To elucidate the neurochemical cause(s) of the CNS abnormalities associated with the fetal alcohol syndrome (FAS), this laboratory has studied the serotonergic (5-HT) system the developing offspring of rats that consumed an ethanol-containing liquid diet on a chronic basis prior to parturition. These studies have shown that the 19- and 35-day-old ethanol-exposed rats have a cortical deficiency of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA). 5-HT uptake sites, and 5-HTl binding sites, but a normal number of 5- HT2 binding sites. These results suggest that in utero ethanol exposure decreases serotonergic projections to the cortex and hence results in a decrease in 5-HT containing terminals. Since 5-HT is an important embryonic factor which promotes neuronal maturation as well as collateral formation between neighboring 5- HT neurons, the observed postnatal serotonergic abnormalities may be due to lack of the embryonic 5-HT signal, or to lack of a receptor response to the 5-HT signal. Thus, the proposed studies will determine how in utero ethanol exposure affects the embryonic development of 5-HT, 5-HTl binding sites, and 5-HT autoreceptor function. (5-HT will be assessed using HPLC. Binding sites will be studied using radioligand techniques. Studies of autoreceptor function will assess K+- stimulated release of (3H)-5-HT.) Additional studies will determine whether prenatal administration of one of three 5-HT agonist (quipazine, 8-OH-DPAT or TFMPP) can overcome or prevent the effects of in utero ethanol exposure. These experiments are important because they will assess potential cause(s) of CNS abnormalities associated with in utero ethanol exposure and possible therapeutic treatments. Additional studies are directed towards elucidating the nature of the postnatal cellular/functional damage caused by in utero ethanol exposure. These studies will determine which of the cortical 5- HT1 receptor subtypes is decreased by in utero ethanol exposure, whether the 5-HT1 receptor deficiency is reflected in altered autoreceptor function, and whether 5-HT stimulation of 2nd messenger (IP3) formation and protein phosphorylation are also affected by in utero ethanol exposure. Finally, presynaptic 5-HT terminals will be selectively destroyed, using chemical denervation, in order to determine whether the 5-HT1 receptor deficiency corresponds to a pre- and/or postsynaptic localization.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA003490-11
Application #
3108839
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1980-01-01
Project End
1992-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Loyola University Chicago
Department
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Antonio, Angeline M; Gillespie, Roberta A; Druse-Manteuffel, Mary J (2011) Effects of lipoic acid on antiapoptotic genes in control and ethanol-treated fetal rhombencephalic neurons. Brain Res 1383:13-21
Lee, Jong-Ho; Tajuddin, Nuzhath F; Druse, Mary J (2009) Effects of ethanol and ipsapirone on the expression of genes encoding anti-apoptotic proteins and an antioxidant enzyme in ethanol-treated neurons. Brain Res 1249:54-60
Sheth, Dhara S; Tajuddin, Nuzhath F; Druse, Mary J (2009) Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells. Brain Res 1285:14-21
Antonio, Angeline M; Druse, Mary J (2008) Antioxidants prevent ethanol-associated apoptosis in fetal rhombencephalic neurons. Brain Res 1204:16-23
Druse, Mary J; Gillespie, Roberta A; Tajuddin, Nuzhath F et al. (2007) S100B-mediated protection against the pro-apoptotic effects of ethanol on fetal rhombencephalic neurons. Brain Res 1150:46-54
Druse, Mary J; Tajuddin, Nuzhath F; Gillespie, Roberta A et al. (2006) The effects of ethanol and the serotonin(1A) agonist ipsapirone on the expression of the serotonin(1A) receptor and several antiapoptotic proteins in fetal rhombencephalic neurons. Brain Res 1092:79-86
Druse, Mary; Tajuddin, Nuzhath F; Gillespie, Roberta A et al. (2005) Signaling pathways involved with serotonin1A agonist-mediated neuroprotection against ethanol-induced apoptosis of fetal rhombencephalic neurons. Brain Res Dev Brain Res 159:18-28
Druse, Mary J; Tajuddin, Nuzhath F; Gillespie, Roberta A et al. (2004) The serotonin-1A agonist ipsapirone prevents ethanol-associated death of total rhombencephalic neurons and prevents the reduction of fetal serotonin neurons. Brain Res Dev Brain Res 150:79-88
Tajuddin, Nuzhath F; Orrico, Luisa A; Eriksen, Jason L et al. (2003) Effects of ethanol and ipsapirone on the development of midline raphe glial cells and astrocytes. Alcohol 29:157-64
Eriksen, Jason L; Gillespie, Roberta; Druse, Mary J (2002) Effects of ethanol and 5-HT1A agonists on astroglial S100B. Brain Res Dev Brain Res 139:97-105

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