26 results on '"Vorhees, Charles V."'
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2. Oligodendrocyte Nf1Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior
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López-Juárez, Alejandro, Titus, Haley E., Silbak, Sadiq H., Pressler, Joshua W., Rizvi, Tilat A., Bogard, Madeleine, Bennett, Michael R., Ciraolo, Georgianne, Williams, Michael T., Vorhees, Charles V., and Ratner, Nancy
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The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1+/−mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1.
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- 2017
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3. Nf1Loss and Ras Hyperactivation in Oligodendrocytes Induce NOS-Driven Defects in Myelin and Vasculature
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Mayes, Debra A., Rizvi, Tilat A., Titus-Mitchell, Haley, Oberst, Rachel, Ciraolo, Georgianne M., Vorhees, Charles V., Robinson, Andrew P., Miller, Stephen D., Cancelas, Jose A., Stemmer-Rachamimov, Anat O., and Ratner, Nancy
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Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12Vmice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.
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- 2013
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4. Developmental deltamethrin: Sex-specific hippocampal effects in Sprague Dawley rats
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Pitzer, Emily M., Sugimoto, Chiho, Regan, Samantha L., Gudelsky, Gary A., Williams, Michael T., and Vorhees, Charles V.
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[Display omitted]
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- 2022
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5. Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and Autophagy
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Adhami, Faisal, Liao, Guanghong, Morozov, Yury M., Schloemer, Aryn, Schmithorst, Vincent J., Lorenz, John N., Dunn, R. Scott, Vorhees, Charles V., Wills-Karp, Marsha, Degen, Jay L., Davis, Roger J., Mizushima, Noboru, Rakic, Pasko, Dardzinski, Bernard J., Holland, Scott K., Sharp, Frank R., and Kuan, Chia-Yi
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Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome cand AIF from mitochondria, cleavage of caspase-9 and −8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.
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- 2006
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6. Hippocampal expression of c‐fosis not essential for spatial learning
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Zhang, Jianhua, McQuade, Jill M. Slane, Vorhees, Charles V., and Xu, Ming
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The formation of long‐term memory is thought to involve underlying changes in synaptic strength. Many studies have focused on the mechanisms of spatial learning behavior in mammals that is critically dependent on the proper function of the hippocampus. Because of the enduring nature of long‐term memory, it is thought that gene expression is involved in this process. The immediate early gene (IEG) c‐fosencodes a transcription factor. The c‐Fos proteins form heterodimeric proteins with the c‐Jun family proteins and the resulting AP‐1 transcription complex plays a key role in coupling short‐term events elicited by stimuli received at the cell membrane to long‐term neuroplastic changes by regulating gene expression. c‐fosis induced in the hippocampus after spatial learning. Despite this knowledge, the precise role of c‐fosin memory formation and the underlying mechanisms remain unknown. To start investigating the role of c‐fosin learning and memory and underlying mechanisms, we evaluated spatial learning capabilities using mice carrying a hippocampal region‐specific mutation of c‐fos.We found that the c‐fosmutant mice exhibit normal spatial learning behaviors in both the Morris water maze and the Barnes maze tests compared to control mice. Our results suggest that hippocampal c‐fosexpression is not essential for spatial learning. Synapse 46:91–99, 2002. © 2002 Wiley‐Liss, Inc.
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- 2002
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7. Effects of lubeluzole on the methamphetamine‐induced increase in extracellular glutamate and the long‐term depletion of striatal dopamine
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Wallace, Tanya L., Vorhees, Charles V., and Gudelsky, Gary A.
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The administration of a neurotoxic regimen of methamphetamine (MA) produces an acute elevation in the extracellular concentrations of dopamine and glutamate in the striatum and a long‐term depletion of striatal dopamine content in rats. The intent of the present study was to determine whether attenuation of the MA‐induced increase in extracellular glutamate would prevent the depletion of striatal dopamine. Male rats were treated with MA (10 mg/kg, i.p.) or vehicle every 2 h for four injections and concomitantly perfused intrastriatally with either artificial cerebrospinal fluid or lubeluzole (300 μM), a novel neuroprotectant that has been shown to prevent the increase in extracellular glutamate after the induction of neocortical infarct in rats. Lubeluzole significantly attenuated the MA‐induced increase in extracellular glutamate in the striatum without affecting the MA‐induced increase in extracellular dopamine or the MA‐induced hyperthermic response. Nevertheless, lubeluzole did not prevent the long‐term depletion of striatal dopamine produced by a neurotoxic regimen of MA. These results suggest that the MA‐induced depletion of striatal dopamine may not be dependent on the increased extracellular concentration of striatal glutamate. Synapse 40:95–101, 2001. © 2001 Wiley‐Liss, Inc.
