Dopaminergic Neuronal Systems Research Articles

Long-term exposure to 6-PPD quinone at environmentally relevant concentrations causes neurotoxicity by affecting dopaminergic, serotonergic, glutamatergic, and GABAergic neuronal systems in Caenorhabditis elegans

6-PPD quinone (6-PPDQ), an emerging environmental pollutant, is converted based on 6-PPD via ozonation. However, a systematic evaluation on possible neurotoxicity of long-term and low-dose 6-PPDQ exposure and the underlying mechanism remain unknown. In the present work, 0.1–10 μg/L 6-PPDQ was added to treat Caenorhabditis elegans for 4.5 days, with locomotion behavior, neuronal development, sensory perception behavior, neurotransmitter content, and levels of neurotransmission-related genes being the endpoints. 6-PPDQ exposure at 0.1–10 μg/L significantly reduced locomotion behavior, and that at 1–10 μg/L decreased sensory perception behavior in nematodes. Moreover, 6-PPDQ exposure at 10 μg/L notably induced damage to the development of dopaminergic, glutamatergic, serotonergic, and GABAergic neurons. Importantly, nematodes with chronic 6-PPDQ exposure at 10 μg/L were confirmed to suffer obviously decreased dopamine, serotonin, glutamate, dopamine, and GABA contents and altered neurotransmission-related gene expression. Meanwhile, the potential binding sites of 6-PPDQ and neurotransmitter synthesis-related proteins were further shown by molecular docking method. Lastly, Pearson's correlation analysis showed that locomotion behavior and sensory perception behavior were positively correlated with the dopaminergic, serotonergic, glutamatergic, and GABAergic neurotransmission. Consequently, 6-PPDQ exposure disturbed neurotransmitter transmission, while such changed molecular foundation for neurotransmitter transmission was related to 6-PPDQ toxicity induction. The present work sheds new lights on the mechanisms of 6-PPDQ and its possible neurotoxicity to organisms at environmentally relevant concentrations.

Photoaged microplastics induce neurotoxicity associated with damage to serotonergic, glutamatergic, dopaminergic, and GABAergic neuronal systems in Caenorhabditis elegans

Microplastics (MPs) are ubiquitous environmental contaminants that cause neurotoxicity in various organisms. MPs are typically affected by light irradiation and undergo photoaging. However, the neurotoxic effects of photoaged polystyrene (P-PS) and its underlying mechanisms remain unclear. In this study, locomotion behaviors, neuronal development, neurotransmitter levels, and the expression of neurotransmission-related genes were investigated in Caenorhabditis elegans exposed to P-PS at environment-relevant concentrations (0.1–100 μg/L). The characterization results showed that photoaging accelerated the aging process and changed the physicochemical properties of the MPs. The toxicity results suggested that exposure to 1–100 μg/L P-PS caused more severe neurotoxicity than virgin polystyrene (V-PS) with endpoints of head thrashes, body bends, wavelength, and mean amplitude. Exposure to P-PS also altered the fluorescence intensity and neurodegeneration percentage of serotonergic, glutamatergic, dopaminergic, and aminobutyric acid (GABA) in transgenic nematodes. Similarly, significant reductions in the levels of these neurotransmitters were also observed. Based on Pearson's correlation, locomotion behaviors were negatively correlated with the neurotransmission of serotonin, glutamate, dopamine, and GABA. Further investigation suggested that the expression of neurotransmitter-related genes (e.g., tph-1, eat-4, and unc-46) was significantly altered in the nematodes. Collectively, the neurotoxic effects of P-PS were attributed to abnormal neurotransmission. This study highlights the potential toxicity of MPs photoaged under environmentally relevant conditions.

