Auditory evoked potential modifications according to clinical and biochemical responsiveness to fenfluramine treatment in children with autistic behavior

Evoked potentials to auditory stimulations varying in intensity were studied in 13 children with autistic behavior treated with fenfluramine. Modifications of both amplitude and single-trial potential variability were considered according to the clinical and biochemical responsiveness to this drug. Six children (responders) were clinically improved by the treatment. Electrophysiological data were affected according to the clinical and biochemical responsiveness to fenfluramine: the auditory evoked potential amplitude increased, and the single-trial potential variability decreased at each intensity level only in responders whose dopaminergic metabolism was significantly modified by fenfluramine treatment. No modification was found in nonresponders. Both biochemical and electrophysiological results argued for an amphetamine-like action of fenfluramine in those autistic children whose attention deficits are associated with motor disturbances including hyperactivity.     

MONOAMINES (SEROTONIN AND CATECHOLAMINES) AND THEIR DERIVATIVES IN INFANTILE AUTISM: AGE-RELATED CHANGES AND DRUG EFFECTS

Levels of dopamine (DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3MT) and norepinephrine+epinephrine (NE + E), and serotonin (5HT) and its derivative 5-hydroxyindolacetic acid (5HIAA) were determined from the urine of 156 autistic children aged two to 12 years 6 months, and compared with those of age-matched mentally retarded non-autistic and normal controls. Very significant group and age effects were found for DA, HVA, 3MT, NE + E and 5HT. High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol, compared with non-medicated autistic children. The results are discussed in relation to the hypothesis of a maturation defect of monoaminergic systems in autism.     

Neurochemical study of dopamine functioning in autistic and normal subjects

Plasma prolactin (PRL) and homovanillic acid (HVA) levels, and urinary HVA and dopamine (DA) excretion, were measured in groups of unmedicated autistics, medicated autistics, and normal controls. No significant differences were found between unmedicated autistics and normal controls in plasma PRL and HVA levels. Excretion rates of urinary HVA and DA were also similar in the unmedicated autistic and normal subjects. Plasma PRL and HVA, as well as urinary HVA excretion, were significantly increased in the autistics on neuroleptic medication compared to the unmedicated autistics. A significant correlation (r = 0.46, p = less than 0.05) was observed between dose of neuroleptics and plasma PRL values; the correlation (r = 0.42) between neuroleptic dose and plasma HVA levels approached significance (p = 0.06). In contrast, no differences were observed in urinary DA excretion between medicated and unmedicated autistics. In general, the findings indicate that peripheral indices of dopamine functioning are normal in autistic subjects.     

Neuromodulation of the prefrontal cortex during sleep: a microdialysis study in rats

To test the hypothesis that biogenic amines of the prefrontal cortex are involved in state-dependent cortical and behavioural activation, changes in extracellular levels of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) were determined during the sleep-wake cycle in freely moving rats using microdialysis probes with parallel EEG recording. Serotonin gradually increased up to 450% during wakefulness (W) as compared to slow wave sleep (SWS), before decreasing toward stable levels during the next episode of SWS. Dopamine and its metabolite homovanillic acid (HVA) were reduced during W as compared to SWS. Although contradictory with the generally admitted enhancement of DA activity related to vigilance, this may be due to the particular role of DA neurons in the prefrontal cortex. However, DA and HVA showed dramatic changes announcing the transition between SWS and W. During paradoxical sleep (PS), DA and 5-HT showed complex changes, the direction of which depended on whether PS was followed by SWS or W. Biogenic amines of the prefrontal cortex are probably involved in cortical and behavioural activation.     

