PRENATAL ALCOHOL--EFFECTS ON CENTRAL DOPAMINE RECEPTOR SUBTYPES

怀孕期间酗酒被认为是一个重大风险

Alcohol abuse during pregnancy is recognized as a significant risk factor to normal fetal growth and development. Prenatal alcohol exposure can result in fetal alcohol syndrome and alcohol-related birth defects (ARBD) which are associated with cognitive disabilities and mental retardation. These neurobehavioral disorders are the most severe and least amenable to treatment. While the mechanism(s) responsible fo rthese effects has not been definitely determine, results of studies with animal model indicate that in utero ethanol exposure markedly impairs the development of most neurotransmitters. Prenatal ethanol decreases concentrations of dopamine in brain regions which contain cell bodies of DA neurons and their projection areas and adversely impacts the development of DA reuptake sites. DA receptor number is also altered, but the net effect of chronic treatment is not clearly defined. The proposed experiements will investigate the role of dopamine receptor subtypes in the etiology of ARDB. Time-pregnant Sprague- Dawley rates will be fed a liquid diet containing 35% ethanol-derived calories on gestation days 11-21 (ETOH). Blood alcohol levels will be measured in the dams on Gds 15 and 19. Pair-Fed (PF) dams will be fed an identical liquid diet, but with dextrin-maltose substituted isocalorically for ethanol. Lab chow controls (LC) will have ad libitum access to standard laboratory and antagonists, either alone or in combination, with specificity for the D1, D2 and D3 DA receptor subtypes to test if prenatal alcohol alters behavioral sensitivity to these compounds. Stimulation and/or blockade of receptor subtypes induced a specific behavioral responses, which will be monitored for 30 minutes, using a time-sampling technique, following drug injection. As behaviors elicited by these drugs are both dose and gender dependent, complete dose-response curves will be generated in both male and female offspring. Treatment effects on dopamine D1, D2 and D3 binding in the striatum, caudate nucleus and the prefrontal cortex as well as concentration of DA and its major metabolite, DOPAC, will also be determined in 21-22 day old offspring. Because of the distinct pharmacological properties, different anatomical distributions and signal transduction mechanisms of each receptors, alterations in a particular DA receptor subtype can provide information about a specific deficit and its localization in the brain. Differential responses by prenatal alcohol-exposed offspring to drugs that act specifically at these receptors may be indicative of a disruptionint he function of a specific neural process and may have implication for treatment regimes to prevent and/or alleviate ARBD.