Dopamine Metabolite Concentrations Research Articles

Changes in DOPAC, 3-MT, DOPAC/DA, HVA/DA, 3-MT/DA in the Hippocampus After Simulated Septoplasty and Maxillary Sinusotomy

Objective: to evaluate changes in DOPAC, 3-MT, DOPAC/DA, HVA/DA, 3-MT/DA in the hippocampus after simulation of septoplasty and maxillofacial surgery in rats. Materials and methods. Simulation of operations was carried out on male Wistar rats under general anesthesia with Zoletil 100 solution. In group 1, septoplasty (n=10) was simulated by the standard method by zigzag scarification of the nasal mucosa. In group 2 (n=10), dental implantation with a titanium implant was performed after the implant bed was formed using drill. In group 3 (n=10), only implant bed was made in the alveolar ridge of the upper jaw without subsequent manipulations. In group 4, 10 rats underwent sinus lifting with bone chips with immediate implantation of a titanium implant. In group 5 (n=10)– with the help of a micro drill through a pre-formed implant bed in the alveolar ridge of the upper jaw, a maxillary sinusotomy was performed with damage to the mucous membrane of the ipsilateral maxillary sinus. Liquid chromatography with electrochemical detection was used to determine the concentration of dopamine (DA), homovanilic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3- methoxytiramine (3-MT) in the hippocampal formation. DOPAC/DA, HVA/DA, 3-MT/DA were also determined. Results. The concentration of dopamine in the hippocampus, compared with the control, was significantly higher in group 5 and lower in group 4. The HVA concentration was significantly higher in group 2, group 5 (p<0.01) and group 1 (p<0.05). An intergroup comparison determined that the concentration of HVA was significantly higher in group 2, compared with the rest of the experimental groups (p<0.001). In groups 1, 3 and 4, this indicator was significantly lower compared to group 5 (p<0.01). The DOPAC level was significantly higher (p<0.01) compared to the control data. The concentration of 3-MT was significantly higher in groups 4 and 5 (p<0.001), as well as in group 1 (p<0.05) and in group 3 (p<0.01). Conclusion. After simulating sinus lifting with immediate implantation and dental implantation complicated by maxillary sinusotomy, there is an increase in the concentration of dopamine metabolites 3-MT, HVA and DOPAC, but at the same time a decrease in dopaminergic activity of the hippocampal formation, compared with simulation of septoplasty and simple damage to the alveolar ridge of the upper jaw. Such changes are markers of disruption of adaptation processes after surgery in the head and neck.

CSF dopamine is elevated in first-episode psychosis and associates to symptom severity and cognitive performance.

The hypothesis of dopamine dysfunction in psychosis has evolved since the mid-twentieth century. However, clinical support from biochemical analysis of the transmitter in patients is still missing. The present study assessed dopamine and related metabolites in the cerebrospinal fluid (CSF) of first-episode psychosis (FEP) subjects. Forty first-episode psychosis subjects and twenty healthy age-matched volunteers were recruited via the Karolinska Schizophrenia Project, a multidisciplinary research consortium that investigates the pathophysiology of schizophrenia. Psychopathology, disease severity, and cognitive performance were rated as well as cerebrospinal fluid concentrations of dopamine and related metabolites were measured using a sensitive high-pressure liquid chromatography assay. CSF dopamine was reliably detected in 50% of healthy controls and in 65% of first-episode psychosis subjects and significantly higher in first-episode psychosis subjects compared to age-matched healthy controls. No difference in CSF dopamine levels was observed between drug-naive subjects and subjects with short exposure to antipsychotics. The dopamine concentrations were positively associated with illness severity and deficits in executive functioning. Dopamine dysfunction has long been considered a cornerstone of the pathophysiology of schizophrenia, although biochemical support for elevated brain dopamine levels has been lacking. The results of the present study, showing that FEP subjects have increased CSF dopamine levels that correlate to disease symptoms, should fill the knowledge gap in this regard.

Central nervous system monoamine metabolite response to alcohol exposure is associated with future alcohol intake in a nonhuman primate model (Macaca mulatta).

It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol-induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol-induced and alcohol-induced change in monoamine activity and their relationship with alcohol intake. Alcohol-naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6-7 months later, subjects were allowed unfettered access to an aspartame-sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5-7 weeks. Results showed strong positive correlations between baseline and post-infusion CSF monoamine metabolite concentrations, indicating a trait-like response. Low baseline and post-infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post-infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol-induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake.

Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus.

