Drinking alcohol during pregnancy leads to fetal alcohol spectrum disorder (FASD). One of the most prominent behavioral symptoms of FASD is attention deficit/hyperactivity disorder (ADHD). Numerous clinical and animal studies have shown a link between ADHD and abnormal functions of the mesolimbic/cortical dopaminergic (DA) system, which originates from DA neurons in the ventral tegmental area (VTA). Attention problems and abnormal DA function are also present in prenatal ethanol exposed rats, indicating the these rats can be used as an animal model to study how abnormal DA functions could lead to ADHD symptoms in individuals with FASD. In the past few years, we have found that prenatal ethanol exposure produces a persistent reduction in the number of VTA DA neurons expressing spontaneous electrical activity (DA neuron population activity). This effect is not due to permanent cell loss and can be normalized by DA agonists, including psychostimulants that are effective in treating ADHD. The effect of DA agonists also suggests that reduced VTA DA neuron population activity in prenatal ethanol exposed animals is caused by increased number of quiescent VTA DA neurons in a state of depolarization inactivation. Namely, these neurons cannot generate action potentials due to excessive excitation. Our hypothesis that reduced VTA DA neuron population activity is a result of depolarization inactivation, also predicts that the overall function of the mesolimbic/cortical DA system is altered in such a way that responses of VTA DA neurons to input signals as well as impulse-dependent DA release in terminal regions will be qualitatively different from that in controls. In the proposed studies, we will test the above hypotheses.
Under Aim 1, we will directly test the hypothesis that prenatal ethanol exposure-induced reduction in VTA DA neuron population activity is due to depolarization inactivation using the in vivo intracellular recording technique.
Under Aim 2, we will investigate the cellular mechanism that leads to reduced VTA DA neuron population activity in prenatal ethanol exposed animals.
Under Aim 3, we will investigate if there is a qualitative change in the responses of VTA DA neurons to input signals and DA release in prenatal ethanol exposed animals. The results from the proposed studies will allow us to understand how prenatal ethanol exposure alters the function of the mesolimbic/cortical DA system, which plays an important role in many behavioral functions such as attention. The information obtained from the proposed studies may help us to elucidate the etiology and treatment options of ADHD symptoms observed in many individuals with FASD. ? ? ?
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