High-Glucose Diet Attenuates the Dopaminergic Neuronal Function in C. elegans, Leading to the Acceleration of the Aging Process.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the selective degeneration of neurons, primarily in the substantia nigra. Environmental or exogenous factors that cause Parkinson’s disease have not been sufficiently elucidated. Our study aims to investigate the causative effect of a high-glucose diet on Parkinson’s disease-relevant dopaminergic neuronal system in Caenorhabditis elegans. Aging parameters were first observed by measuring the lifespan, body movement, and body sizes with and without the background of high glucose. The toxic effect of a high-glucose diet was further explored by observing the dopaminergic neurons using transgenic Pdat-1::gfp strains, BZ555, under a Zeiss microscope, and the experiments were extended by assessing dopamine-related behavioral analysis including basal slowing response and alcohol avoidance. The aggregation of the α-synucleins was also assessed by observing the NL5901 mutants. Worms fed with 250 mM glucose showed daf-2-independent regulation of aging, displaying a short lifespan (≤15 days), long body size (max. 140%), and slow movement (min. 30%, 10 bends/min). Anterior dopaminergic neurons were rapidly inactivated (70%) by a glucose-rich diet from 12 h of exposure, suggesting specific degeneration in ADE neurons. The dysregulation of neurons led to deteriorations in dopaminergic behaviors including basal slowing response (BSR). A high-glucose diet decreased dopamine synthesis (40 pg/mg vs 15 pg/mg protein) and induced α-synuclein aggregation in the muscles. Results demonstrate the potential of a high-glucose diet as a trigger of dopaminergic neuronal dysregulation conjugating aging acceleration.

Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications.

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder primarily affecting dopaminergic neuronal systems, with impaired motor function as a consequence. The most effective treatment for PD remains the administration of oral levodopa (LD). Long-term LD treatment is frequently associated with motor fluctuations and dyskinesias, which exert a serious impact on a patient’s quality of life. The aim of our study was to determine the pharmacokinetics of LD: used as monotherapy or in combination with ropinirole, in patients with advanced PD. Furthermore, an effect of ropinirole on the pharmacokinetics of 3-OMD (a major LD metabolite) was assessed. We also investigated the correlation between the pharmacokinetic parameters of LD and 3-OMD and the occurrence of motor complications. Twenty-seven patients with idiopathic PD participated in the study. Thirteen patients received both LD and ropinirole, and fourteen administered LD monotherapy. Among 27 patients, twelve experienced fluctuations and/or dyskinesias, whereas fifteen were free of motor complications. Inter- and intra-individual variation in the LD and 3-OMD concentrations were observed. There were no significant differences in the LD and 3-OMD concentrations between the patients treated with a combined therapy of LD and ropinirole, and LD monotherapy. There were no significant differences in the LD concentrations in patients with and without motor complications; however, plasma 3-OMD levels were significantly higher in patients with motor complications. A linear one-compartment pharmacokinetic model with the first-order absorption was adopted for LD and 3-OMD. Only mean exit (residence) time for 3-OMD was significantly shorter in patients treated with ropinirole. Lag time, V/F, CL/F and tmax of LD had significantly lower values in patients with motor complications. On the other hand, AUC were significantly higher in these patients, both for LD and 3-OMD. 3-OMD Cmax was significantly higher in patients with motor complications as well. Our results showed that ropinirole does not influence LD or 3-OMD concentrations. Higher 3-OMD levels play a role in inducing motor complications during long-term levodopa therapy.

The Cerebellar Dopaminergic System.

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments.

The Dopaminergic Neuronal System Regulates the Inflammatory Status of Mouse Lacrimal Glands in Dry Eye Disease.