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- 2001
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8. Neurotoxic regimen of methamphetamine produces evidence of behavioral sensitization in the rat
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Wallace, Tanya L., Gudelsky, Gary A., and Vorhees, Charles V.
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A neurotoxic regimen of methamphetamine (MA) produces long‐term depletions in neostriatal dopamine and serotonin concentrations. In addition to evidence of dopaminergic and serotonergic neurotoxicity, there is evidence of MA‐induced behavioral changes. In this regard, stereotypic behavior elicited by MA is greater in rats treated previously with a neurotoxic regimen of MA than in control animals. The present study was designed to determine whether the enhanced stereotypy observed in MA‐treated rats is due to the MA‐induced loss of dopamine (neurotoxicity) or to the repeated exposure to MA (sensitization). Rats were treated with MA (10 mg/kg every 2 h for four injections) or vehicle at either a normal (24°C) room temperature or a cold (4°C) room temperature, which has been shown to attenuate the MA‐induced loss of dopamine. Stereotypy was assessed 7 days after treatment. Rats that had received a neurotoxic regimen of MA at 24°C exhibited 49% and 45% reductions in neostriatal dopamine and serotonin concentrations, respectively, whereas rats treated with MA at 4°C had no significant neurochemical depletions. Stereotypy elicited by MA (5.0 mg/kg) was significantly greater in rats treated with a neurotoxic regimen of MA regardless of the initial treatment temperature. In addition, an injection of apomorphine (0.5 mg/kg) elicited an enhanced stereotypic response in MA‐treated rats. These data suggest that the augmented stereotypic behavior observed in rats treated with a neurotoxic regimen of MA is not due to the loss of dopamine, but rather the manifestation of behavioral sensitization, possibly due to an increase in dopamine receptor sensitivity. Synapse 39:1–7, 2001. © 2001 Wiley‐Liss, Inc.
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- 2001
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9. Methamphetamine‐Induced Neurotoxicity in Rats: Effects on Neostriatal Monoamines and Glial Fibrillary Acidic Protein
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FUKUMURA, Masao, CAPPON, Gregg D., PU, Cunfeng, BROENING, Harry W., and VORHEES, Charles V.
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In order to investigate methamphetamine (MA)‐induced neurotoxicity, two studies were carried out.
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- 1999
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10. Genetic differences in spatial learning between Dark Agouti and Sprague-Dawley strains possible correlation with the CYP2D2polymorphism in rats treated neonatally with methamphetamine
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Vorhees, Charles V., Morford, LaRonda L., Inman, Sandra L., Reed, Tracy M., Schilling, Mary A., Cappon, Gregg D., Moran, Mary S., and Nebert, Daniel W.
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Following neonatal exposure to d-methamphetamine, adult rats have previously been shown to exhibit augmented acoustic startle and spatial learning deficits. d-Methamphetamine is structurally similar to several phenylethylamines that are metabolized by CYP2D6. In humans, allelic differences in the CYP2D6confer the extensive or poor metabolizer phenotype for the more than three dozen drugs that are members of the CYP2D6-mediated ‘debrisoquine/sparteine panel.’ An analogous genotype exists with the CYP2D2gene in rats. Female Dark Agouti rats show the poor metabolizer phenotype, whereas Sprague-Dawley rats show the extensive metabolizer phenotype; male Dark Agouti rats are intermediate. We sought to test the possibility that these strains might exhibit altered d-methamphetamine-induced developmental neurotoxicity. Dark Agouti and Sprague-Dawley litters (11–20 days of age) were given d-methamphetamine or vehicle alone subcutaneously twice daily (15 mg/kg). Offspring were assessed as adults (beginning at 50 days of age) on acoustic startle, straight-channel swimming, and spatial learning and memory in a Morris hidden platform maze. Increases in d-methamphetamine-induced acoustic startle were found in both male and female Dark Agouti rats, but not Sprague-Dawley rats. In the Morris maze, d-methamphetamine-induced spatial navigation deficits were found in both strains among males, suggesting some mechanism other than the CYP2D2polymorphism. In contrast, among females only the d-methamphetamine-treated Dark Agouti rats showed deficits in spatial navigation. The maze deficits in Dark Agouti females, and enhanced acoustic startle in Dark Agouti females and males, support the hypothesis that the CYP2D2poor metabolizer phenotype confers increased vulnerability to d-methamphetamine-induced developmental neurotoxicity, indicating that the parent drug rather than a CYP2D2-mediated metabolite is responsible for this behavioural defect – which occurs in adults who had been exposed to d-methamphetamine during the neonatal period.
