Decrease In Homovanillic Acid Research Articles

Age- and sex-dependent cardiovascular impact of maternal perinatal stress and altered dopaminergic metabolism in the medulla oblongata of the offspring.

M Maternal Major Depressive Disorder with Peripartum Onset presents health risks to the mother and the developing fetus. Using a rat model of chronic mild stress, we previously reported on the neurodevelopmental impact of maternal perinatal stress on their offspring; the present study examined the cardiovascular impact of maternal perinatal stress on their offspring. The cardiovascular impact was assessed in terms of blood pressure and echocardiographic parameters. The results examined by a three-way ANOVA showed a significant association of cardiovascular parameters with maternal perinatal stress, and offspring sex and age. Increased blood pressure was observed in adolescent female and adult male offspring of stress-exposed dams. Echocardiography showed an increase in left atrial dimension and a reduction in left ventricular systolic function in adolescent stress-exposed female offspring. Increased interventricular septum thickness at end-diastole and left ventricular diastolic dysfunction were observed in adult stress-exposed male offspring. The underlying mechanisms of cardiovascular impact were examined in stress-exposed adult offspring by assessing the levels of neurotransmitters and their metabolites in the medulla oblongata using high-performance liquid chromatography. A significant decrease in homovanillic acid, a dopamine metabolite and indicator of dopaminergic activity, was observed in adult stress-exposed female offspring. These results suggest a significant sex- and age-dependent impact of maternal stress during the peripartum period on the cardiovascular system in the offspring that extends to adulthood and suggests a multigenerational effect. The presented data urgently need a follow-up to confirm its potential clinical and public health relevance.

Ethanol concentration induces production of 3,4-dihydroxyphenylacetic acid and homovanillic acid in mouse brain through activation of monoamine oxidase pathway

First, we aimed to investigate ex vivo the effects of ethanol (EtOH) on levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites in the frontal cortex, hippocampus, and striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Animals were treated intraperitoneally with saline (control) or EtOH (1.0, 2.0, or 3.0 g/kg). Brain samples were collected 60 and 120 min after EtOH injection, and monoamines and their metabolites were measured by HPLC-ECD. We found in both WT and Aldh2-KO mice that 3.0 g/kg EtOH increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the level of 3-methoxytyramine (3-MT). A 2.0 g/kg dose of EtOH also increased HVA, but there was not a consistent effect within the brain regions of Aldh2-KO and WT mice. There were inconsistent findings of genotype differences in the levels of DA, 5-HT, and their metabolites in the brain regions tested. None of the EtOH doses altered NE, DA, 5-HT, or 5-hydroxyindoleacetic acid contents in any of the brain regions studied. Second, we tested whether EtOH-induced increases in DOPAC and HVA are mediated by increased monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) activity. To test this, we used the MAO blocker clorgyline (2.0 and 4.0 mg/kg) and the COMT blocker tolcapone (15 and 30 mg/kg) alone or in combination with EtOH (3.0 g/kg). Clorgyline alone increased 3-MT and decreased DOPAC and HVA levels, whereas tolcapone alone increased DOPAC and decreased 3-MT and HVA levels. Surprisingly, the combination of EtOH with clorgyline (4.0 mg/kg) or tolcapone (30 mg/kg) further decreased 3-MT and increased DOPAC and HVA levels, an effect that reversed the inhibitor-induced decreases in HVA. These results suggest that a high concentration of EtOH can accelerate DA metabolism, as evidenced by the increase in DOPAC and HVA, and this effect is likely a consequence of increased degradation of DA by MAO.

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found thatLIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

Need for medication to complement catecholamines in smoking cessation of hardcore smokers.

