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A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

ABSTRACT: Polychlorinated Biphenyls (PCBs) are very stable environmental contaminants whose exposure induces a number of health and cognitive concerns. Currently, it is well known that PCB exposure leads to poor performance on inhibitory control tasks. It is also well known that dopamine (DA) depletion within medial prefrontal cortex (mPFC) leads to poor performance on inhibitory control tasks. However, what is not well established is whether or not the inhibitory control problems found following PCB exposure are mediated by DA depletion in mPFC. This study was an investigation into the link between perinatal exposure to PCBs, the effect of this exposure on DA neurotransmission in the mPFC, and inhibitory-control problems during adulthood using a rodent model. The current study served to determine if microinjections of different DA agonists (the presynaptic DA transporter inhibitor and vesicular monoamine transporter agonist bupropion, the postsynaptic DA receptor 2 (DAD2) agonist quinpirole, and the postsynaptic DA receptor 1 (DAD1) agonist SKF81297) directly into the mPFC would differentially improve performance on an inhibitory control task in rats perinatally exposed to an environmentally relevant PCB mixture. Findings suggest several significant sex-based differences on differential reinforcement of low rates (DRL) 15 performance as well as some evidence of differential effectiveness of the DA agonists based on PCB exposure group.

SUBMITTER: Meyer AE

PROVIDER: S-EPMC4522349 | biostudies-literature | 2015 Jul-Aug

REPOSITORIES: biostudies-literature

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A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

Meyer Abby E AE Miller Mellessa M MM Nelms Sprowles Jenna L JL Levine Lauren R LR Sable Helen J K HJ

Neurotoxicology and teratology 20150527

Polychlorinated Biphenyls (PCBs) are very stable environmental contaminants whose exposure induces a number of health and cognitive concerns. Currently, it is well known that PCB exposure leads to poor performance on inhibitory control tasks. It is also well known that dopamine (DA) depletion within medial prefrontal cortex (mPFC) leads to poor performance on inhibitory control tasks. However, what is not well established is whether or not the inhibitory control problems found following PCB expo ...[more]

PMID: 26022001

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Project description:Along with the well-established effects on fertility and fecundity, perinatal exposure to endocrine disrupting chemicals, and notably to xeno-estrogens, is strongly suspected of modulating general metabolism. The metabolism of a perinatally exposed individual may be durably altered leading to a higher susceptibility of developing metabolic disorders such as obesity and diabetes; however, experimental designs involving the long term study of these dynamic changes in the metabolome raise novel challenges. 1H-NMR-based metabolomics was applied to study the effects of bisphenol-A (BPA, 0; 0.25; 2.5, 25 and 250 ?g/kg BW/day) in rats exposed perinatally. Serum and liver samples of exposed animals were analyzed on days 21, 50, 90, 140 and 200 in order to explore whether maternal exposure to BPA alters metabolism. Partial Least Squares-Discriminant Analysis (PLS-DA) was independently applied to each time point, demonstrating a significant pair-wise discrimination for liver as well as serum samples at all time-points, and highlighting unequivocal metabolic shifts in rats perinatally exposed to BPA, including those exposed to lower doses. In BPA exposed animals, metabolism of glucose, lactate and fatty acids was modified over time. To further explore dynamic variation, ANOVA-Simultaneous Component Analysis (A-SCA) was used to separate data into blocks corresponding to the different sources of variation (Time, Dose and Time*Dose interaction). A-SCA enabled the demonstration of a dynamic, time/age dependent shift of serum metabolome throughout the rats' lifetimes. Variables responsible for the discrimination between groups clearly indicate that BPA modulates energy metabolism, and suggest alterations of neurotransmitter signaling, the latter finding being compatible with the neurodevelopmental effect of this xenoestrogen. In conclusion, long lasting metabolic effects of BPA could be characterized over 200 days, despite physiological (and thus metabolic) changes connected with sexual maturation and aging.

Project description:Polychlorinated biphenyls (PCBs) consist of a range of toxic substances which are directly proportional to carcinogenesis and tumor-promoting factors as well as having neurotoxic properties. Reactive oxygen species, which are produced from PCBs, alter blood-brain barrier (BBB) integrity, which is paralleled by cytoskeletal rearrangements and redistribution and disappearance of tight junction proteins (TJPs) like claudin-5 and occludin. Brain-derived neurotrophic factor (BDNF), plays an important role in the maintenance, survival of neurons and synaptic plasticity. It is predominant in the hippocampal areas vital to learning, memory and higher thinking. Quercetin, a flavonoid, had drawn attention to its neurodefensive property. The study is to assess the role of quercetin on serum PCB, estradiol and testosterone levels and mRNA expressions of estrogen receptor ? and ?, TJPs and BDNF signaling molecules on the hippocampus of PCBs-exposed rats. Rats were divided into 4 groups of 6 each. Group I rats were intraperitoneally (i.p.) administered corn oil (vehicle). Group II received quercetin 50 mg/kg/bwt (gavage). Group III received PCBs (Aroclor 1254) at 2 mg/kg bwt (i.p). Group IV received quercetin 50 mg/kg bwt (gavage) simultaneously with PCBs 2 mg/kg bwt (i.p.). The treatment was given daily for 30 days. The rats were euthanized 24 h after the experimental period. Blood was collected for quantification of serum PCBs estradiol and testosterone. The hippocampus was dissected and processed for PCR and Western blot; serum PCB was observed in PCB treated animals, simultaneously quercetin treated animals showed PCB metabolites. Serum testosterone and estradiol were decreased after PCB exposure. Quercetin supplementation brought back normal levels. mRNA expressions of estrogen ? and ? were decreased in the hippocampus of PCB treated rats. TJPS and BDNF signalling molecules were decreased in hippocampus of PCB treated rats. Quercetin supplementation retrieved all the parameters. Quercetin alone treated animals showed no alteration. Thus in PCB caused neurotoxicity, quercetin protects and prevents neuronal damage in the hippocampus.

Dataset Information

A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

Publications

A comparison of presynaptic and postsynaptic dopaminergic agonists on inhibitory control performance in rats perinatally exposed to PCBs.

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