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- 1999
11. A Perspective on Tachibana's Eta-Squared Analyses of the Results of the Nctr Collaborative Behavioral Teratology Study
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Vorhees, Charles V.
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The NCTR Collaborative Behavioral Teratology Study (CBTS) data have been reanalyzed by Tachibana (1989) using the strength of association statistic η2as a means of examining the reliability of the data. This is an important issue, because determining the reliability of behavioral teratological measures was one of the CBTS's principal aims. The η2approach is a useful one, but its value is critically dependent on the assumption that it is applied to the data appropriately. The CBTS was a project which involved large numbers of pregnant rats and their offspring, tested postnatally on a large number of physical and behavioral tests. The project was conducted in six laboratories and involved two experiments with four treatment groups/experiment, 16 dams/group, and 8 offspring/dam. For practical more than theoretical reasons, each of these large experiments was conducted in balanced replicates of 4 dams/group. Since this had to be done, replicate was included in the statistical models used to evaluate the data. Tachibana (1989) has performed a series of η2analyses on the CBTS data as if each replicate constituted an independent experiment and concluded that the reproducibility of the CBTS data was not particularly good. Tachibana's η2analyses are discussed as problematic because the data should have been analyzed as intended, by experiment (n= 16/group), not by replicates. There are well-known problems associated with the reliability of small sample sizes in any experiment and Tachibana's conclusion, based as it is on replicates, offers little insight into the reproducibility of behavioral teratogenicity data generally or from the CBTS project specifically.
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- 1989
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12. Methamphetamine selectively damages dopaminergic innervation to the nucleus accumbens core while sparing the shell
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Broening, Harry W., Pu, Cunfeng, and Vorhees, Charles V.
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Dopaminergic innervation to the nucleus accumbens was investigated following a neurotoxic regimen of methamphetamine (MA) treatment. Four 10 mg/kg doses of MA were administered s.c. to male Sprague‐Dawley rats with a 2 h interval between doses. Rectal temperatures were monitored for the induction of MA‐induced hyperthermia. Three days or 2 weeks after MA treatment the animals were sacrificed by transcardial perfusion and processed for tyrosine hydroxylase (TH‐IR) and glial fibrillary acidic protein immunoreactivity (GFAP‐IR). MA treatment produced a severe loss of TH‐IR throughout the striatum, including the nucleus accumbens. However, within the nucleus accumbens, there was substantial sparing of TH‐IR in the shell, while in the core immunoreactivity was almost entirely lost. Furthermore, astrogliosis, as demonstrated by GFAP‐IR, was prevalent in the core but present only in sparse patches in the medial and lateral shell. Thus, dopaminergic innervation to the nucleus accumbens core undergoes degeneration following MA treatment, while innervation to the shell is resistant to the neurodegenerative effects of MA. Synapse 27:153–160, 1997.© 1997 Wiley‐Liss, Inc.
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- 1997
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13. Methamphetamine selectively damages dopaminergic innervation to the nucleus accumbens core while sparing the shell
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Broening, Harry W., Pu, Cunfeng, and Vorhees, Charles V.
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Dopaminergic innervation to the nucleus accumbens was investigated following a neurotoxic regimen of methamphetamine (MA) treatment. Four 10 mg/kg doses of MA were administered s.c. to male Sprague-Dawley rats with a 2 h interval between doses. Rectal temperatures were monitored for the induction of MA-induced hyperthermia. Three days or 2 weeks after MA treatment the animals were sacrificed by transcardial perfusion and processed for tyrosine hydroxylase (TH-IR) and glial fibrillary acidic protein immunoreactivity (GFAP-IR). MA treatment produced a severe loss of TH-IR throughout the striatum, including the nucleus accumbens. However, within the nucleus accumbens, there was substantial sparing of TH-IR in the shell, while in the core immunoreactivity was almost entirely lost. Furthermore, astrogliosis, as demonstrated by GFAP-IR, was prevalent in the core but present only in sparse patches in the medial and lateral shell. Thus, dopaminergic innervation to the nucleus accumbens core undergoes degeneration following MA treatment, while innervation to the shell is resistant to the neurodegenerative effects of MA. Synapse 27:153160, 1997. © 1997 Wiley-Liss, Inc.
