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Methylphenidate-induced developmental neurobehavioral toxicity in zebrafish
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NBTS 2010 Abstract
NBTS14 Methylphenidate-induced developmental neurobehavioral toxicity in zebrafish Edward Levina, Damiyon Sledgea,b, Stephanie Roacha, Susan Donerlya, Elwood Linneya a Duke University, Durham, NC, United States b Department of Biology, North Carolina Central University, Durham, NC, United States
swimming speed were found. In the CWM increased errors and latency were found in the MA-early and MA-all groups but not in the MA-late group. In MWM-acquisition, MA-early and MA-late groups were both impaired (on latency and path length) and the MA-all group was even more impaired. MWM reversal, shift, and cued trials and conditioned fear data are still being analyzed. It appears that extending the exposure period increased allocentric deficits as predicted but MA-late egocentric learning was unexpectedly unaffected. (Supported by DA006733 and ES07051.)
As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to the potential risks of early developmental exposure if people taking the medication becomes pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it may also cause persistent behavioral impairment after developmental exposure. In a preliminary study, zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0–5 days post fertilization (50 and 100 mg/l). They were tested for long-term behavioral effects as adults. In the novel tank diving test of stress response, developmental methylphenidate exposure caused a significantly greater anxiety-like diving behavior during the second and third test sessions when the controls showed a diminution of diving with repeated exposures to the tank. In the three-chamber spatial learning task methylphenidate caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state. Supported by ES10356.
doi:10.1016/j.ntt.2010.04.016
doi:10.1016/j.ntt.2010.04.015
doi:10.1016/j.ntt.2010.04.017
NBTS15 Effects of overlapping ages of exposure to (+)-methamphetamine (MA) in rats on later allocentric and egocentric learning
NBTS17 Messages from the womb: Maternal antidepressant use and fetal neurobehavior
Charles Vorhees, Matthew Skelton, Devon Graham, Tori Schaefer, Curtis Grace, Amanda Braun, Robyn Amos-Kroohs, Michael Williams Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Amy Salisbury Alpert Medical School of Brown University, Providence, RI, United States
We previously found that P11–20 MA leads to allocentric (Morris water maze; MWM) and egocentric (Cincinnati water maze; CWM) deficits whereas P1–10 exposure does not. Testing overlapping exposure periods (P1–10, 6–15, and 11–20) showed P6–10 and 11– 20 exposures caused larger deficits in allocentric and egocentric learning than P1–10 and on some measures (CWM) the P6–15 MA group was more affected whereas on other measures (MWM-shift trials) the P11–20 MA group was more affected. Here we tested whether maximum susceptibility might be a combination of the two periods. Twenty SD litters (4 male/4 females) were injected 4×/day at 2-h intervals on P6–20. Within each litter 1 male/female pair received saline on P6–20, 1 pair received on MA P6–15 + saline on P16–20 (MA-early), 1 pair received saline on P6–10 + MA on P11–20 (MAlate), and 1 pair received MA on P6–20 (MA6-all) (10 mg/kg/ injection). Offspring were tested as adults for straight channel swimming, CWM, MWM, and fear conditioning. No differences in
NBTS16 Prenatal SRI exposure: Where does neonatal behavioral syndrome end and neurobehavioral teratogenicity begin? T.F. Oberlander University of British Columbia, Canada Prenatal exposure to depressed maternal mood and serotonin reuptake inhibitor [SRI] antidepressants may be one of the earliest adverse life events. Both are associated with neonatal behavior disturbances. While symptoms are typically self-limited, the underlying mechanisms and long-term sequelae are unknown. While, SRIexposure related risk may differ from the effects of maternal depression alone and appear to be modified by genotype for the serotonin transporter gene (SLC6A4), it remains unclear whether adverse outcomes also reflect increased drug levels, suppressed monoamine neurotransmitter levels, or reflect long term gestational changes in brain development related to altered central serotonergic tone. This session will focus on recent data illustrating how we might begin to distinguish neonatal behavioral disturbances from SRI related neurobehavioral teratogenicity.
Major depressive disorder (MDD) occurs in at least 10–15% of pregnant women, with greater than 30% of affected women choosing to take antidepressant medications for treatment. Although some data exists about the effects of these medications in the newborn, little is known about fetal behavior during the exposure. Data from 158 pregnant women, ages 18 to 40 will be presented examining neurobehavioral development of fetuses prenatally exposed to maternal MDD and/or antidepressant medications will be presented. Women were interviewed for current and past psychiatric history using a semi-structured interview (SCID-IV-NP). The timing of exposure to medication and psychiatric illness as well as drug doses of SRIs was recorded on a graphic timeline. Fetal neurobehavior was recorded at 26 and 36 weeks gestational age (GA) using ultrasound and fetal actocardiograph monitoring for 60 min (40 min baseline, 3 s stimulus, 20 min post-stimulus). Ultrasound video recordings were played back in the lab and scored in 10 s epochs for the presence of fetal behaviors (Salisbury et al., 2005) using the Mangold Interact coding software (Germany). Newborn neurobehavior was then examined at
NBTS 2010 Abstract
NBTS14 Methylphenidate-induced developmental neurobehavioral toxicity in zebrafish Edward Levina, Damiyon Sledgea,b, Stephanie Roacha, Susan Donerlya, Elwood Linneya a Duke University, Durham, NC, United States b Department of Biology, North Carolina Central University, Durham, NC, United States
swimming speed were found. In the CWM increased errors and latency were found in the MA-early and MA-all groups but not in the MA-late group. In MWM-acquisition, MA-early and MA-late groups were both impaired (on latency and path length) and the MA-all group was even more impaired. MWM reversal, shift, and cued trials and conditioned fear data are still being analyzed. It appears that extending the exposure period increased allocentric deficits as predicted but MA-late egocentric learning was unexpectedly unaffected. (Supported by DA006733 and ES07051.)
