There is now a large and compelling literature demonstrating that ethanol has different neurobehavioral effects in adolescent animals than in adults. For example, ethanol has been shown to impair spatial learning more potently in adolescent rats, and one study of early post-adolescent humans indicated that they were more vulnerable to acute ethanol-induced learning impairment than slightly older individuals. These behavioral findings are underscored by a substantial number of studies showing that ethanol is a more potent antagonist of memory-related synaptic plasticity and NMD A receptor-mediated synaptic activity in the developing brain compared to the adult brain. In contrast to its more potent effects on learning and glutamatergic function in adolescents, ethanol is a less potent sedative in developing animals. Indeed, at the behavioral level, this difference in sensitivity is even more pronounced than the difference in sensitivity on learning tasks. This strongly suggests a difference in the sensitivity of GABAA receptor function to ethanol during development, but there has been only one study addressing this question directly. That report, from our laboratory, shows that the sensitivity of evoked GABAA receptor-mediated IPSCs to ethanol increases steadily during juvenile and adolescent development in the rat. The experiments proposed in this application are designed to determine the mechanisms underlying this developmental sensitivity to ethanol in rats of both genders.
Specific Aim 1 of this application will assess the sensitivity of evoked GABAA receptor-mediated IPSCs to acute ethanol in pyramidal neurons from juvenile, adolescent, and adult rats using whole cell recording techniques. This will extend our earlier findings to include full concentration-response curves.
Specific Aims 2 &3 will assess the pre- vs. post-synaptic nature of the developmental sensitivity that we have observed, and directly test several candidate mechanisms which may underlie these developmental changes in ethanol sensitivity ? ?
| Yan, Haidun; Li, Qiang; Fleming, Rebekah et al. (2009) Developmental sensitivity of hippocampal interneurons to ethanol: involvement of the hyperpolarization-activated current, Ih. J Neurophysiol 101:67-83 |
| Fleming, Rebekah L; Wilson, Wilkie A; Swartzwelder, H Scott (2007) Magnitude and ethanol sensitivity of tonic GABAA receptor-mediated inhibition in dentate gyrus changes from adolescence to adulthood. J Neurophysiol 97:3806-11 |
| Cha, Young May; Li, Qiang; Wilson, Wilkie A et al. (2006) Sedative and GABAergic effects of ethanol on male and female rats. Alcohol Clin Exp Res 30:113-8 |