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- 1997
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14. A Developmental Neurotoxicity Evaluation of the Effects of Prenatal Exposure to Fluoxetine in Rats
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Vorhees, Charles V., Acuff-Smith, Karen D., Schilling, Mary A., Fisher, J. Edward, Moran, Mary S., and Buelke-Sam, Judy
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A Developmental Neurotoxicity Evaluation of the Effects of Prenatal Exposure to Fluoxetine in Rats. Vorhees, C. V., Acuff-Smith, K. D., Schilling, M. A., Fisher, J. E., Moran, M. S., and Buelke-Sam, J. (1994). Fundam. Appl. Toxicol. 23, 194-205. Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7-20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat. Copyright 1994, 1999 Academic Press
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- 1994
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15. Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats
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Schoenig, Gerald P., Hartnagel, Ralph E., Schardein, James L., and Vorhees, Charles V.
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Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats. Schoenig, G. P., Hartnagel, G. E., Jr., Schardein, J. L., and Vorhees, C. V. (1993). Fundam. Appl. Toxicol.21, 355-365.
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- 1993
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16. Branched Chain Amino Acids Improve Complex Maze Learning in Rat Offspring Prenatally Exposed to Hyperphenylalaninemia Implications for Maternal Phenylketonuria
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VORHEES, CHARLES V. and BERRY, HELEN K.
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Maternal phenylketonuria results in a high incidence of children born who are mentally retarded. It has been suggested that blood-brain-barrier transport of phenylalanine may be reduced by competitive inhibition of transporter uptake by supplemental administration of other large neutral amino acids. We hypothesized that large neutral amino acids might also be effective at improving the outcome of fetuses exposed to hyperphenylalaninemia in utero. If correct, sparing of embryonic CNS development might be possible. Pregnant rats were given a hyperphenylalaninemic diet alone or the same diet supplemented with a combination of valine, isoleucine, and leucine. As adults, the progeny exposed in uteroto hyperphenylalaninemia showed characteristic learning deficits in a complex maze, while those exposed in uteroto hyperphenylalaninemia combined with valine, isoleucine, and leucine showed no deficits in maze acquisition. The valine, isoleucine, and leucine supplement may show promise as a treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.
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- 1989
17. Cyp2d1Polymorphism in Methamphetamine-Treated Rats
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Vorhees, Charles V., Reed, Tracy M., Schilling, Mary A., Fisher, J.Edward, Moran, Mary S., Cappon, Gregg D., and Nebert, Daniel W.
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d-Methamphetamine (MA) is one of more than two dozen drugs included in the cytochrome P450-mediated “debrisoquine oxidation polymorphism” panel. The human gene (CYP2D6) is responsible for the “poor metabolizer” (PM) and “extensive metabolizer” (EM) phenotypes for drugs such as MA; a similar polymorphism (the CYP2D1gene) exists in rats. Female Black or Dark Agouti rats exhibit the PM phenotype, whereas Sprague–Dawley (SD) rats show the EM trait. We sought to test the possibility that these strains of rats might exhibit altered MA-induced developmental neurotoxicity. Neonatal exposure to MA on days 11–20 has previously been shown to induce spatial learning deficits in Sprague–Dawley rats when tested as adults. Therefore, in the present experiment, on postpartum days 11 through 20, ACI (Black Agouti) and SD progeny were administered 30 mg/kg MA twice daily. MA treatment caused larger increases in mortality in ACI than in SD rats, suggesting that decreased MA metabolism leads to enhanced toxicity and lethality. Female offspring were assessed behaviorally as adults. No differences were observed in acoustic startle or straight swimming channel performance. In the Morris maze, both MA-treated rat strains showed longer latencies to find the hidden platform during acquisition, reinstatement, and shift trials, and spent less time in the target quadrant on probe trials; no strain differences in learning were found. Although these data do not support our hypothesis that MA-induced developmental neurotoxicity might be enhanced in the ACI rat, this interpretation is tempered by the high mortality rate (65%) of MA-treated ACI neonates, suggesting a possible “survivor effect” in this strain.
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- 1998
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18. Genomic structure and chromosome location of the murine PDE1B phosphodiesterase gene
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Reed, Tracey M., Browning, James E., Blough, Ruthann I., Vorhees, Charles V., and Repaske, David R.