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3LDat/wt, with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[18F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3LDat/wt mice compared to Dnmt3a2/3Lwt/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3LDat/wt animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[18F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3LDat/wt mice and controls. [18F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3LDat/wt mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis.

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.

Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior Through Signaling Changes in the Hypothalamus

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3LDat/wt, with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[18F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3LDat/wt mice compared to Dnmt3a2/3Lwt/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3LDat/wt animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[18F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3LDat/wt and controls. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, regulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis. Keywords: DNA methylation, transgenic mouse model, behavioral paradigms, positron emission tomography, dopaminergic system.

Intracerebroventricular injection of ouabain causes mania-like behavior in mice through D2 receptor activation

Intracerebroventricular (ICV) administration of ouabain, an inhibitor of the Na, K-ATPase, is an approach used to study the physiological functions of the Na, K-ATPase and cardiotonic steroids in the central nervous system, known to cause mania-like hyperactivity in rats. We describe a mouse model of ouabain-induced mania-like behavior. ICV administration of 0.5 µl of 50 µM (25 pmol, 14.6 ng) ouabain into each lateral brain ventricle results in increased locomotor activity, stereotypical behavior, and decreased anxiety level an hour at minimum. Fast-scan cyclic voltammetry showed that administration of 50 µM ouabain causes a drastic drop in dopamine uptake rate, confirmed by elevated concentrations of dopamine metabolites detected in the striatum 1 h after administration. Ouabain administration also caused activation of Akt, deactivation of GSK3β and activation of ERK1/2 in the striatum of ouabain-treated mice. All of the abovementioned effects are attenuated by haloperidol (70 µg/kg intraperitoneally). Observed effects were not associated with neurotoxicity, since no dystrophic neuron changes in brain structures were demonstrated by histological analysis. This newly developed mouse model of ouabain-induced mania-like behavior could provide a perspective tool for studying the interactions between the Na,K-ATPase and the dopaminergic system.

The effects of Engelhardtia chrysolepis Hance on long-term memory and potential dopamine involvement in mice.

Engelhardtia chrysolepis Hance (ECH) is a perennial plant used in traditional medicine. A major active ingredient of ECH is astilbin (ASB), which has recently been shown to have neuroprotective effects as well as to affect catecholamine neurotransmissions in brain areas such as the prefrontal cortex. In this study, we investigated the effects of ECH and ASB on long-term memory in mice using a battery of behavioral tests. Acute ECH treatments dose-dependently facilitated nonspatial, but not spatial, memory. ECH treatments also upregulated expression of tyrosine hydroxylase, the enzyme mediating catecholamine synthesis, in neuroblastoma cell culture. Acute ASB treatments similarly improved nonspatial memory, whereas chronic ASB treatments improved both nonspatial and spatial memory. In accordance with such behavioral effects, the increased ratio of tissue concentrations of dopamine metabolites over dopamine in striatal regions was observed in mice with chronic ASB treatments. These results suggest that ECH and its active ingredient ASB may facilitate long-term memory by modulating catecholamine transmission.

Нейропротекторные эффекты антител к глутамату при нарушениях памяти, индуцированных олигомерами провоспалительного белка S100A9, у стареющих животных

