While it is well known that prenatal ethanol (ETOH) exposure has detrimental effects on the developing CNS, there are still numerous questions regarding the mechanisms underlying the CNS damage observed. The effects of ETOH on the glutamate/NMDA receptor (NMDAR) are well established. ETOH-induced alterations in NMDAR function during development causes hippocampal damage by at least two mechanisms; reduced NMDAR function during the presence of ETOH (via apoptosis) and enhanced NMDAR function during ETOH withdrawal (via excitotoxicity). Which of these mechanisms predominates may be age- dependent with suppression of NMDAR activity being more damaging at earlier developmental stages and overexcitation during ETOH WD being a more dominant component in older cultures. Polyamines are ubiquitous compounds that also play an important trophic role during CNS development and one of the mechanisms by which polyamines work is by potentiation of the NMDAR. Since hippocampal NMDAR subtypes and their response to polyamines change during the first neonatal weeks in rats, the timing when ETOH exposure occurs may have significant influences on response to polyamines, NMDAR and outcome. These hypotheses can be tested directly in vitro using the organotypic cell culture model and comparing cultures obtained from neonatal rats at PND 2 versus PND 8.
The specific aims are 1) to examine how developmental age affects the response to ETOH as measured by cell damage in our in vitro organotyplc hippocampal model; 2) to examine how developmental age and ETOH exposure interact with polyamines as measured by cell damage in the in vitro hippocampal model and 3) To assess whether in vivo ETOH exposure correlates with the findings from in vitro exposure. The model proposed in this application will provide an innovative and novel approach for using hippocampal organotypic cell cultures to address specific developmental questions related to ETOH's effects and to assess the predictive validity of the model to predict in vivo results. With these findings, it may also be possible to gain a better understanding of some of the mechanisms underlying neonatal ETOH exposure and the role of polyamines that will provide grounds for pharmacological interventions that will reduce some of ETOH effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA014032-03
Application #
6929947
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Sorensen, Roger
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$147,300
Indirect Cost
Name
University of Kentucky
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lewis, B; Wellmann, K A; Kehrberg, A M H et al. (2012) Behavioral deficits and cellular damage following developmental ethanol exposure in rats are attenuated by CP-101,606, an NMDAR antagonist with unique NR2B specificity. Pharmacol Biochem Behav 100:545-53
Barron, Susan; Lewis, Ben; Wellmann, Kristen et al. (2012) Polyamine modulation of NMDARs as a mechanism to reduce effects of alcohol dependence. Recent Pat CNS Drug Discov 7:129-44
Smith, A M; Wellmann, K A; Lundblad, T M et al. (2012) Lobeline attenuates neonatal ethanol-mediated changes in hyperactivity and dopamine transporter function in the prefrontal cortex in rats. Neuroscience 206:245-54
Wellmann, Kristen; Lewis, Ben; Barron, Susan (2010) Agmatine reduces ultrasonic vocalization deficits in female rat pups exposed neonatally to ethanol. Neurotoxicol Teratol 32:158-63
Rubin, Maribel A; Wellmann, Kristen A; Lewis, Ben et al. (2009) Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats. Pharmacol Biochem Behav 92:44-50
Stepanyan, Tracy D; Farook, Justin M; Kowalski, Alexandra et al. (2008) Alcohol withdrawal-induced hippocampal neurotoxicity in vitro and seizures in vivo are both reduced by memantine. Alcohol Clin Exp Res 32:2128-35
Farook, Justin M; Krazem, Ali; Lewis, Ben et al. (2008) Acamprosate attenuates the handling induced convulsions during alcohol withdrawal in Swiss Webster mice. Physiol Behav 95:267-70
Barron, Susan; Mulholland, Patrick J; Littleton, John M et al. (2008) Age and gender differences in response to neonatal ethanol withdrawal and polyamine challenge in organotypic hippocampal cultures. Alcohol Clin Exp Res 32:929-36
Lewis, B; Wellmann, K A; Barron, S (2007) Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure. Pharmacol Biochem Behav 88:114-21
Mello, Carlos Fernando; Rubin, Maribel Antonello; Sultana, Rukhsana et al. (2007) Difluoromethylornithine decreases long-lasting protein oxidation induced by neonatal ethanol exposure in the hippocampus of adolescent rats. Alcohol Clin Exp Res 31:887-94

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