Many smokers find it difficult to stop smoking without assistance. The antidepressants bupropion and nortriptyline can aid smoking cessation. The main aim of this study was to understand the pathophysiology of smoking cessation better based on biological backgrounds. We investigated the following biological markers for any alterations during smoking cessation in the absence of pharmacotherapy: the dopamine metabolite homovanillic acid (HVA), the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF). Assessment and blood sampling were performed at a baseline (the start) time point and at a critical time point during smoking cessation. Seven of 30 smokers quit during a 16-week follow-up period; these smokers were defined as remission group from tobacco dependence. The remaining 23 smokers were categorized as hardcore smokers. The smoking group was compared with 23 non-smokers matched for age and gender. We compared blood levels of biological markers in each of the three groups. The hardcore smoker group showed significant decreases in HVA and MHPG levels between baseline and the critical time point (p=0.018 and p=0.033, respectively). However, the remission from tobacco dependence group exhibited no significant changes in any of the biomarkers examined. They had lower scores on the Minnesota nicotine withdrawal scale than the hardcore smoker group (p=0.002). The hardcore smoker group had higher MHPG and BDNF levels than the non-smoker group (p=0.002 and p<0.001, respectively). Hardcore smokers experience severe nicotine withdrawal symptoms. Nicotine withdrawal is associated with catecholamine deficiency. The resulting withdrawal symptoms make quitting difficult for hardcore smokers. These hardcore smokers may require medication to compensate for the catecholamine deficit. Non-nicotinic medications such as bupropion, nortriptyline, or varenicline may be required to bolster the catecholamine deficit in hardcore smokers.

Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration

Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague–Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Decrease in homovanillic acid as evidence for dopamine receptor stimulation by apomorphine in the neostriatum of the rat

Decrease in homovanillic acid as evidence for dopamine receptor stimulation by apomorphine in the neostriatum of the rat

Decreased homovanillic acid concentrations in cerebrospinal fluid in children without a known defect in dopamine metabolism

Homovanillic acid (HVA) is a metabolite of dopamine, reflecting central dopamine metabolism, primarily situated in the striatum. Low HVA concentrations in the cerebrospinal fluid (CSF) may indicate metabolic deficiencies in the pathways of the biosynthesis or catabolism of dopamine. In this retrospective study, we investigated the clinical presentation of patients whose HVA concentration in the CSF had been determined routinely after spinal taps for a variety of clinical reasons. A decrease of HVA concentration in the CSF, due to a defect in the biosynthesis or reuptake of dopamine, is expected to cause extrapyramidal features. However, we found a remarkable variability in the clinical symptoms. Similarly, a decreased HVA concentration in the CSF failed to coincide with specific abnormalities at neuroimaging. In view of the diversity of the clinical presentation and in the absence of specific enzyme deficiencies, a decrease of HVA may be due to dysfunction of dopamine neurons, not resulting in specific extrapyramidal symptoms. Thus, with the exception of diseases associated with a specific enzyme deficiency in the metabolic pathways involving dopamine, a decrease of HVA concentration in the CSF is mainly a secondary or epiphenomenon in a variety of clinical conditions.

Comparative effects of substituted amphetamines (PMA, MDMA, and METH) on monoamines in rat caudate: a microdialysis study.

Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has been used illicitly in Australia since 1994. PMA is also becoming popular at rave parties in the United States. PMA raised concern when a series of fatalities resulted after its use in South Australia, where it was marketed as "ecstasy," which is the colloquial name for MDMA. In the present study, we evaluated the comparative neurotoxicity of substituted amphetamines in rats. Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed in the caudate of freely moving rats using microdialysis and HPLC-EC. Dialysates were assayed every 20 minutes for 4 hours after an intraperitoneal (i.p.) injection of PMA (2.5, 5, 10, 20 mg/kg), MDMA (10 and 20 mg/kg), or METH (2.5 mg/kg). METH produced a significant increase in extracellular DA (700%), and significant decreases in extracellular DOPAC and HVA (30% and 50%), with no detectable changes in either 5-HT or 5-HIAA. MDMA produced significant increases in DA (700% at 10 mg/kg and 950% at 20 mg/kg) and decreases in DOPAC (15% for both 10 and 20 mg/kg), and HVA (50% at 10 mg/kg and 35% at 20 mg/kg). MDMA also increased 5-HT (350% at 10, and 575% at 20 mg/kg), and decreased 5-HIAA to 60% for both dose levels. PMA produced no detectable increases in DA at dose levels of 2.5, 5, or 10 mg/kg, but significantly increased DA (975%) at a dose of 20 mg/kg. However, PMA significantly decreased DOPAC at all dose levels (75% at 2.5; 40% at 5; 30% at 10; 10% at 20 mg/kg), with comparable decreases in HVA at all dose levels. PMA also produced significant increases in 5-HT at 10 and 20 mg/kg (350% for both dose levels), with no detectable changes in 5-HT at 2.5 or 5 mg/kg. All dose levels of PMA significantly decreased 5-HIAA (50 to 70%). These data suggest that PMA, like MDMA and METH, is capable of producing dopaminergic and serotonergic neurotoxicity.

