32.5 vs. 115.8 +/- 47.1, P = 0.039) and 5-HIAA (88.7 +/- 38.5 vs. 116 +/- 47.9, P = 0.021) than pure bipolar patients. CSF MHPG did not differ between the groups. The WURS-25 score correlated negatively with both HVA (r = -0.27, P = 0.048) and 5-HIAA (r = -0.30, P = 0.027). Likewise, the Brown ADD total score correlated negatively with both HVA (r = -0.34, P = 0.013) and 5-HIAA (r = -0.35, P = 0.011). These findings indicate different monoaminergic function in patients with and without childhood ADHD in bipolar disorder type 1. This lends biological support to the notion that those with childhood ADHD represent a valid subphenotype of bipolar disorder.

Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

BackgroundSerotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain.Methodology/Principal FindingsCitalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition.Conclusions/SignificanceTaken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies.

Extracellular serotonin level in the basolateral nucleus of the amygdala and dorsal periaqueductal gray under unconditioned and conditioned fear states: An in vivo microdialysis study

Serotonin (5-HT) plays a key role in the neural circuitry mediating unconditioned and conditioned fear responses related to panic and generalized anxiety disorders. The basolateral nucleus of the amygdala (BLA) and the dorsal periaqueductal gray (dPAG) appear to be mainly involved in these conditions. The aim of this study was to measure the extracellular level of 5-HT and its metabolite 5-hydroxyindolacetic acid (5-HIAA) in the BLA and dPAG during unconditioned and conditioned fear states using in vivo microdialysis procedure. Thus, for the unconditioned fear test, animals were chemically stimulated in the dPAG with semicarbazide, an inhibitor of the γ-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase. For the conditioned fear test, animals were subjected to a contextual conditioned fear paradigm using electrical footshock as the unconditioned stimulus. The results show that the 5-HT and 5-HIAA level in the BLA and dPAG did not change during unconditioned fear, whereas 5-HT concentration, but not 5-HIAA concentration, increased in these brain areas during conditioned fear. The present study showed that the 5-HT system was activated during conditioned fear, whereas it remained unchanged during unconditioned fear, supporting the hypothesis that 5-HT has distinct roles in conditioned and unconditioned fear (dual role of 5-HT in anxiety disorders).

Plasma serotonin is a predictor for deterioration of urinary albumin excretion in men with type 2 diabetes mellitus

We performed an observational study to investigate if plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of serotonin (5-hydroxytryptamine), concentration could be a predictor for deterioration of urinary albumin excretion. The relationship between baseline plasma 5-HIAA concentration and changes in urinary albumin excretion for 24 months was investigated in 162 male patients with type 2 diabetes mellitus. Patients were divided into tertiles according to plasma 5-HIAA concentration. Greater changes in urinary albumin excretion were seen in patients with high plasma 5-HIAA concentration (112.8 ± 36.2 mg/g creatinine) than in patients with low plasma 5-HIAA concentration (7.6 ± 8.0 mg/g creatinine, P = .0011) or in patients with intermediate plasma 5-HIAA concentration (25.6 ± 15.0 mg/g creatinine, P = .0070) after adjustment for baseline values of urinary albumin excretion. A positive correlation was observed between log (plasma 5-HIAA concentration) and changes in urinary albumin excretion ( r = 0.314, P < .0001). Multiple regression analysis demonstrated that log (plasma 5-HIAA concentration) ( β = .284, P = .0013) was an independent determinant of changes in urinary albumin excretion. In conclusion, plasma 5-HIAA concentration was positively correlated with changes in urinary albumin excretion, which may indicate causality in diabetic nephropathy in male patients with type 2 diabetes mellitus and high plasma 5-HIAA concentration.

Central l-proline attenuates stress-induced dopamine and serotonin metabolism in the chick forebrain

Using microdialysis, we investigated the effect of l-proline on monoamine release in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of freely moving and restricted chicks. A 30 min handling-stress resulted in a significant increase in extracellular homovallinic acid (HVA), a dopamine metabolite, and 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, in the MNH. l-Proline, perfused through the microdialysis probe into the MNH during the stressed condition, significantly attenuated the average dialysate concentration of HVA produced by handling-stress. Handling-stress resulted in a significant increase in 5-HIAA levels in the control group, which were attenuated by profusion with l-proline. l-Proline did not significantly modify basal concentrations of HVA or 5-HIAA in the MNH during control conditions. These results show that perfusion of l-proline modified the turnover/metabolism of dopamine and serotonin in the MNH caused by handling-stress.

Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy.

The possibility of disturbed dopamine and serotonin metabolism in the progressive myoclonus epilepsy (PME) occurring in Finland (a type of PME without Lafora bodies) was examined. Both basal concentrations of HVA and 5-HIAA in the CSF and their increase after oral probenecid administration were studied in 19 PME patients and in 19 age- and sex-matched control patients. The control patients had grand mal epilepsy but not myoclonus or ataxia. The basal value of HVA was significantly reduced and that of 5-HIAA was also slightly reduced in the PME patients as compared to the values of the epileptic controls or to those of 26 nonepileptic controls. The concentrations of HVA and 5-HIAA also seemed to correlate with the severity of the PME. The most severely affected patients had generally the lowest values. After oral probenecid this trend was also seen when the increases of HVA and 5-HIAA were expressed per microgram CSF probenecid, i.e. the mildly affected PME group showed higher increases in response to probenecid than the most severely affected PME group. The PME patients had higher probenecid levels in the CSF than the epileptic controls.