Цель исследования - изучение эффектов хронического интраназального введения антител к глутамату совместно с полученными in vitro олигомерами провоспалительного белка S100A9 на процесс воспроизведения пространственной памяти, а также на содержание нейромедиаторных аминокислот и биогенных аминов в релевантных структурах мозга - гиппокампе и префронтальной коре у 12-месячных мышей С57Bl/6. Методика. В поведенческих экспериментах у всех животных проводили выработку условного рефлекса пассивного избегания и тестировали воспроизведение памятного следа, после этого в нейрохимическом исследовании в гиппокампе и префронтальной коре методом ВЖХ проводили определение концентрации нейромедиаторных аминокислот и биогенных аминов. Результаты. Показано, что введение белка S100A9 олигомеров индивидуально приводило к нарушению воспроизведения памятного следа, а в сочетании с антителами к глутамату данного эффекта выявлено не было. Обнаружено значительное повышение концентрации глутамата в обеих церебральных структурах стареющих животных при действии S100A9 олигомеров и снижение содержания аминокислоты при совместном введении с антителами к глутамату до нормы. Показано существенное снижение содержания дофамина в гиппокампе и префронтальной коре в условиях влияния S100A9 олигомеров, а также повышение уровня его метаболитов в гиппокампе с нормализацией обмена дофамина в присутствии антелел к глутамату. Заключение. Выявленные антиамнестические эффекты антител к глутамату и нормализация нейрохимического профиля в условиях вызванной центральной токсичностью S100A9 олигомерами могут быть использованы в разработке подходов нейропротективной коррекции в том числе при болезни Альцгеймера. The aim of this study was to investigate effects of chronic intranasal administration of glutamate antibodies with in vitro -generated proinflammatory S100A9 protein oligomers, on spatial memory of 12-month old C57Bl/6 mice. In addition, the brain content of neurotransmitter amino acids and biogenic amines was monitored in memory-relevant brain structures (hippocampus and prefrontal cortex) of these animals. Methods. In behavioral experiments, all animals were conditioned in a passive avoidance reflex test and the memory trace was evaluated. In a simultaneous neurochemical study, HPLC-electrochemical detection analysis was performed to measure concentrations of neurotransmitter amino acids and biogenic amines in the hippocampus and prefrontal cortex. Results. Administration of S100A9 oligomers alone resulted in disruption of the memory trace retrieval whereas their combination with glutamate antibodies abolished this memory disorder. Significant increases in glutamate concentration were observed in both of the cerebral structures of ageing animals in response to S100A9 oligomers alone, and there was a reduction of the amino acid levels when coadministered with glutamate antibodies. S100A9 oligomers also evoked a decrease in hippocampal and prefrontal cortical dopamine and synchronously elevated dopamine metabolite concentrations, both of these actions being normalized by glutamate antibody coadministration. Conclusion. Disclosure of the antiamnesic effects of glutamate antibodies, along with their neurochemical stabilizing activity to S100A9 oligomer neurotoxicity might be utilized in the development of neuroprotective approaches in Alzheimer’s disease.

Mechanisms of the development and integration of nerve processes: Age-related dynamics of the development of absence epilepsy, changes in the concentration of monoamines and their metabolites in the brain structures of WAG/Rij and Wistar rats, and the dynamics of the disruption of learning and memory

We studied peak-wave activity in WAG/Rij rats at ages of 2 and 6 months. We found age-dependent enhancement of peak-wave discharges. At 2 months, the discharges were rare and weak, whereas 6-month-old rats had robust peak-wave discharges. We measured the concentrations of monoamines and their metabolites in 2- and 6-month-old WAG/Rij and Wistar rats in five brain structures: the prefrontal cortex, nucleus accumbens, hypothalamus, striatum, and hippocampus. In 2-month-old WAG/Rij rats, we found a decrease in the concentration of dopamine (DA) metabolites (HVA) in the prefrontal cortex and striatum compared to Wistar rats. In 6-month-old WAG/Rij rats, we found a considerable decrease in the activity of DA system compared to Wistar rats in all five studied brain structures. Concentrations of both DA and its metabolites decreased. We found impairments of learning and memory of WAG/Rij rats compared to Wistar rats. Impairment of learning and memory were more pronounced in 6-month-old WAG/Rij rats compared to 2-month-old WAG/Rij rats. We believe that the DA system not only responds to emotionally positive states but is also a reward and reinforcement system. An increase in the concentration of DA and its metabolites by madopar prevents disturbances of learning and memory. Our general conclusion is that enhancement of absence epilepsy induces a strong deficit of activity of the mesocorticolimbic and nigrostriatal DA system, which induces depression-like behavior and disturbance of learning and memory in WAG/Rij rats. These are the mechanisms of the development of impairments and the integration of these impairments, as well as the aggravation and widening of pathological states.