COMT-inhibition increases serum levels of dihydroxyphenylacetic acid (DOPAC) in patients with advanced Parkinson's disease.

Inhibition of the catechol-O-methyltransferase (COMT) is an effective treatment for end-of-dose fluctuations in advanced Parkinson's disease. The aim of the present investigation was to analyse the consequences of subsequent alterations in levodopa metabolism under common treatment conditions when the levodopa dose is adjusted due to the occurrence of dyskinesias after initiation of the COMT-inhibitor. Ten patients with advanced Parkinson's disease (Hoehn & Yahr stage IV) were medicated with tolcapone. Prior to and five to ten days after the initiation of tolcapone 300 mg/d, serum level profiles of levodopa and its metabolites (3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) were performed. The mean daily levodopa dose was reduced from 894 +/- 248 mg to 646 +/- 252 mg (p = 0.003). There was a significant increase in the area under the curve (AUC) of DOPAC during COMT-inhibition compared to the baseline profile (p = 0.009). There were significant decreases of the AUC of HAV (p = 0.001) and the ratios of the AUC HVA / AUC DOPAC (p = 0.0001) and AUC 3-OMD / AUC levodopa (p = 0.0001). The elevation of DOPAC and the decrease of HVA and HVA / DOPAC reflect a shift of the levodopa metabolism towards the MAO-B dependent oxidative pathway. This might contribute to production of hydroxyl radicals and induction of oxidative stress.

CSF Neurotransmitter metabolites in comatose head injury patients during changes in their clinical state

The main metabolites of noradrenaline, serotonin, and dopamine, methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindole-acetic acid (5HIAA), and homovanillic acid (HVA), respectively, were assessed in CSF samples of patients in coma after severe head injury, the first days after the accident and again after an improvement (13 patients) or deterioration (7 patients) in their clinical state, evaluated by the score on the Glasgow Coma Scale. Improvement was accompanied by significant decreases in HVA and 5HIAA. In the patients who deteriorated, the levels of the three metabolites remained high. The results show that the increased turnover of CNS neurotransmitters in severe head injury normalizes during recovery. The use of noradrenaline, dopamine, and serotonin antagonists in brain injury experimental models may clarify the role of the increased biogenic amine turnover in the processes that lead to recovery. We propose relevant pharmacological intervention influencing neurotransmission in severe head injury.

Changes in concentrations of dopamine, serotonin, and their metabolites induced by carbon monoxide (CO) in the rat striatum as determined by in vivo microdialysis

Striatal microdialysis was performed in rats exposed to carbon monoxide (CO). Extracellular changes of dopamine, serotonin, and their metabolites were monitored before and after CO exposure at 15-min intervals by HPLC analysis. After CO exposure, extracellular dopamine increased (3.8 times that of baseline), whereas 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased (by 20–25% of baseline). The decrease in HVA at individual time points, however, was not significant. After a transient increment of the dopamine, it was cleared from the extracellular fluid within 45 min and reached a stable level. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) showed a pattern different to that of dopamine and its acid metabolites, i.e., the changes in extracellular levels were small. Pretreatment with dizocilpine (MK-801), a noncompetitive N- methyl- D-aspartate (NMDA) receptor antagonist, 45 min before CO exposure antagonized the changes in the extracellular concentration of DOPAC. However, the change in dopamine levels was not antagonized by pretreatment with MK-801. MK-801 itself had no effect on the levels of monoamines. Therefore, NMDA receptors may not have an important role for regulating striatal dopamine neurons in hypoxic condition.

Neurotensin increases extracellular striatal dopamine levels in vivo

This study employed intracranial microdialysis to assess the effects of neurotensin (NT) infusion on extracellular dopamine (DA) and DA metabolite concentrations in the rat striatum and nucleus accumbens, and the effects of NT on alterations in extracellular DA levels induced by cocaine and the DA D-2 receptor agonist, quinpirole. Direct NT infusion (.10, 1.0, 10.0 μM) did not significantly affect extracellular DA in the nucleus accumbens, but did produce a significant increase in the DA metabolite homovanillic acid (HVA). In contrast, direct NT infusion produced an increase in striatal DA levels, without altering DA metabolites. Neurotensin infusion (.10 μM) into the striatum significantly attenuated the peak DA increase induced by an intraperitoneal (IP) injection of a low dose (10.0 mg/kg) but not a high dose (30.0 mg/kg) of cocaine. Neurotensin infusion (.10 μM) did not affect the decrease in DA and its metabolites induced by an IP injection of a low dose of quinpirole (.03 mg/kg), but did alter the decrease in HVA induced by a high dose of quinpirole (.10 mg/kg). These results suggest that NT differentially affects in vivo DA release in the striatum and nucleus accumbens, and further strengthens the assertion that NT is an important modulator of dopaminergic function.