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Abstract.: Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby participating in regulation of the intracellular concentrations of these second messengers. The PDE1 family is defined by regulation of activity by calcium and calmodulin. We have cloned and characterized the mouse PDE1B gene, which encodes the 63-kDa calcium/calmodulin-dependent PDE (CaM-PDE), an isozyme that is expressed in the CNS in the olfactory tract, dentate gyrus, and striatum and may participate in learning, memory, and regulation of phosphorylation of DARPP-32 in dopaminergic neurons. We screened an I-129/SvJ mouse genomic library and identified exons 2–13 of the PDE1B gene that span 8.4 kb of genomic DNA. Exons range from 67 to 205 nucleotides and introns from 91 to 2250 nucleotides in length. Exon 1 was not present in the 3 kb of genomic DNA 5′ to exon 2 in our clones. The mouse PDE1B gene shares many similar or identical exon boundaries as well as considerable sequence identity with the rat PDE4B and PDE4D genes and the Drosophila dunce cAMP-specific PDE gene dnc, suggesting that these genes all arose from a common ancestor. Using fluorescence in situ hybridization, we localized the PDE1B gene to the distal tip of mouse Chromosome (Chr) 15.
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- 1998
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19. Effects of Thiamin Deficiency on Acetylcholine Levels and Utilization in vivo in Rat Brain
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Vorhees, Charles V., Schmidt, Dennis E., Barrett, Robert J., and Schenker, Steven
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Cerebral regional acetylcholine (ACh) levels and utilization were studied in vivo in thiamin deficient (TD), pair-fed asymptomatic (PFC) and ad libitum fed control (ALC) rats. ACh levels in the cortex, corpus striatum, midbrain, diencephalon and brainstem of TD rats were comparable to those observed in the control groups. However, ACh utilization was slightly to moderately (10–41%) decreased in cortex, midbrain, diencephalon and brainstem. The decrease was significantly different in the midbrain of TD rats as compared to PFC and ALC rats. J. Nutr. 107: 1902-1908, 1977.
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- 1977
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20. Branched Chain Amino Acids Improve Complex Maze Learning in Rat Offspring Prenatally Exposed to Hyperphenylalaninemia: Implications for Maternal Phenylketonuria
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Vorhees, Charles V and Berry, Helen K
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ABSTRACT: Maternal phenylketonuria results in a high incidence of children born who are mentally retarded. It has been suggested that blood-brain-barrier transport of phenylalanine may be reduced by competitive inhibition of transporter uptake by supplemental administration of other large neutral amino acids. We hypothesized that large neutral amino acids might also be effective at improving the outcome of fetuses exposed to hyperphenylalaninemia in utero. If correct, sparing of embryonic CNS development might be possible. Pregnant rats were given a hyperphenylalaninemic diet alone or the same diet supplemented with a combination of valine, isoleucine, and leucine. As adults, the progeny exposed in utero to hyperphenylalaninemia showed characteristic learning deficits in a complex maze, while those exposed in utero to hyperphenylalaninemia combined with valine, isoleucine, and leucine showed no deficits in maze acquisition. The valine, isoleucine, and leucine supplement may show promise as a treatment for intrauterinely acquired mental deficiency associated with maternal phenylketonuria.
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- 1989
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21. An Experimental Evaluation of Phototherapy for Hyperbilirubinemia in the Gunn Rat
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Butcher, Richard E., Vorhees, Charles V., Kindt, Charles W., and Keenan, William J.
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Jaundiced rats of the Gunn substrain were exposed to light for two to seven hours per day between the third and 25th day of life. Compared to untreated jaundiced subjects, treated rats showed no improvement in their performance on behavioral tests although increased vitality was observed.
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- 1972
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22. Assessing Spatial Learning and Memory in Rodents
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Vorhees, Charles V. and Williams, Michael T.
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Maneuvering safely through the environment is central to survival of almost all species. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and nearby proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures; in humans this system encodes allocentric, semantic, and episodic memory. This form of memory is assessed in laboratory animals in many ways, but the dominant form of assessment is the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and, when overlearned, becomes procedural memory. In this article, several allocentric assessment methods for rodents are reviewed and compared with the MWM. MWM advantages (little training required, no food deprivation, ease of testing, rapid and reliable learning, insensitivity to differences in body weight and appetite, absence of nonperformers, control methods for proximal cue learning, and performance effects) and disadvantages (concern about stress, perhaps not as sensitive for working memory) are discussed. Evidence-based design improvements and testing methods are reviewed for both rats and mice. Experimental factors that apply generally to spatial navigation and to MWM specifically are considered. It is concluded that, on balance, the MWM has more advantages than disadvantages and compares favorably with other allocentric navigation tasks.
