Developmental methylphenidate (MPH) treatment in rats: Few effects on spatial memory (SM) in the...
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maturation and function of the cochlea. To test this hypothesis, we conducted a study to investigate if developmental exposure to environmentally relevant doses of BPA would result in auditory dysfunction. Female rats were exposed to BPA orally at 0, 50, 500 or 5000 μg/kg/day throughout gestation. Male and female offspring were directly exposed to BPA at the same doses from postnatal day 1 until weaning, by pipetting the solution into their mouths. From weaning on postnatal day (PND) 21 until the time of auditory testing the rats received no further exposure to BPA. Starting at PND 90 we tested the cochlear function of both male and female offspring using distortion product otoacoustic emissions (DPOAE) and transiently evoked otoacoustic emissions (TEOAE). For both DPOAEs and TEOAEs we did not find an effect of BPA on otoacoustic strength. For TEOAEs, again no effect of BPA was observed. However, we did observe a sex effect, whereby females had stronger TEOAE signals than males, similar to the sex difference that has been observed in humans. This is the first time a sex difference in TEOAEs has been reported in rats. The findings suggest that TEOAEs may have utility as an endpoint to assess toxicants that affect sexual differentiation of the central nervous system. Research funding: The University of Illinois Research Board. http://dx.doi.org/10.1016/j.ntt.2013.03.050 NBTS P13 Cyp1a1_Cyp1a2(-/-) double knockout mice exhibit impaired motor function Christine Curran, Anna Lang, Helen Garber, Kelsey Taylor, Melinda Stegman, Breann Hays, Smitha Infante Northern Kentucky University, Highland Hts., KY, USA CYP1A1 and CYP1A2, members of the cytochrome P450 superfamily, are key detoxifying enzymes normally expressed in the liver. Though they are also reportedly expressed in the cortex and cerebellum of the brain, their physiological function in the brain remains unknown. Previous work in our lab uncovered motor deficits in Cyp1a2(-/-) knockout mice. To confirm those findings, we obtained Cyp1a1_1a2(-/-) double knockout mice which had the Cyp1a2 gene deleted using a different genetic strategy. We compared Cyp1a1_1a2(-/-) double knockout mice with wild-type Cyp1a1_Cyp1a2(+/+) mice using a battery of four behavior tests: rotarod, gait analysis, adhesive removal, and pole climbing We found significant impairments in Cyp1a1_1a2(-/-) double knock- out mice in rotarod testing and adhesive removal. Male knockouts demonstrated the greatest impairment in adhesive removal compared with females. Interestingly, Cyp1a1_1a2(-/-) double knockout mice had shorter latencies in the pole-climbing test. There were no significant differences in the gait test for stride length, stride width or stride differential. Together, these data suggest that a CYP1A2 is required for normal motor function. http://dx.doi.org/10.1016/j.ntt.2013.03.051 NBTS P14 Developmental methylphenidate (MPH) treatment in rats: Few effects on spatial memory (SM) in the Morris water (MWM) and Barnes mazes (BM) John Panos, C. Delbert Law, Sherry Ferguson National Center for Toxicological Research (NCTR)/FDA, Jefferson, AR, USA MPH is often prescribed for Adult Attention Deficit Hyperactivity Disorder (ADHD) and both warranted and unlawful use occurs during pregnancy. Although MPH has beneficial effects for ADHD symptoms, there exists paucity in the literature regarding its developmental effects. Here, pregnant Sprague–Dawley rats (n = 18–19/group) were orally treated during gestational days 6–21 with 0 (water), 6 (low), 18 (medium), or 42 (high) mg/kg/day (t.i.d.: i.e., the low dose was given as 2 mg/kg 3×/day). Pups were orally treated with the same daily dose as their dam (b.i.d.) on postnatal days (PNDs) 1–21. Serum MPH levels of low dose dams were within the range as produced by typical MPH doses in humans. On PNDs 47–51, 1/sex/litter was assessed for SM using the BM and, on PNDs 75–79, the same subjects were assessed for MWM performance. Females located the BM escape box significantly faster. High MPH males were slower to locate the BM escape box on the fourth session than male controls. No MPH effects occurred at reversal testing (fifth session). Latency to locate the MWM platform was significantly faster in males. A significant MPH treatment × sex × day interaction indicated dose influences on sex and day. Control and high MPH females had longer latencies than control males on day 4. Similar effects (i.e., increased latencies for females) occurred on day 3 for the control and low MPH groups. Developmental MPH treatment does not appear to have substantial effects on SM of rats. There was a methodological sex difference in performance of the MWM and BM. Females have shorter BM, but longer MWM, latencies. This effect may be related to sex differences in