PurposeComparison of the parasympathetic and sympathetic neurons, including the dopaminergic neural system, in dry eye (DE)–induced pathophysiology has not been elucidated well. This study investigated the presence of dopamine receptors (DRs) and their functional roles in the lacrimal glands (LGs) of DE-induced mice.MethodsAfter DE was induced in B6 mice for 2 weeks, the expression of tyrosine hydroxylase (TH), dopamine, and DRs (DR1, DR2, etc.) in the LGs and corneas were measured by quantitative RT-PCR, immunoblot, and ELISA. Using flow cytometry and ELISA, immune cell infiltration and inflammatory cytokine expression were determined in DE-induced LGs with or without DR blockers, SCH-23390 (DR1i), or melperone (DR2i). Corneal erosion scores were also investigated.ResultsThe mRNA and protein levels of TH significantly increased in DE-induced LGs. The dopamine concentration of LGs was 9.51 pmol in DE (versus naive: 1.39 pmol; P < 0.001). Both DR1 and DR2 mRNA expression were significantly enhanced in desiccating stress compared with those in naive (3.7- and 2.1-fold, P < 0.001). Interestingly, DR1 and DR2 immunostaining patterns stained independently in DE-induced LGs. CD3+ and CD19+ cell infiltration was significantly increased by DR2i (P < 0.001) but not by DR1i. Furthermore, IFN-γ, IL-17, and TNF-α were significantly upregulated by DR2i compared with the blow-only condition. The severity of corneal erosion and inflammation was also aggravated by DR2i.ConclusionsUpregulation of DR1 and DR2 was observed in DE-induced mouse LGs. As the inflammatory conditions are aggravated by the inhibition of DRs, especially DR2, their activity may be an important factor preserving ocular surface homeostasis.

QPRT Deficit Leads Motor and Cognitive Dysfunction through Increase of Oxidative Stress in the Dopaminergic Neuronal System by Quinolinic Acid

QPRT Deficit Leads Motor and Cognitive Dysfunction through Increase of Oxidative Stress in the Dopaminergic Neuronal System by Quinolinic Acid

Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging.

SummaryMonoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Zinc enhances the expression of morphine-induced conditioned place preference through dopaminergic and serotonergic systems.

The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.

A non-human primate model for stable chronic Parkinson’s disease induced by MPTP administration based on individual behavioral quantification

BackgroundThe guidelines for applying individual adjustments to macaques according to the severity of behavioral symptoms during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment were provided to reproduce stable chronic Parkinsonism in a recent study (Potts et al., 2014). But, since there are insufficient guidelines regarding objective severity criteria of individual symptoms for adjustments of MPTP treatment, it is difficult to develop MPTP-induced chronic non-human primate (NHP) models with stable symptoms. New methodThe individual adjustments of MPTP administration based on results of automatic quantification of global activity (GA) using a video-based tracking system were applied to develop MPTP-PD model. Low-dose (0.2 mg/kg) intramuscular injection was repeated continuously until GA was lower than 8% of baseline Parkinsonian behavior scores. The positron emission tomography imaging were used to follow the longitudinal course of Parkinson’s disease (PD). ResultsSignificant reductions in GA and dopamine transporter activity, along with significant increases in Parkinsonian behavior scores were found from 4 to 48 weeks following the first administration. GA was correlated with the Parkinsonian behavior score. The dopamine transporter activity was correlated with GA and the Parkinsonian behavior score. However, it was not correlated with the total dose of MPTP. Damage of dopaminergic neuronal systems in the basal ganglia was confirmed by immunohistochemistry and Western blot. Comparison with existing methodThis study reinforces previous guidelines regarding production of NHP models with stable Parkinsonian symptoms. ConclusionsThis novel strategy of MPTP administration based on global activity evaluations provides an important conceptual advance for the development of chronic NHP Parkinsonian models.

Dysregulation of major functional genes in frontal cortex by maternal exposure to carbon black nanoparticle is not ameliorated by ascorbic acid pretreatment