Levels of biogenic amines, their metabolites, and tyrosine hydroxylase activity in the human epileptic temporal cortex

The levels of serotonin (5-HT), 5 hydroxyindoleacetic acid (5-HIAA), dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), and tyrosine hydroxylase (TH) activity were measured in the focus (spiking) and nonfocus (nonspiking) regions of the temporal neocortex of 20 patients with intractable complex partial seizures. The levels of 5-HT, DA, 5-HIAA, and HVA were higher in the focus when compared to the nonfocus. Values for NE and TH activity were not different when focus and nonfocus were compared. The ratios of metabolite to precursor for 5-HT and DA were not significantly different between the focus and the nonfocus, suggesting that the changes observed were the result of a modification in the synthesis and release of these amines. Such changes in the epileptic focus could be caused by altered transsynaptic regulatory processes, which occur as a result of neuronal loss, gliosis, or neuronal sprouting.     

Levels of biogenic amines and their metabolites in rat whole brain after rapid tissue fixation with microwave irradiation (author's transl)]

Levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid were measured fluorometrically in the whole brain of rats killed either by decapitation or by 5kW microwave irradiation for 1.6 sec. which inactivates the relevant brain enzymes rapidly and irreversibly. There were statistically no differences in the levels of NE, DA, 5-HT and 5-HIAA between the two methods of sacrifice, while the level of DA increased slightly in irradiated brains. On the other hand, the level of DOPAC, an oxidative deaminated metabolite of DA, increased significantly and the level of HVA, a final metabolite of DA, reduced markedly in the irradiated brains compared to that in the decapitated brains, respectively. These findings suggest that the turnover rates for metabolism of DA at synaptic nerve terminals and synaptic clefts may be relatively rapid. Therefore, it may be concluded that rapid inactivation of the brain enzymes involved in metabolism of DA is necessary prior to analysis of DA and its metabolites and microwave irradiation is the most suitable method available at the present time.     

Electrodermal orienting response and central nervous system dopamine and serotonin activity in schizophrenia.

The present study was designed to examine the relationship between electrodermal activity and the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid. Lumbar cerebrospinal fluid from 36 unmedicated and six medicated schizophrenic patients and 23 controls was analyzed by gas chromatograph-mass spectrometer. The schizophrenic patients and a group of 14 normal controls were presented with a series of orienting tones (1000 Hz, 80 db, 2-second duration) while electrodermal activity was monitored. For the patients, this occurred during an acute episode of schizophrenia. The results suggest an inverse relation between electrodermal activity and the CSF-level of HVA. Although the picture is not entirely consistent, electrodermal nonresponders appear to have normal HVA levels, while electrodermal responders have decreased levels compared with normal controls. There is also a relation between electrodermal activity and 5-HIAA, but this association is not as clear-cut as the one between electrodermal activity and HVA.     

Low platelet-poor plasma concentrations of serotonin in patients with combat-related posttraumatic stress disorder.

BACKGROUND: Combat-related posttraumatic stress disorder (CR-PTSD) is associated with a dysregulation of various neurotransmitter systems. METHODS: We assessed levels of platelet-poor plasma (PPP) norepinephrine (NE), and serotonin (5-HT), and 24-hour urinary excretion of NE, dopamine (DA), and homovanillic acid (HVA) in 17 male outpatients with untreated chronic CR-PTSD (age, 33.1 +/- 7.4 years) and 10 normal control subjects (age, 35.8 +/- 2.7 years). RESULTS: Compared with the control subjects, the PTSD patients showed significantly lower PPP 5-HT levels, elevated PPP NE levels, and significantly higher mean 24-hour urinary excretion of all three catecholamines (NE, DA, and HVA). The 24-hour urinary HVA values of the CR-PTSD patients correlated significantly and positively with the total Impact of Event Scale scores and the avoidance symptoms cluster scores, and the PPP 5-HT levels correlated negatively with the Hamilton Anxiety Rating Scale scores. The PPP NE/5-HT ratio was significantly higher in the study group than in the control subjects. CONCLUSIONS: We believe this combined enhanced noradrenergic activity and diminished 5-HT activity may be relevant to the neurobiology of CR-PTSD.     