Clorgyline-induced increases in presynaptic DA: Changes in the behavioral and neurochemical effects of amphetamine using in vivo microdialysis

Microdialysis was used in behaving rats to further characterize the behavioral and regional dopamine (DA) response to the monoamine oxidase (MAO) inhibitor clorgyline and determine how MAO inhibition affects amphetamine (AMPH)-induced changes in behavioral and extracellular DA dynamics. Although clorgyline (4.0 mg/kg) did not significantly alter behavior, it produced prolonged increases in caudate and accumbens extracellular DA and 3MT and corresponding decreases in homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC). Clorgyline pretreatment altered the behavioral response to both low (0.25 mg/kg) and moderate (2.5 mg/kg) doses of AMPH, which was characterized by a shift to more intense forms of stereotypy and corresponding decreases in locomotion. The caudate and accumbens DA response to AMPH (0.25 mg/kg) was also significantly augmented, consistent with an increase in AMPH-releasable cytoplasmic DA. Thus, the potentiated DA response in clorgyline-pretreated animals may be responsible for the changes in the stereotypy profile. Possible implications of these observations for the augmented behavioral response observed with repeated AMPH administration are discussed.

Effect of aging on dopamine metabolism in the rat cerebral cortex: a regional analysis

Age-related changes in the levels of dopamine (DA) and its metabolites were measured in seven cerebral cortical areas and in the striatum of 3, 10 and 27 month-old Sprague-Dawley rats. An age-related increase in DA levels was observed in the somatomotor (SM) cortex. In contrast, a decrease was observed in the temporal (T) cortex. Decreases in homovanillic acid (HVA) levels were observed in prelimbic (PL), pyriform (PY) and T cortex of aged rats, whereas significant increases in the levels of 3-methoxytyramine (3-MT) were observed in PL, prefrontal (PF), cingulate (C) as well as in T cortex. In the striatum, DA and HVA were decreased but the level of 3-MT remained unchanged. Norepinephrine (NE) levels increased in rats from 3 to 27 months in all the cortical areas. The increase in the levels of the DA extraneuronal metabolite, 3-MT, confirms our previous results showing that the release of DA might be increased with age in some cortical areas. The present results show that there is no general age-related decrease in the level of monoamines and of their metabolites in the rat cerebral cortex and that the changes display a complex, area-specific pattern.

Partial attenuation of chronic fluphenazine-induced changes in regional monoamine metabolism by D-α-tocopherol in rat brain

Recent evidence has suggested a role for free radicals in tardive dyskinesia. We, therefore, investigated the effects of chronic administration of fluphenazine decanoate (FLU) and/or vitamin E (VIT E) on regional monoamine metabolism in rat brain. Chronic FLU caused significant increases in dopamine (DA) in nucleus accumbens and brainstem, significant decreases in dihydroxyphenylacetic acid (DOPAC) in frontal cortex, nucleus accumbens and hippocampus and significant decreases in homovanillic acid (HVA) in nucleus accumbens, caudate-putamen and brainstem. Coadministration of FLU and VIT E normalized HVA in caudateputamen, nucleus accumbens and brainstem as well as DOPAC in nucleus accumbens and hippocampus. Chronic FLU caused significant increases in norepinephrine (NE) levels in all regions studied. VIT E attenuated FLU-induced increases in NE levels in nucleus accumbens and hippocampus. Significant increases in serotonin (5-HT) levels occurred in nucleus accumbens and hippo-campus whereas significant decreases in 5-hydroxyindole-acetic acid (5-HIAA) occurred in all brain regions after chronic FLU. Coadministration of VIT E attenuated the changes observed in hippocampal 5-HIAA but potentiated the FLU-induced increases in 5-HT in this region. Our data suggest that VIT E can attenuate some of the FLU-induced changes in monoamine metabolism. Results are discussed in relation to possible involvement of free radicals in monoamine metabolism during chronic neuroleptic use.

Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase‐A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.

1. The effects of two reversible, predominantly monoamine oxidase-A (MAO-A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400-200-400 mg day-1) on monoamine metabolites and psychometric performance were compared in a double-blind placebo controlled crossover study in 12 healthy subjects. 2. After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8. Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4-dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA). Urine was collected for measurements of normetanephrine and 3-methoxytyramine excretion. Psychometric performance (short- and long-term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening). 3. Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA. The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P less than 0.001) and the overall decrease in HVA was 38% and 20% (P less than 0.005) on moclobemide and toloxatone, respectively. 4. Before the next drug intake, MAO-A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone. 5. Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5-hydroxytryptamine (5-HT) as judged by the fall in plasma 5-HIAA concentration. Neither drug influenced plasma NA concentration. 6. A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone. The urinary excretion of 3-methoxytyramine was significantly raised by moclobemide but not by toloxatone. 7. Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.

Pharmacological effects of methylphenidate on plasma homovanillic acid and growth hormone

The acute pharmacological actions of methylphenidate, a potent psychotogenic stimulant, were studied by measuring plasma homovanillic acid (HVA) and serum growth hormone (GH) as indices of presynaptic and postsynaptic functions, respectively. Twenty psychiatric inpatients participated in a double-blind, placebo-randomized study of methylphenidate infusion. Multiple samples of plasma HVA and GH were measured before and up to 24 hours after both methylphenidate and placebo infusions. There was a robust and significant GH response during the 2-hour postmethylphenidate period when compared to placebo. The peak response was significantly greater in male patients than in female patients. Although there were no changes in plasma HVA during the 2 hours following the infusion, there was a significant decrease in HVA 24 hours after methylphenidate as compared to preinfusion baseline values. Plasma HVA values also tended to be lower 24 hours after methylphenidate when compared to the corresponding postplacebo value. Schizophrenic patients did not differ significantly from nonschizophrenic patients in their physiological or biochemical responses.

5‐Hydroxyindoleacetic Acid and Homovanillic Acid in Cerebrospinal Fluid of Children with Febrile Convulsions

5-Hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by high-performance liquid chromatography (HPLC) in lumbar cerebrospinal fluid (CSF) obtained from febrile children subdivided according to the presence or absence of convulsions. Lumbar puncture was made either early (mean time 2 h) or late (3-6 days) after the febrile convulsion. The level of 5-HIAA was significantly decreased in children early and late after the febrile convulsion as compared with the convulsion-free group, but the HVA level was reduced only early after the febrile convulsion. These results support the hypothesis that a decrease in CSF 5-HIAA may be a biologic marker of susceptibility to convulsions and indicate that the transient decrease in HVA is a secondary phenomenon related to occurrence of convulsions.

Age-related changes in dopaminergic and serotonergic indices in the rat forebrain

Age-related changes in the content of dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in anterior cerebral cortex, hippocampus and striatum of the rat have been investigated using HPLC with electrochemical detection. A significant decrease in HVA was observed in the striatum and hippocampus of the aged (27 months) animals, as compared to the controls (2.4 to 2.6 months). A significant decrease in DA levels was also observed in the hippocampus but not in the striatum. In contrast, the level of DA in the cerebral cortex was markedly increased in the aged animals. A concomitant increase in 3-MT level was observed. Finally the level of 5-HIAA was significantly increased in striatum and hippocampus.

Neurochemical effects of cyclopiazonic acid in chickens.

Chickens dosed (per os) with cyclopiazonic acid (CPA) at 0.5, 5.0, and 10 mg/kg body weight showed significant (P less than or equal to 0.05) increases in brain dopamine and serotonin concentrations 96 hr after dosing. The increases coincide with significant decreases in homovanillic acid and subtle increases of dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations. The elevated dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid concentrations may be related to the elevated concentrations of dopamine and serotonin, respectively. The observed changes in neurotransmitter/metabolite concentrations 96 hr after dosing parallel elimination of CPA from the birds skeletal muscles; however, they do not correlate with the significant weight losses in these birds at 48 and 96 hr after dosing. The brain weights of the treated birds were statistically insignificant from their respective controls, although increases in brain weight-body weight ratio within treatments and with time correlated with CPA toxicity. No significant changes were observed in dopamine, dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid concentrations among the treatments at 3, 24, and/or 48 hr after dosing.