search strategies. These results indicate few effects of developmental MPH treatment, but also emphasize the need for research in sex differences in behavioral assessments. (Supported by NCTR E3718.) http://dx.doi.org/10.1016/j.ntt.2013.03.052 NBTS P15 Development of hyperactivity and anxiety responses in dopamine transporter-deficient mice Alex Carpenter, Tommy Saborido, Gregg Stanwood Vanderbilt University, Nashville, TN, USA Dopamine is a catecholamine neurotransmitter that regulates many aspects of motivated behavior in animals. Extracellular dopa- mine is highly regulated by the presynaptic high affinity dopamine transporter (DAT), and drug- or genetically induced deficiencies in DAT function result in loss of DA reuptake. Mice in which DAT expression has been ablated have been previously proposed to be a relevant model of attention deficit hyperactivity disorder and have led to mechanistic insights regarding psychostimulant drug actions. However, very little previous work has emphasized the biobehavioral development of DAT-deficient mice. We therefore examined motoric, emotional and cognitive phenotypes in preadolescent (P22–26) DAT mutant mice. Consistent with previous reports in adult DAT −/− mice, we observed a hyperlocomotive phenotype in preadolescent mice across multiple assays. Somewhat surprisingly, spatial working memory in a Y-maze appeared intact, suggesting that cognitive phenotypes may emerge relatively late in development following hyperdopaminergia. Anxiety levels appeared to be reduced in DAT −/− mice, as defined by elevated plus maze and light–dark preference assays. No significant differences were observed between wild-type and heterozygous mice, suggesting a minimal impact of DAT haploinsufficiency on neurobehavioral status. Taken together, these data establish behavioral phenotypes of DAT mutant mice during development and suggest complex developmen- tal stage-dependent effects of dopamine signaling on cognitive and emotional behaviors. http://dx.doi.org/10.1016/j.ntt.2013.03.053 NBTS 2013 Abstracts 88
Transcript of Developmental methylphenidate (MPH) treatment in rats: Few effects on spatial memory (SM) in the...
maturation and function of the cochlea. To test this hypothesis, weconducted a study to investigate if developmental exposure toenvironmentally relevant doses of BPA would result in auditorydysfunction. Female rats were exposed to BPA orally at 0, 50, 500 or5000 μg/kg/day throughout gestation. Male and female offspringweredirectly exposed to BPA at the same doses from postnatal day 1 untilweaning, by pipetting the solution into theirmouths. Fromweaning onpostnatal day (PND) 21 until the time of auditory testing the ratsreceived no further exposure to BPA. Starting at PND 90 we tested thecochlear function of both male and female offspring using distortionproduct otoacoustic emissions (DPOAE) and transiently evokedotoacoustic emissions (TEOAE). For both DPOAEs and TEOAEs we didnot find an effect of BPA on otoacoustic strength. For TEOAEs, again noeffect of BPA was observed. However, we did observe a sex effect,whereby females had stronger TEOAE signals thanmales, similar to thesex difference that has been observed in humans. This is the first time asex difference inTEOAEshas been reported in rats. The findings suggestthat TEOAEs may have utility as an endpoint to assess toxicants thataffect sexual differentiation of the central nervous system. Researchfunding: The University of Illinois Research Board.
http://dx.doi.org/10.1016/j.ntt.2013.03.050
NBTS P13Cyp1a1_Cyp1a2(−/−) double knockout mice exhibit impairedmotor function
Christine Curran, Anna Lang, Helen Garber, Kelsey Taylor,Melinda Stegman, Breann Hays, Smitha InfanteNorthern Kentucky University, Highland Hts., KY, USA
CYP1A1 and CYP1A2, members of the cytochrome P450 superfamily,are keydetoxifying enzymesnormallyexpressed in the liver. Though theyare also reportedly expressed in the cortex and cerebellum of the brain,their physiological function in the brain remains unknown. Previouswork in our lab uncovered motor deficits in Cyp1a2(−/−) knockoutmice. To confirm those findings, we obtained Cyp1a1_1a2(−/−) doubleknockout mice which had the Cyp1a2 gene deleted using a differentgenetic strategy.We comparedCyp1a1_1a2(−/−)double knockoutmicewith wild-type Cyp1a1_Cyp1a2(+/+) mice using a battery of fourbehavior tests: rotarod, gait analysis, adhesive removal, andpole climbingWe found significant impairments in Cyp1a1_1a2(−/−) double knock-out mice in rotarod testing and adhesive removal. Male knockoutsdemonstrated the greatest impairment in adhesive removal comparedwith females. Interestingly, Cyp1a1_1a2(−/−) double knockout micehad shorter latencies in the pole-climbing test. There were no significantdifferences in the gait test for stride length, stride width or stridedifferential. Together, these data suggest that a CYP1A2 is required fornormal motor function.