抑郁症患者自杀与脑脊液单胺代谢产物的关系

目的：探讨抑郁症患者自杀与脑脊液单胺代谢产物之间的关系。方法：应用高效液相色谱法，测定24例抑郁症患者(自杀组10例，无自杀组14例)及25例对照组5-羟色胺(5-HT)代谢产物5-羟吲哚乙酸(5-HIAA)，去甲肾上腺素(NE)代谢产物3-甲基-4-羟苯乙二醇(MHPG)及多巴胺(DA)代谢产物高香草酸(HVA)的浓度。结果：抑郁症自杀组5-HIAA浓度显著低于对照组，男性自杀组5-HIAA浓度、HVA浓度和HVA／MHPG比值均显著低于男性对照组，女性则无显著差异：结论：抑郁症患者自杀可能与5-HT和DA功能低下以及DA和NE之间的关系改变有关。     

Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain

Previous studies indicate that the repeated administration of D-methylamphetamine (MA) produces a long-lasting depletion of dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) in various brain regions of a number of species. The objectives of the present study were: (1) to establish a short, subcutaneous injection regimen which would reliably produce the neuronal alterations; (2) to evaluate MA-induced NE depletions produced by this new regimen; and (3) to determine whether central MA-induced neuronal changes are reflected in changes in cerebrospinal fluid monoamine metabolite concentrations. It was observed that high doses of MA administered (s.c.) over a 2-week period to rhesus monkeys produced decreases in DA and 5-HT, but not NE levels, in various brain regions. The decrease in caudate DA levels was accompanied by a decrease in the number of DA uptake sites, a decrease in the level of homovanillic acid (HVA) and an increase in DA turnover. This decrease in brain DA was also accompanied by a decrease in the cerebrospinal fluid concentration of HVA.     

Cerebrospinal fluid (CSF) and brain monoamine metabolites in the developing rat pup

Concentrations of the neurotransmitters, serotonin (5-HT), dopamine (DA), and norepinephrine (NE) were measured in the developing rat brain at 12, 19, 26 and 42 days of age. The amino acid precursors, tryptophan (TRP) and tyrosine (TYR) were measured along with the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in brain and cerebrospinal fluid (CSF) at the above ages. This first report of CSF HVA levels in the developing rat shows that it, like 5-HIAA, declines with age. In contrast, the ontogeny of the compounds in brain are dissimilar, with 5-HIAA remaining relatively constant with age while HVA declines markedly. Possible reasons for the differences and similarities in the ontogeny of 5-HIAA and HVA levels in brain and CSF are discussed. The persistence of the ontogenetic pattern for the neurotransmitters and acid metabolites after central DA depletion is also reported.     

家族性与散发性精神分裂症中枢5—羟色胺与多巴胺相互作用比较研究

比较家族性与散发性精神分裂症中枢５－ＨＴ与ＤＡ相互作用的差异。方法应用高效液相色谱对２０例家族性和４７例散发性精神分裂症的脑脊液中５－ＨＴ、５－ＨＩＡＡ、ＤＡ、ＨＶＡ进行测试，并以比值作为相作用指标。结论两类型精神分裂症存在着５－ＨＴ与ＤＡ相互作用的差异。     

Regional changes in central monoamine and metabolite levels during the hibernation cycle in the golden-mantled ground squirrel.

We assayed various brain regions for levels of monoamines and their metabolites throughout the hibernation cycle of the golden-mantled ground squirrel Spermophilus lateralis. The tissue concentrations of serotonin, dopamine, norepinephrine and their metabolites were determined in the parietal cortex, striatum, midbrain, hippocampus, hypothalamus, and pons. Telencephalic regions exhibited the most significant variations in biogenic amine content. Cortical serotonin (5-HT) levels increased significantly at entrance (P less than 0.0001) relative to other periods of the hibernation cycle, suggesting a role for 5-HT in the initiation of hibernation. Among striatal dopamine (DA) metabolites, 3-methoxytyramine was detectable only during euthermia and arousal; from entrance through arousal, homovanillic acid (HVA) levels were half that found during euthermia (P = 0.0001); and dihydroxyphenylacetic acid (DOPAC) levels increased during day 1 of hibernation (P less than 0.0005). Midbrain DA (P = 0.0295) and hippocampal HVA (P = 0.0194) levels also changed significantly across the hibernation bout. The absence of a consistent change in any monoamine or metabolite throughout the brain precludes the possibility of preferential temperature-dependent impairment of an enzyme involved in biogenic amine synthesis or degradation and suggests that the levels observed reflect changes in neural activity specific to each brain region. Together with previous studies of brain 2-deoxyglucose uptake throughout the hibernation cycle, these data indicate that a transient change in afferent monoaminergic metabolism and neurotransmission in the forebrain is a necessary component for the entrance to hibernation.     