Recent cohort studies have revealed that perinatal exposure to particulate air pollution, including carbon-based nanoparticles, increases the risk of brain disorders. Although developmental neurotoxicity is currently a major issue in the toxicology of nanoparticles, critical information for understanding the mechanisms underlying the developmental neurotoxicity of airway exposure to carbon black nanoparticle (CB-NP) is still lacking. In order to investigate these mechanisms, we comprehensively analyzed fluctuations in the gene expression profile of the frontal cortex of offspring mice exposed maternally to CB-NP, using microarray analysis combined with Gene Ontology information. We also analyzed differences in the enriched function of genes dysregulated by maternal CB-NP exposure with and without ascorbic acid pretreatment to refine specific alterations in gene expression induced by CB-NP. Total of 652 and 775 genes were dysregulated by CB-NP in the frontal cortex of 6- and 12-week-old offspring mice, respectively. Among the genes dysregulated by CB-NP, those related to extracellular matrix structural constituent, cellular response to interferon-beta, muscle organ development, and cysteine-type endopeptidase inhibitor activity were ameliorated by ascorbic acid pretreatment. A large proportion of the dysregulated genes, categorized in hemostasis, growth factor, chemotaxis, cell proliferation, blood vessel, and dopaminergic neurotransmission, were, however, not ameliorated by ascorbic acid pretreatment. The lack of effects of ascorbic acid on the dysregulation of genes following maternal CB-NP exposure suggests that the contribution of oxidative stress to the effects of CB-NP on these biological functions, i.e., cell migration and proliferation, blood vessel maintenance, and dopaminergic neuron system, may be limited. At least, ascorbic acid pretreatment is hardly likely to be able to protect the brain of offspring from developmental neurotoxicity of CB-NP. The present study provides insight into the mechanisms underlying developmental neurotoxicity following maternal nanoparticle exposure.

Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles

BackgroundExtensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles.MethodsJuvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress.ResultsStress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects.ConclusionsThese findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Parkinson's Disease Model.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It is known that there are many factors, either genetic or environmental factors, involved in PD, but the mechanism of PD is still not fully understood. Several animal models have been established to study the mechanisms of PD. Among these models, Drosophila melanogaster has been utilized as a valuable model to get insight into important features of PD. Drosophila melanogaster possesses a well-developed dopaminergic (DA) neuron system which is known to play an important role in PD pathogenesis. The well understanding of DA neurons from early larval through adult stage makes Drosophila as a powerful model for investigating the progressive neurodegeneration in PD. Besides, the short life cycle of Drosophila melanogaster serves an advantage in studying epidemiological features of PD. Most of PD symptoms can be mimicked in Drosophila model such as progressive impairment in locomotion, DA neuron degeneration, and some other non-motor symptoms. The Drosophila models of PD, therefore, show a great potential in application for PD genetic and drug screening.

Methamphetamine induces Shati/Nat8L expression in the mouse nucleus accumbens via CREB- and dopamine D1 receptor-dependent mechanism.

Shati/Nat8L significantly increased in the nucleus accumbens (NAc) of mice after repeated methamphetamine (METH) treatment. We reported that Shati/Nat8L overexpression in mouse NAc attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference. We recently found that Shati/Nat8L overexpression in NAc regulates the dopaminergic neuronal system via the activation of group II mGluRs by elevated N-acetylaspartylglutamate following N-acetylaspartate increase due to the overexpression. These findings suggest that Shati/Nat8L suppresses METH-induced responses. However, the mechanism by which METH increases the Shati/Nat8L mRNA expression in NAc is unclear. To investigate the regulatory mechanism of Shati/Nat8L mRNA expression, we performed a mouse Shati/Nat8L luciferase assay using PC12 cells. Next, we investigated the response of METH to Shati/Nat8L expression and CREB activity using mouse brain slices of NAc, METH administration to mice, and western blotting for CREB activity of specific dopamine receptor signals in vivo and ex vivo. We found that METH activates CREB binding to the Shati/Nat8L promoter to induce the Shati/Nat8L mRNA expression. Furthermore, the dopamine D1 receptor antagonist SCH23390, but not the dopamine D2 receptor antagonist sulpiride, inhibited the upregulation of Shati/Nat8L and CREB activities in the mouse NAc slices. Thus, the administration of the dopamine D1 receptor agonist SKF38393 increased the Shati/Nat8L mRNA expression in mouse NAc. These results showed that the Shati/Nat8L mRNA was increased by METH-induced CREB pathway via dopamine D1 receptor signaling in mouse NAc. These findings may contribute to development of a clinical tool for METH addiction.