http://dx.doi.org/10.1016/j.ntt.2013.03.051
NBTS P14Developmental methylphenidate (MPH) treatment in rats: Feweffects on spatial memory (SM) in the Morris water (MWM) andBarnes mazes (BM)
John Panos, C. Delbert Law, Sherry FergusonNational Center for Toxicological Research (NCTR)/FDA, Jefferson, AR, USA
MPH is often prescribed for Adult Attention Deficit HyperactivityDisorder (ADHD) and both warranted and unlawful use occurs during
pregnancy. Although MPH has beneficial effects for ADHD symptoms,there exists paucity in the literature regarding its developmentaleffects. Here, pregnant Sprague–Dawley rats (n = 18–19/group) wereorally treated during gestational days 6–21 with 0 (water), 6 (low), 18(medium), or 42 (high) mg/kg/day (t.i.d.: i.e., the low dose was givenas 2 mg/kg 3×/day). Pups were orally treated with the same dailydose as their dam (b.i.d.) on postnatal days (PNDs) 1–21. Serum MPHlevels of low dose dams were within the range as produced by typicalMPH doses in humans. On PNDs 47–51, 1/sex/litter was assessed forSM using the BM and, on PNDs 75–79, the same subjects wereassessed for MWM performance. Females located the BM escape boxsignificantly faster. High MPH males were slower to locate the BMescape box on the fourth session than male controls. No MPH effectsoccurred at reversal testing (fifth session). Latency to locate theMWM platform was significantly faster in males. A significant MPHtreatment × sex × day interaction indicated dose influences on sexand day. Control and high MPH females had longer latencies thancontrol males on day 4. Similar effects (i.e., increased latencies forfemales) occurred on day 3 for the control and low MPH groups.Developmental MPH treatment does not appear to have substantialeffects on SM of rats. There was a methodological sex difference inperformance of the MWM and BM. Females have shorter BM, butlonger MWM, latencies. This effect may be related to sex differences insearch strategies. These results indicate few effects of developmentalMPH treatment, but also emphasize the need for research in sexdifferences in behavioral assessments. (Supported by NCTR E3718.)
http://dx.doi.org/10.1016/j.ntt.2013.03.052
NBTS P15Development of hyperactivity and anxiety responses in dopaminetransporter-deficient mice
Alex Carpenter, Tommy Saborido, Gregg StanwoodVanderbilt University, Nashville, TN, USA
Dopamine is a catecholamine neurotransmitter that regulatesmany aspects of motivated behavior in animals. Extracellular dopa-mine is highly regulated by the presynaptic high affinity dopaminetransporter (DAT), anddrug- or genetically induced deficiencies inDATfunction result in loss of DA reuptake. Mice in which DAT expressionhas been ablated have beenpreviously proposed to be a relevantmodelof attention deficit hyperactivity disorder and have led to mechanisticinsights regarding psychostimulant drug actions. However, very littleprevious work has emphasized the biobehavioral development ofDAT-deficient mice. We therefore examined motoric, emotional andcognitive phenotypes in preadolescent (P22–26) DAT mutant mice.Consistent with previous reports in adult DAT−/−mice, we observeda hyperlocomotive phenotype in preadolescent mice across multipleassays. Somewhat surprisingly, spatial working memory in a Y-mazeappeared intact, suggesting that cognitive phenotypes may emergerelatively late in development following hyperdopaminergia. Anxietylevels appeared to be reduced in DAT−/−mice, as defined by elevatedplus maze and light–dark preference assays. No significant differenceswere observed betweenwild-type and heterozygous mice, suggestingaminimal impact of DAT haploinsufficiency on neurobehavioral status.Taken together, these data establish behavioral phenotypes of DATmutant mice during development and suggest complex developmen-tal stage-dependent effects of dopamine signaling on cognitive andemotional behaviors.
http://dx.doi.org/10.1016/j.ntt.2013.03.053
NBTS 2013 Abstracts88
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