2350

OBJECTIVES/SPECIFIC AIMS: Several clinical studies have established a correlation between changes in relative bacterial populations in the gut and Parkinson disease. However, few published experiments have been able to parse out whether these associations are causative or correlative. Our aim is to determine how bacteria in the gut may impact the health and resilience of dopaminergic signaling. Our experiment is designed to serve as a proof-of-principle that controlled alterations to the gut microbiome alters mechanisms in dopamine homeostasis in the midbrain. METHODS/STUDY POPULATION: Bacterial inoculation 8–10-week-old germ-free male mice (C57BL/6) were exclusively used in this experiment. Mice were orally gavaged every 3 days (D0, 3, 6, and 9) with 100 µL novel bacterial suspension (~108 CFU resuspended in PBS with 1.5% NaHCO3) or vehicle and were sacrificed on D11. Tissue preparation—brains were quickly extracted and the striatum was isolated and homogenized in either RIPA buffer with protease inhibitors (for Western blot analysis) or in 0.1 N HClO4 (for HPLC processing). The homogenates were processed through fractional centrifugation to remove cellular debris. Lysate samples were frozen at −80°C until ready for analysis. Protein expression quantification—expression of proteins were measured using intensity of bands from Western blots. Lysates were denatured prior to loading with LB with 10% β-mercaptoethanol and 30-minute incubation at 37°C. All immunoblots were normalized to immunoreactivity to α-tubulin. Immunoblot intensity was determined using the ImageJ software. Dopamine/dopamine metabolite quantification HPLC analysis was used to determine dopamine and dopamine metabolite concentration. Aliquots of the lysate were injected onto a C18 column using a mobile phase consisting of 50 mM H2NaO4P·H2O, 0.72 mM sodium octyl sulfate, 75 µM Na2 EDTA, and 10% acetonitrile (pH 3.0). The mobile phase was pumped through the system at 0.3 mL/minute. RESULTS/ANTICIPATED RESULTS: Measured total dopamine concentration through HPLC analysis in the striatum showed no significant differences in the bacteria-treated group relative to the control group. The metabolites DOPAC and HVA had an elevated measured concentration in the bacteria-treated group relative to the control group. Western blot analysis showed decreased immunoreactivity for DAT and TH in the bacteria-treated group compared with the control group. There was no significance difference in the immunoreactivity for VMAT2. DISCUSSION/SIGNIFICANCE OF IMPACT: This study demonstrates that dopamine signaling dynamics in the midbrain can be altered by changes in the gut flora in mice. These results further substantiate the impact of the gut-brain axis and may even point to a potential avenue of bolstering the resilience of dopaminergic neurons in preventing the onset of PD. Further experiments must be performed to understand the mechanism of the observed changes and to determine if these changes have any salutary effect.

Non-parametric analysis of neurochemical effects and Arc expression in amphetamine-induced 50-kHz ultrasonic vocalization

A number of studies have identified the importance of dopaminergic, opioid, serotonergic, noradrenergic and glutamatergic neurotransmission in amphetamine-induced “50-kHz” ultrasonic vocalizations (USVs). Amphetamine became a topic of interest for many researchers interested in USVs due to its ability to induce 50-kHz USVs. To date, it has been difficult to identify the neurotransmitters responsible for this phenomenon. The aim of this study was to determine the following: (i) concentrations of neurotransmitters in selected structures of the rat brain after re-exposure of the rats to amphetamine administration; (ii) changes in Arc in the medial prefrontal cortex, striatum, nucleus accumbens core and shell, hippocampus, amygdala and ventral tegmental area; and (iii) a biological basis for differences in 50-kHz USV emissions in response to amphetamine administration. Re-exposure to amphetamine increased 50-kHz USVs. This parameter do not correlate with distance covered by the investigated animals. An increased concentration of noradrenaline in the nucleus accumbens (NAcc) strongly correlated with the number of 50-kHz USVs. We found that NAcc noradrenaline concentrations negatively correlated with the concentration of dopamine and dopamine metabolites and positively correlated with the concentration of GABA and 5-HIAA (serotonin metabolite) in this structure. We have also identified a positive correlation between striatal 3-MT (dopamine metabolite) concentrations and Arc expression in the hippocampal DG as well as a negative correlation between the concentration of GABA in the amygdala and Arc expression in the central amygdala. Thus, the relationship between the emission of 50-kHz USVs and the neurochemical changes that occur after re-exposure to amphetamine indicates cross-talk between NA, DA, 5-HT and GABA neurotransmission in the NAcc.

Mesocortical Dopamine Phenotypes in Mice Lacking the Sonic Hedgehog Receptor Cdon

Motivated behaviors and many psychopathologies typically involve changes in dopamine release from the projections of the ventral tegmental area (VTA) and/or the substantia nigra pars compacta (SNc). The morphogen Sonic Hedgehog (Shh) specifies fates of midbrain dopamine neurons, but VTA-specific effects of Shh signaling are also being uncovered. In this study, we assessed the role of the Shh receptor Cdon in the development of VTA and SNc dopamine neurons. We find that Cdon is expressed in the proliferating progenitor zone of the embryonic ventral midbrain and that the number of proliferating cells in this region is increased in mouse Cdon−/− embryos. Consistent with a role of Shh in the regulation of neuronal proliferation in this region, we find that the number of tyrosine hydroxylase (TH)-positive neurons is increased in the VTA of Cdon−/− mice at birth and that this effect endures into adulthood. In contrast, the number of TH-positive neurons in the SNc is not altered in Cdon−/− mice at either age. Moreover, adult Cdon−/− mice have a greater number of medial prefrontal cortex (mPFC) dopamine presynaptic sites, and increased baseline concentrations of dopamine and dopamine metabolites selectively in this region. Finally, consistent with increased dopamine function in the mPFC, we find that adult Cdon−/− mice fail to exhibit behavioral plasticity upon repeated amphetamine treatment. Based on these data, we suggest that Cdon plays an important role encoding the diversity of dopamine neurons in the midbrain, influencing both the development of the mesocortical dopamine pathway and behavioral outputs that involve this neural circuitry.

Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis

Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder.We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls.We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.

Cerebrospinal Fluid Monoamine Metabolite Analysis in Pediatric Movement Disorders.

Abnormal concentrations of dopamine and serotonin metabolites in the cerebrospinal fluid is the diagnostic hallmark of a group of treatable conditions known as the monoamine neurotransmitter disorders. We assessed cerebrospinal fluid dopamine and serotonin metabolite concentrations in a series of 69 patients affected by movement disorders of unknown etiology. Abnormal results were disclosed in 13/69 subjects (19%). Both primary and secondary monoamine neurotransmitter disorders were observed. The clinical presentation of both forms was hypokinetic-rigid syndrome or dystonia. L-Dopa treatment resulted in significant improvement of the clinical picture in the majority of primary neurotransmitter disorders. Eight patients presented a secondary neurotransmitter disorder. One suffered from a GM2 gangliosidosis and one from infantile bilateral striatal necrosis. Etiologic diagnoses were not established in the others. L-Dopa was started in four patients, leading to a significant improvement of hypokinesia in the patient suffering from GM2 gangliosidosis and a slight improvement in 3 unclassified patients.

The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer's disease.

IntroductionDepression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present.MethodsEleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer’s Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection.ResultsDLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7-fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead.ConclusionsMonoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved.

Endometrial stem cell transplantation in MPTP- exposed primates: an alternative cell source for treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra. Cell-replacement therapies have emerged as a promising strategy to slow down or replace neuronal loss. Compared to other stem cell types, endometrium-derived stem cells (EDSCs) are an attractive source of stem cells for cellular therapies because of their ease of collection and vast differentiation potential. Here we demonstrate that endometrium-derived stem cells may be transplanted into an MPTP exposed monkey model of PD. After injection into the striatum, endometrium-derived stem cells engrafted, exhibited neuron-like morphology, expressed tyrosine hydroxylase (TH) and increased the numbers of TH positive cells on the transplanted side and dopamine metabolite concentrations in vivo. Our results suggest that endometrium-derived stem cells may provide a therapeutic benefit in the primate model of PD and may be used in stem cell based therapies.

Dietary administration of paraquat for 13 weeks does not result in a loss of dopaminergic neurons in the substantia nigra of C57BL/6J mice

Several investigations have reported that mice administered paraquat dichloride (PQ·Cl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQ·Cl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators ‘blinded’ to the origin of the tissue. Neither dose of PQ·Cl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH+) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH+ neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQ·Cl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc.

Effect of traumatic imagery on cerebrospinal fluid dopamine and serotonin metabolites in posttraumatic stress disorder

Dopaminergic mechanisms may be involved in the pathophysiology of posttraumatic stress disorder (PTSD), although the evidence for this is limited; serotonergic mechanisms are implicated largely by virtue of the modest efficacy of serotonergic drugs in the treatment of the disorder. Basal cerebrospinal fluid (CSF) dopamine and serotonin metabolite concentrations are normal in PTSD patients. However, in the present experiment, we postulated that perturbations in CSF dopamine and serotonin metabolites could be induced by acute psychological stress. Ten volunteers with war-related chronic PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6–9 weeks apart), using a randomized, within subject-controlled, crossover design. During one session a 1-h video with trauma-related footage (traumatic video) was shown and in the other session subjects viewed a 1-h neutral video. We quantified the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF at 10-min intervals, before, during, and after video provocation. Blood pressure, heart rate, and subjective anxiety and mood were monitored. Significant drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral movie. CSF HVA concentrations diminished significantly after the traumatic video (p < 0.05), in comparison with the neutral, while 5-HIAA tended to diminish (p < 0.10). We conclude that an acute decline in CNS HVA concentrations is associated with laboratory-induced symptoms in chronic PTSD patients. While further research is required to determine if the stress-induced dopaminergic changes are normative or pathological, the present data suggest that increasing dopaminergic neurotransmission be explored as a potential therapy, or adjunctive therapy, for PTSD.

Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis.

Background[18 F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [18 F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques.Methods[18 F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [11C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity.ResultsThe different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BPND; r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BPND) but not with the contralateral PET measures. EDVR and BPND in the contralateral striatum were not different from controls and were not correlated with the denervation severity.ConclusionsThe demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [18 F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control.