Effects of (-)-sesamin on chronic stress-induced memory deficits in mice

This study investigated the effects of (-)-sesamin on memory deficits induced by chronic electric footshock (EF)-induced stress in mice. Mice were treated with (-)-sesamin (25 and 50mg/kg, p.o., daily for 21day) prior to chronic EF stress (0.6mA, 1s every 5s for 3min, daily for 21day). Transfer retention latencies in the elevated plus maze test and N-methyl-d-aspartate (NMDA) receptor (type 1) phosphorylation in the hippocampus increased with chronic EF stress, and they were reduced by treatment with (-)-sesamin at both doses. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-responsive element binding protein (CREB), which were reduced by chronic EF stress, were increased by treatment with (-)-sesamin. Retention latencies in the passive avoidance test and dopamine levels in the substantia nigra-striatum were also reduced by chronic EF stress, and similarly recovered with (-)-sesamin treatment. These results suggest that (-)-sesamin ameliorates the effects of chronic EF stress-induced spatial and habit learning memory deficits by modulating both NMDA receptor and dopaminergic neuronal systems.

Studies on the regulatory effect of Peony-Glycyrrhiza Decoction on prolactin hyperactivity and underlying mechanism in hyperprolactinemia rat model

Clinical trials have demonstrated the beneficial effects of Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL) in schizophrenic patients. In previous experiment, PGD suppressed prolactin (PRL) level in MMQ cells, involving modulating the expression of D2 receptor (DRD2) and dopamine transporter (DAT). In the present study, hyperPRL female rat model induced by dopamine blocker metoclopramide (MCP) was applied to further confirm the anti-hyperpPRL activity of PGD and underlying mechanism. In MCP-induced hyperPRL rats, the elevated serum PRL level was significantly suppressed by either PGD (2.5–10g/kg) or bromocriptine (BMT) (0.6mg/kg) administration for 14 days. However, in MCP-induced rats, only PGD restored the under-expressed serum progesterone (P) to control level. Both PGD and BMT administration restore the under-expression of DRD2, DAT and TH resulted from MCP in pituitary gland and hypothalamus. Compared to untreated group, hyperPRL animals had a marked reduction on DRD2 and DAT expression in the arcuate nucleus. PGD (10g/kg) and BMT (0.6mg/kg) treatment significant reversed the expression of DRD2 and DAT. Collectively, the anti-hyperPRL activity of PGD associates with the modulation of dopaminergic neuronal system and the restoration of serum progesterone level. Our finding supports PGD as an effective agent against hyperPRL.

Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model

Tebufenpyrad and pyridaben are two agro-chemically important acaricides that function like the known mitochondrial toxicant rotenone. Although these two compounds have been commonly used to kill populations of mites and ticks in commercial greenhouses, their neurotoxic profiles remain largely unknown. Therefore, we investigated the effects of these two pesticides on mitochondrial structure and function in an in vitro cell culture model using the Seahorse bioanalyzer and confocal fluorescence imaging. The effects were compared with rotenone. Exposing rat dopaminergic neuronal cells (N27 cells) to tebufenpyrad and pyridaben for 3h induced dose-dependent cell death with an EC50 of 3.98μM and 3.77μM, respectively. Also, tebufenpyrad and pyridaben (3μM) exposure induced reactive oxygen species (ROS) generation and m-aconitase damage, suggesting that the pesticide toxicity is associated with oxidative damage. Morphometric image analysis with the MitoTracker red fluorescent probe indicated that tebufenpyrad and pyridaben, as well as rotenone, caused abnormalities in mitochondrial morphology, including reduced mitochondrial length and circularity. Functional bioenergetic experiments using the Seahorse XF96 analyzer revealed that tebufenpyrad and pyridaben very rapidly suppressed the basal mitochondrial oxygen consumption rate similar to that of rotenone. Further analysis of bioenergetic curves also revealed dose-dependent decreases in ATP-linked respiration and respiratory capacity. The luminescence-based ATP measurement further confirmed that pesticide-induced mitochondrial inhibition of respiration is accompanied by the loss of cellular ATP. Collectively, our results suggest that exposure to the pesticides tebufenpyrad and pyridaben induces neurotoxicity by rapidly initiating mitochondrial dysfunction and oxidative damage in dopaminergic neuronal cells. Our findings also reveal that monitoring the kinetics of mitochondrial respiration with Seahorse could be used as an early neurotoxicological high-throughput index for assessing the risk that pesticides pose to the dopaminergic neuronal system.