Effects of neurotensin on regional brain concentrations of dopamine, serotonin and their main metabolites.

The effects of neurotensin, 7.5 or 30 micrograms, on concentrations of DA, DOPAC, (HVA), serotonin 5-HT and 5-HIAA were measured in 8 regions of the rat brain either 5 or 30 min following intracerebroventricular administration. Regions examined include the frontal cortex, striatum, nucleus accumbens, amygdala, septum, hypothalamus, ventral tegmentum and substantia nigra. Results indicate that both doses of neurotensin significantly elevated concentrations of dopamine in the striatum and amygdala 5 min following injection. The effects of the peptide on DOPAC and HVA were more pervasive and enduring, with significant increases in metabolite levels occurring in both mesolimbic and nigrostriatal terminal regions. In order to assess effects on turnover of dopamine, the ratios of each metabolic to dopamine concentrations were examined. Results indicate that, while the DOPAC/DA ratio was elevated in many regions, the HVA/DA ratio was increased in all regions examined. The effects of neurotensin on serotoninergic parameters were less pervasive and more variable, with both increases and decreases in 5-HT and 5-HIAA concentrations being observed. The effects of the peptide on 5-HIAA/5-HT were limited to the nucleus accumbens, where this ratio was increased, and the ventral tegmentum, where 5-HIAA/5-HT was decreased. These findings reveal that the effects of the neurotensin on dopaminergic transmission are more widespread than previously reported in that all major dopamine pathways are affected by the peptide. Also, the observed changes in the ratios of both DOPAC and HVA to DA suggest that neurotensin enhances the turnover of this transmitter.     

Differential effects of kainic acid on dopamine and serotonin metabolism in ventral and dorsal striatal regions

The comparative effects of kainic acid (KA) on dopamine (DA) and serotonin (5-HT) metabolism in ventral and dorsal striatum were investigated. Local injection of KA into the caudate-putamen (CP) increased by 155% DOPAC (2,3-dihydrophenylacetic acid), by 114% HVA (homovanillic acid) and by 79% 5-HIAA (5-hydroxyindoleacetic acid) concentrations: with little or no effect on monoamine levels. The (DOPAC + HVA)/DA ratio increased from 0.33 ± 0.2 in vehicle-treated to 0.77 ± 0.1 in KA-treated CP. 5-HIAA/5-HT ratio increased from 2.7 ± 0.2 to 5.9 ± 0.1 after KA treatment. However, direct KA injections into the olfactory tubercle (OT), the most ventral part of the ventral striatum, did not alter significantly the levels of DA, 5-HT, DOPAC, HVA or 5-HIAA. Since KA is a neurotoxin which preferentially destroys perykaria and dendrites, leaving unchanged terminal boutons and axons of passage, the lack of effects on DA and 5-HT metabolism in OT suggests, that contrary to the CP, interneurons and projecting neurons in the OT play no role in inhibitory feedback mechanisms to control DA and 5-HT activities.     