As more adults take the stimulant medication methylphenidate to treat attention deficit hyperactivity disorder (ADHD) residual type, the risk arises with regard to the potential risks of early developmental exposure if people taking the medication becomes pregnant. We studied the neurobehavioral effects of methylphenidate in zebrafish. Zebrafish offer cellular reporter systems, continuous visual access and molecular interventions such as morpholinos to help determine critical mechanisms underlying neurobehavioral teratogenicity. Previously, we had seen that persisting neurobehavioral impairment in zebrafish with developmental chlorpyrifos exposure was associated with disturbed dopamine systems. Because methylphenidate is an indirect dopamine agonist, it was thought that it may also cause persistent behavioral impairment after developmental exposure. In a preliminary study, zebrafish embryos were exposed to the ADHD stimulant medication methylphenidate 0–5 days post fertilization (50 and 100 mg/l). They were tested for long-term behavioral effects as adults. In the novel tank diving test of stress response, developmental methylphenidate exposure caused a significantly greater anxiety-like diving behavior during the second and third test sessions when the controls showed a diminution of diving with repeated exposures to the tank. In the three-chamber spatial learning task methylphenidate caused a significant impairment in choice accuracy. These data show that early developmental exposure of zebrafish to methylphenidate causes a long-term impairment in neurobehavioral plasticity. The identification of these functional deficits in zebrafish enables further studies with this model to determine how molecular and cellular mechanisms are disturbed to arrive at this compromised state. Supported by ES10356.
doi:10.1016/j.ntt.2010.04.016
doi:10.1016/j.ntt.2010.04.015
doi:10.1016/j.ntt.2010.04.017
NBTS15 Effects of overlapping ages of exposure to (+)-methamphetamine (MA) in rats on later allocentric and egocentric learning
NBTS17 Messages from the womb: Maternal antidepressant use and fetal neurobehavior
Charles Vorhees, Matthew Skelton, Devon Graham, Tori Schaefer, Curtis Grace, Amanda Braun, Robyn Amos-Kroohs, Michael Williams Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Amy Salisbury Alpert Medical School of Brown University, Providence, RI, United States
We previously found that P11–20 MA leads to allocentric (Morris water maze; MWM) and egocentric (Cincinnati water maze; CWM) deficits whereas P1–10 exposure does not. Testing overlapping exposure periods (P1–10, 6–15, and 11–20) showed P6–10 and 11– 20 exposures caused larger deficits in allocentric and egocentric learning than P1–10 and on some measures (CWM) the P6–15 MA group was more affected whereas on other measures (MWM-shift trials) the P11–20 MA group was more affected. Here we tested whether maximum susceptibility might be a combination of the two periods. Twenty SD litters (4 male/4 females) were injected 4×/day at 2-h intervals on P6–20. Within each litter 1 male/female pair received saline on P6–20, 1 pair received on MA P6–15 + saline on P16–20 (MA-early), 1 pair received saline on P6–10 + MA on P11–20 (MAlate), and 1 pair received MA on P6–20 (MA6-all) (10 mg/kg/ injection). Offspring were tested as adults for straight channel swimming, CWM, MWM, and fear conditioning. No differences in
NBTS16 Prenatal SRI exposure: Where does neonatal behavioral syndrome end and neurobehavioral teratogenicity begin? T.F. Oberlander University of British Columbia, Canada Prenatal exposure to depressed maternal mood and serotonin reuptake inhibitor [SRI] antidepressants may be one of the earliest adverse life events. Both are associated with neonatal behavior disturbances. While symptoms are typically self-limited, the underlying mechanisms and long-term sequelae are unknown. While, SRIexposure related risk may differ from the effects of maternal depression alone and appear to be modified by genotype for the serotonin transporter gene (SLC6A4), it remains unclear whether adverse outcomes also reflect increased drug levels, suppressed monoamine neurotransmitter levels, or reflect long term gestational changes in brain development related to altered central serotonergic tone. This session will focus on recent data illustrating how we might begin to distinguish neonatal behavioral disturbances from SRI related neurobehavioral teratogenicity.
Major depressive disorder (MDD) occurs in at least 10–15% of pregnant women, with greater than 30% of affected women choosing to take antidepressant medications for treatment. Although some data exists about the effects of these medications in the newborn, little is known about fetal behavior during the exposure. Data from 158 pregnant women, ages 18 to 40 will be presented examining neurobehavioral development of fetuses prenatally exposed to maternal MDD and/or antidepressant medications will be presented. Women were interviewed for current and past psychiatric history using a semi-structured interview (SCID-IV-NP). The timing of exposure to medication and psychiatric illness as well as drug doses of SRIs was recorded on a graphic timeline. Fetal neurobehavior was recorded at 26 and 36 weeks gestational age (GA) using ultrasound and fetal actocardiograph monitoring for 60 min (40 min baseline, 3 s stimulus, 20 min post-stimulus). Ultrasound video recordings were played back in the lab and scored in 10 s epochs for the presence of fetal behaviors (Salisbury et al., 2005) using the Mangold Interact coding software (Germany). Newborn neurobehavior was then examined at