Functional Interplay between Dopaminergic and Serotonergic Neuronal Systems during Development and Adulthood.

The complex integration of neurotransmitter signals in the nervous system contributes to the shaping of behavioral and emotional constitutions throughout development. Imbalance among these signals may result in pathological behaviors and psychiatric illnesses. Therefore, a better understanding of the interplay between neurotransmitter systems holds potential to facilitate therapeutic development. Of particular clinical interest are the dopaminergic and serotonergic systems, as both modulate a broad array of behaviors and emotions and have been implicated in a wide range of affective disorders. Here we review evidence speaking to an interaction between the dopaminergic and serotonergic neuronal systems across development. We highlight data stemming from developmental, functional, and clinical studies, reflecting the importance of this transmonoaminergic interplay.

PRDX6 Exacerbates Dopaminergic Neurodegeneration in a MPTP Mouse Model of Parkinson's Disease.

Peroxiredoxin 6 (PRDX6) is a bifunctional protein with both glutathione peroxidase (GPx) and calcium-independent phospholipase A2 (iPLA2) activities. Expression of PRDX6 has been detected in human Parkinson's disease (PD) and dementia patients. However, no study has described PRDX6 function in the dopaminergic neurodegeneration in PD. Herein, we investigated the effects of PRDX6 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration using PRDX6 transgenic (Tg) mice. Immunohistochemistry (IHC) and Western blot data for tyrosine hydroxylase (TH) showed that PRDX6 Tg mice had much higher loss of dopaminergic neurons by MPTP administration compared to non-Tg mice, as well as there was much higher behavioral impairment and astrocyte activation in PRDX6 Tg mice. MPTP-induced GPx activity was not different between PRDX6 Tg mice and non-Tg mice, which is accompanied by hyperoxidation of PRDX6. While iPLA2 activity was increased in PRDX6 Tg mice followed by an increase in the level of ROS and 4-hydroxynonenal (4-HNE). Intriguingly, the expression pattern of PRDX6 showed similar distribution and co-localization with astrocytes, but not neuron in the mouse and human brain. Furthermore, we demonstrated that iPLA2 activity of PRDX6 induced astrocytic activation followed by increased proinflammatory cytokines (TNF-α and IL1-β), 4-HNE, and PRDX6 hyperoxidation in primary cultured astrocytes. Our findings provide novel insights for PRDX6 function on nigrostriatal dopaminergic neuronal system, and we suggest that PRDX6 has an important role in dopaminergic neurodegeneration of PD.

SY33-3 * SHATI/NAT8L REGULATES DOPAMINE RELEASE-INDUCED BY NICOTINE IN NUCLEUS ACCUMBENS

Many psychiatric disorders are caused by the abnormalities of the dopaminergic neuronal system. A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously, we reported that suppression of Shati/Nat8l in the NAc enhanced METH-induced behavioral impairment via dopaminergic neuronal regulation by activation of group II mGluRs. In this study, we investigated the effects of Shati/Nat8l on the action of nicotine. AAV vector containing the entire cDNA sequence of Shati/Nat8l (AAV-Shati/Nat8l vector) or AAV-Mock vector were injected in the NAc. Dopamine release were measured by in vivo microdiarysis. The expression of nAChR mRNA were determined by RT-PCR. Shati/Nat8lmRNA in 6 times in AAV Shati/Nat8l-injected site. Overexpression of Shati/Nat8l in the NAc inhibited NIC-induced increasing of dopamine release. The effect of Shati/Nat8l was partially rescued by LY341495, the antagonist of mGluR2/3. Furthermore, Shati/Nat8l overexpressed mice, the expression of alpha7 nAChR mRNA was upregulated in the NAc compared with Mock mice. On the other hands, alpha4 nAChR mRNA in the ventral tegmental area was downregulated compared with Mock mice. These results indicate that Shati/Nat8l in the NAc, plays an important role of the mediation by nicotine of the extracellular dopamine level.