Prenatal exposure to alcohol causes a wide range of deficits known as fetal alcohol spectrum disorders (FASDs). Many factors determine vulnerability to developmental alcohol exposure including timing and pattern of exposure, nutrition and genetics. Here, we characterized how a prevalent single nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene (val66met) modulates FASDs severity. This polymorphism disrupts BDNF's intracellular trafficking and activity-dependent secretion, and has been linked to increased incidence of neuropsychiatric disorders such as depression and anxiety. We hypothesized that developmental ethanol (EtOH) exposure more severely affects mice carrying this polymorphism. We used transgenic mice homozygous for either valine (BDNF ) or methionine (BDNF ) in residue 68, equivalent to residue 66 in humans. To model EtOH exposure during the second and third trimesters of human pregnancy, we exposed mice to EtOH in vapor chambers during gestational days 12 to 19 and postnatal days 2 to 9. We found that EtOH exposure reduces cell layer volume in the dentate gyrus and the CA1 hippocampal regions of BDNF but not BDNF mice during the juvenile period (postnatal day 15). During adulthood, EtOH exposure reduced anxiety-like behavior and disrupted trace fear conditioning in BDNF mice, with most effects observed in males. EtOH exposure reduced adult neurogenesis only in the ventral hippocampus of BDNF male mice. These studies show that the BDNF val66met polymorphism modulates, in a complex manner, the effects of developmental EtOH exposure, and identify a novel genetic risk factor that may regulate FASDs severity in humans.
Although alcohol (i.e., ethanol) is a major drug of abuse, the acute functional effects of ethanol on the reward circuitry are not well defined in vivo. In freely moving rats, we examined the effect of intravenous ethanol administration on neuronal unit activity in the posterior ventral tegmental area (VTA), a central component of the mesolimbic reward system. VTA units were classified as putative dopamine (DA) neurons, fast‐firing GABA neurons, and unidentified neurons based on a combination of electrophysiological properties and DA D2 receptor pharmacological responses. A gradual infusion of ethanol significantly altered the firing rate of DA neurons in a concentration‐dependent manner. The majority of DA neurons were stimulated by ethanol and showed enhanced burst firing activity, but a minority was inhibited. Ethanol also increased the proportion of DA neurons that exhibited pacemaker‐like firing patterns. In contrast, ethanol mediated a variety of effects in GABA and other unidentified neurons that were distinct from DA neurons, including a nonlinear increase in firing rate, delayed inhibition, and more biphasic activity. These results provide evidence of discrete electrophysiological effects of ethanol on DA neurons compared with other VTA cell types, suggesting a complex role of the VTA in alcohol‐induced responses in freely moving animals.
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