Dopamine may be 'hyper' with respect to noradrenaline metabolism, but 'hypo' with respect to serotonin metabolism in children with attention-deficit hyperactivity disorder

Noradrenaline: Hechtman (J Psychiat Neurosci 1994;19:193) argued for a role for frontal dopamine (DA) and noradrenaline (NA) in ADHD, where Oades (Prog Neurobiol 1987;29:365) has described lateralised functional impairments. Mechanisms (e.g. via alpha-2 sites) for stimulating low NA activity in ADHD children (J Am Acad Child Adolesc Psychiatry 1997;36:1688) in order to promote interactions with mesocortical DA have been discussed (J Psychopharmacology 1997;11:151; Psychiatr Res 1994;52:305). We described with indicators of overall transmitter metabolism (monoamines, metabolites in 24 h urine samples (Behav Brain Res 1997;88:95)) significantly lower utilisation ratios (MHPG/NA) in ADHD children with respect to healthy controls. Interestingly, a comparison of between catecholamine levels (DA/NA) showed a correlation with the conditioned blocking measure of selective attention recorded at the time of collection. This measure was negatively associated with blocking in controls. These results are consistent with reports of lower DOPEG and increased DOPAC in ADHD urine (J Child Adolesc Psychopharmacol 1996;6:63) and indicate that the relatively hyperactive DA versus NA systems may have functional consequences. Serotonin: the relevance for ADHD of an association of impulsivity with low serotonin (5-HT) metabolism (Behav Brain Sci 1986;9:319) has long been played down. Yet, some symptoms have been related to CSF measures of the metabolite 5-HIAA, and in particular the HVA/5-HIAA ratio has been reported to correlate with ratings of activity (Psychiatr Res 1994;52:305). We find that while urinary measures of 5-HIAA are somewhat higher, the ratio HVA/5-HIAA is markedly lower in ADHD children versus controls. In these ADHD children 5-HIAA levels were negatively related to d-prime measures in a continuous performance task (CPTax), and the HVA/5-HIAA was negatively associated with conditioned blocking. These results suggest a relatively low DA versus 5-HT activity may have functional consequences, albeit in a subgroup of ADHD. This is consistent with drug-induced prolactin changes reported by Verbaten et al. (Eur Child Adolesc Psychiatry 1999;8:30).     

Characterization of monoamine release in the lateral hypothalamus of awake, freely moving rats using in vivo microdialysis

Extracellular levels of serotonin (5-HT), dopamine (DA) and their major metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), were measured in the lateral hypothalamus of awake, freely moving rats using microdialysis combined with HPLC and electrochemical detection. To characterize the factors which control 5-HT release, the effects of various drugs were assessed. TTX had a reversible inhibitory effect on the basal levels of 5-HT, 5-HIAA, DOPAC and HVA. Infusion of K+ concomitantly increased 5-HT and DA and decreased 5-HIAA and HVA. Imipramine increased extracellular levels of 5-HT and DA and decreased 5-HIAA levels; this effect was TTX-sensitive. Systemic pargyline increased extracellular 5-HT and markedly decreased the metabolic levels. Pargyline pretreatment in the presence of imipramine, infused through the dialysis probe, slowly increased 5-HT levels above that produced by the reuptake blocker alone. Infusion with AMPH produced a dramatic, TTX-insensitive, increase in 5-HT and DA and a decrease in the metabolic levels. These results provide evidence that (1) basal release of 5-HT in the lateral hypothalamus results from neuronal activity, (2) the metabolites in the extracellular fluid derive primarily from intracellular monoamine oxidase (MAO) activity, (3) 5-HT is mainly removed from the extracellular space by a reuptake mechanism, with minimal contribution of an extracellular MAO, and (4) the AMPH-evoked release of 5-HT and DA is a Na+ channel-independent process.     