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- 2014
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23. Behavioral and Physical Development of Rats Chronically Exposed to Caffeinated Fluids
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BUTCHER, RICHARD E., VORHEES, CHARLES V., and WOOTTEN, VIRGINIA
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Behavioral and Physical Development of Rats Chronically Exposed to Caffeinated Fluids. BUTCHER, R. E., VORHEES, C. V., AND WOOTTEN, V. (1984). Fundam. Appl. Toxicol. 4, 1–13. Coffee and caffeine solutions were administered as the sole source of fluid to male and female Sprague-Dawley rats (F
0 ) beginning 60 days before breeding and continuing until the litters (F1 ) from these animals were weaned. Treatments were administered as 100% brewed coffee (COF-100), and a 25% dilution of coffee (COF-25), together with solutions of caffeine in water that paralleled the caffeine content of the coffee groups, 0.056% caffeine (CAF-100) and 0.014% (CAF-25). Controls received measured amounts of plain water (CNL) and another group received vitamin A (40,000 IU/kg) on Days 7–20 of gestation (positive control treatment). During pregnancy all groups receiving COF and CAF consumed significantly more fluid than CNLs. Offspring from the COF-100 and CAF-100 dams were significantly lower in weight than CNLs. No abnormalities of reproductive performance were observed. Of 10 preweaning tests, COF-100 and CAF-100 litters displayed delayed incisor eruption, delayed swimming development, and altered activity. On 7 postweaning measures, these groups showed decreased running wheel activity and increased open-field ambulation and/or defecation. The CAF-25 group, by contrast, showed an increase in running wheel activity. Vitamin A (VTT-A) offspring showed multiple effects, including delayed incisor eruption, increased pre- and postweaning open-field activity, and reduced running wheel activity. COF and CAF produced effects on tests for psychoteratogenesis that appear consistent with the morphological consequences (delayed development) known to be associated with pre- and neonatal administration of caffeine, alone or in coffee, at high doses. The data indicate that most of the behavioral effects observed from caffeine exposure were consistent with the expected effects of concurrent administration of this agent, while the postweaning exposure effects suggest a longer-term change in activity. No effects of caffeine were found, however, on measures of learning, memory, or motoric functioning.- Published
- 1984
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24. Neurotoxicity Evaluation of N,N-Diethyl-m-toluamide (DEET) in Rats
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SCHOENIG, GERALD P., HARTNAGEL, RALPH E., SCHARDEIN, JAMES L., and VORHEES, CHARLES V.
- Abstract
The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) was evaluated following acute oral administration or following multigeneration plus chronic dietary administration to the rat. For the acute study, rats were administered undiluted DEET at dose levels of 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kg was considered to be the highest practical dose that could be evaluated in this study based upon observations of overt toxicity at 500 mg/kg and mortality at 1000 mg/ kg in a dose range-finding study. The two measures of neurotoxicity evaluated in the acute study were functional observational battery (FOB) and motor activity measurements. An apparent treatment-related effect in thermal response time (increased) was noted for both sexes 1 hr after dosing at the 500 mg/kg dose level. A questionable effect on rearing activity (decreased) also was noted at the same dose level. For the multigeneration plus chronic dietary administration study, rats were administered DEET at dietary concentrations of 0, 500, 2000, or 5000 ppm continuously over two generations and then chronically for 9 months. A dietary concentration of 5000 ppm meets the criteria for a maximum tolerated dose (MTD) based on traditional chronic toxicology assessments. Evaluations included FOB, motor activity, discriminative acquisition and reversal in an Mmaze, acoustic startle habituation, passive avoidance acquisition and retention, and microscopic examination of central and peripheral nervous tissue. The only effect that was considered to be possibly treatment-related was a slight increase in exploratory locomotor activity at the 5000 ppm dose level. Based on the results of these studies, the nervous system does not appear to be a selective target when DEET is administered to rats either as a single oral dose at high dose levels or chronically at the MTD.
- Published
- 1993
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25. Methods for Assessing the Adverse Effects of Foods and Other Chemicals on Animal Behavior
- Author
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Vorhees, Charles V.
- Published
- 1986
- Full Text
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26. A Developmental Neurotoxicity Evaluation of the Effects of Prenatal Exposure to Fluoxetine in Rats
- Author
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VORHEES, CHARLES V., ACUFF-SMITH, KAREN D., SCHILLING, MARY A., FISHER, J. EDWARD, MORAN, MARY S., and BUELKE-SAM, JUDY
- Abstract
Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7–20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat.
- Published
- 1994
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