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The role of serotonin in brain development and 3,4-methylenedioxymethamphetamine-induced cognitive deficits

Schaefer, Tori L.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243227311

Abstract Details

2009, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
Serotonin (5-hydroxytryptamine, 5-HT) is thought to be important during brain development and is one of the first neurotransmitters to appear. It appears to act as a neurotrophic factor supporting the growth and maturation of both serotonergic and non-serotonergic cells during the pre and early postnatal periods prior to its role as a neurotransmitter. Disruption of 5-HT functioning during human development is thought to be associated with autism and schizophrenia. Early developmental exposure to stress or drugs of abuse disrupt 5-HT development and produces altered cognitive ability. To better understand the relationship between the developing serotonergic system and long-term cognitive function we employed the use of a genetic model in which 5-HT levels are depleted ~80% throughout life and the use of a model of 3,4-methylenedioxymethamphetamine (MDMA) exposure in which administration from postnatal day (P)11-20 is used; a period analogous to the second half of human gestation. Pet-1 is a transcription factor that is restricted in the brain to 5-HT neurons and has been shown to be important for their development and function. A loss of Pet-1 results in an 80% reduction of the number of 5-HT neurons as well as 5-HT tissue content. Pet-1 knockouts were tested as adults in both the Cincinnati and Morris water mazes that assess path integration and spatial learning, respectively. A reduction in cognitive ability was not observed in Pet-1 knockout mice, although they displayed decreased locomotor activity, increased marble burying, and increased startle reactivity. To better assess the role 5-HT plays during development for circuits involved in memory formation, we used a model of MDMA exposure that has previously been reported to produce protracted path integration and spatial learning deficits that last late into adulthood. In adults, MDMA produces an initial release of 5-HT followed by dramatic depletions, and these depletions can last for weeks. It was previously shown that neonatal MDMA administration on P11, the first day of the exposure period known to result in memory impairment (P11-20), also produced significant depletions in 5-HT. We further characterized the degree of 5-HT depletion that was experienced by rats exposed to P11 MDMA exposure and compared this to 5-HT reductions induced by other substituted amphetamines as well as determining the length and degree of depletion following P11-20 MDMA exposure. Substantial 5-HT depletions existed during all ten days of MDMA exposure, however, these depletions were not observed on P30. Citalopram (CIT), a highly selective SSRI, was used in combination with P11-20 MDMA exposure to attenuate the 5-HT depletions. Thereafter, cognitive ability was assessed in MDMA-treated animals with attenuated 5-HT depletions. The combination of CIT and MDMA did not improve learning ability; however CIT treatment alone produced deficits in path integration learning. These data suggest that 5-HT alterations during vulnerable critical periods can affect later cognitive ability, and they suggest that depletions in 5-HT alone may not account for cognitive dysfunction in neonatal rats treated with MDMA. Examination of specific 5-HT receptors is likely the next step to understand the mechanism involved in 5-HT disruption during development and later cognitive ability.
Michael Williams (Committee Chair)
Charles Vorhees (Committee Member)
Gary Gudelsky (Committee Member)
Kenneth Campbell (Committee Member)
Steve Danzer (Committee Member)
239 p.
Behaviorial Sciences

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Citations

  • Schaefer, T. L. (2009). The role of serotonin in brain development and 3,4-methylenedioxymethamphetamine-induced cognitive deficits [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243227311

    APA Style (7th edition)

  • Schaefer, Tori. The role of serotonin in brain development and 3,4-methylenedioxymethamphetamine-induced cognitive deficits. 2009. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243227311.

    MLA Style (8th edition)

  • Schaefer, Tori. "The role of serotonin in brain development and 3,4-methylenedioxymethamphetamine-induced cognitive deficits." Doctoral dissertation, University of Cincinnati, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1243227311

    Chicago Manual of Style (17th edition)

ucin1243227311
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© 2009, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.