Plasma levels of homovanillic acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed patients

Plasma levels of ACTH, cortisol and monoamines were examined in 23 depressed patients and 31 healthy subjects. Patients showed increased plasma cortisol levels, but not plasma adrenocorticotropic hormone (ACTH) levels. The plasma levels of a dopamine metabolite, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), were significantly decreased in the patients. In contrast, the plasma levels of a serotonin (5-HT) metabolite, hydroxyindoleacetic acid (5-HIAA), and 5-HT turnover (5-HIAA/5-HT) were increased in the depressed patients. Therefore, plasma levels of HVA and 5-HIAA are proven to be dissociable. Furthermore, plasma levels of 5-HIAA and L-DOPA have positive relationships with severity of depression. On the basis of this and the previous studies, we speculate that an increase in the plasma 5-HIAA levels might be a compensatory mechanism for stress, whereas 5-HT turnover might reflect depressive state. Taken together, plasma levels of HVA and 5-HIAA, and 5-HT turnover (5-HIAA/5-HT) could be good markers for evaluating depression.     

Neonatal 3,4-methylenedioxymethamphetamine (ecstasy) alters dopamine and serotonin neurochemistry and increases brain-derived neurotrophic factor in the forebrain and brainstem of the rat

Growing concerns surround the risk of fetal exposure to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy). Prior animal studies using neonatal rats administered MDMA from postnatal days (P) 11-20 (a period approximating third trimester brain development in humans) have demonstrated long-lasting decrements in serotonin (5-HT) and learning; however, no studies have examined the acute post-MDMA response of the brain at this early age. Specifically, it is of interest whether MDMA administration to neonatal rats produces the expected depletion of monoamines and whether the brain exhibits any ameliorative response to the pharmacologic insult. In the current study, this model was employed to determine whether forebrain and brainstem dopamine (DA) and 5-HT neurochemistry were altered 24 h after the last injection (P21), and whether brain-derived neurotrophic factor (BDNF) was upregulated in response to MDMA exposure. All forebrain structures examined (frontal cortex, hippocampus, and striatum) showed significant MDMA-induced reductions in 5-HT and its metabolite, 5-HIAA, and significant increases in the DA metabolite, HVA, as well as DA turnover (HVA/DA). In the brainstem, there were significant increases in 5-HIAA, HVA and DA turnover. BDNF was significantly increased (19-38%) in all forebrain structures and in the brainstem in MDMA-exposed neonates versus saline controls. These data suggest that MDMA exposure to the developing rat brain from P11-20 produces similar alterations in serotonin and dopamine neurochemistry to those observed from adult administrations. In addition, a compensatory increase in BDNF was observed and may be the brains ameliorative response to minimize MDMA effects. This is the first report demonstrating that MDMA exposure results in increased levels of BDNF and that such increases are correlated with changes in monoamine levels. Future research is needed to elucidate any deleterious effects MDMA-induced increases in trophic activity might have on the developing brain and to examine earlier gestational exposure periods in order to assess the risk throughout pregnancy.     

急性Dieldrin中毒对C57BL小鼠纹状体多巴胺含量的影响

目的：探讨急性Ｄｉｅｌｄｒｉｎ（氧桥氯甲桥奈）中毒对Ｃ５７ＢＬ 小鼠纹状体多巴胺及其代谢产物含量的影响。方法：给３组小鼠分别喂食 Ｄｉｅｌｄｒｉｎ ５０ ｍｇ·ｋｇ－１体重、Ｄｉｅｌｄｒｉｎ ４０ ｍｇ·ｋｇ－１体重和等量的生理盐水,３ ｈ后处死小鼠,取纹状体匀浆用高效液相色谱－电化学检测法测定纹状体中多巴胺（ＤＡ）、５－羟色胺（５－ＨＴ）、高香草酸（ＨＶＡ）、５－羟基吲哚乙酸（５－ＨＩＡＡ）和去甲肾上腺素（ＮＡ）的含量。结果：喂食 Ｄｉｅｌｄｒｉｎ ５０ ｍｇ·ｋｇ－１体重能降低小鼠纹状体中 ＮＡ、ＤＡ及 ＨＶＡ的含量．结论：大剂量的Ｄｉｅｌｄｒｉｎ可影响小鼠纹状体中 ＤＡ的代谢．可能是致帕金森病的环境因素之一。