Effects of Ethanol on Anxiety in Adolescent Mice

乙醇对青春期小鼠焦虑的影响

• 批准号: 7312167
• 负责人: KARA Irene GABRIEL
• 金额: $ 4.68万
• 依托单位: CALIFORNIA STATE UNIVERSITY HAYWARD
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312167
• 关键词: GABA receptor; age difference; animal puberty; anxiety; behavioral /social science research tag; behavioral genetics; benzodiazepines; developmental neurobiology; diazepam; drug withdrawal; ethanol; immature animal; laboratory mouse; mature animal; pharmacogenetics; pharmacokinetics; psychopharmacology; receptor expression

The goal of this proposal is to investigate developmental differences in ethanol responsiveness and in the biological substrates that underlie ethanol's effects. Specifically, the proposed experiments will examine the role of GABA-A receptor activity in ethanol-induced changes in anxiety in adolescent and adult BALB/cByJ and C57BL/6J mice. Initial experiments will characterize the anxiety-reducing (i.e., anxiolytic) effects of acute ethanol exposure (0, 1, 2 or 3 g/kg) in adolescent and aduit mice on three tests of anxiety-like behavior, the elevated zero-maze, the light/dark choice test, and novel object exploration (i.e., cork gnawing). After examining the behavioral effects of the GABA-A receptor antagonist, picrotoxin (0, 0.75, or 2.5 mg/kg), on the above tests, the ability of picrotoxin to attenuate or block ethanol's anxiolytic effects in adolescent and adult mice will be determined. A second series of experiments will characterize the anxiety-increasing (i.e., anxiogenic) effects of ethanol withdrawal (0 or 4 g/kg) in adolescent and adult BALB/cByJ and C57BL/6J mice (following determination of blood ethanol clearance rates). Because drugs that enhance GABA-A receptor activity, such as benzodiazepines, have been shown to attenuate withdrawal-induced increases in anxiety in adults, we will examine the ability of the benzodiazepine, diazepam (0, 1 or 2 mg/kg) to attenuate the anxiogenic effects of ethanol withdrawal in adolescent and adult mice. These experiments will provide data on anxiety-like behavior and ethanol responsiveness in adolescent animals as well as determine if behavioral differences in adolescent animals are mediated by developmental alterations in GABA-A receptor activity. Comparisons of inbred strains will permit a preliminary examination into the manner in which genetic influences on ethanol responses vary over ontogeny. It is hoped that a better understanding of ethanol's effects in adolescence will aid in the development of more effective prevention strategies or treatment for human adolescents.

该提案的目标是研究乙醇反应性和乙醇作用的生物底物的发育差异。具体来说，拟议的实验将检查 GABA-A 受体活性在乙醇诱导的青少年和成年 BALB/cByJ 和 C57BL/6J 小鼠焦虑变化中的作用。初步实验将通过三项类似焦虑行为、高架零迷宫、光/暗选择测试和新奇物体探索（即啃软木塞）。在检查了 GABA-A 受体拮抗剂印防己毒素（0、0.75 或 2.5 mg/kg)，在上述测试中，将测定印防己毒素在青少年和成年小鼠中减弱或阻断乙醇的抗焦虑作用的能力。第二系列实验将表征青少年和成年 BALB/cByJ 和 C57BL/6J 小鼠中乙醇戒断（0 或 4 g/kg）的焦虑增加（即致焦虑）效应（在测定血液乙醇清除率后）。由于增强 GABA-A 受体活性的药物（例如苯二氮卓类药物）已被证明可以减轻成人戒断引起的焦虑增加，因此我们将检查苯二氮卓类药物地西泮（0、1 或 2 毫克/千克）的能力 减轻青少年和成年小鼠乙醇戒断的焦虑作用。这些实验将提供有关青春期动物的焦虑样行为和乙醇反应性的数据，并确定青春期动物的行为差异是否是由 GABA-A 受体活性的发育改变介导的。近交系的比较将允许对乙醇反应的遗传影响随个体发育而变化的方式进行初步检查。希望更好地了解乙醇对青春期的影响将有助于为人类青少年制定更有效的预防策略或治疗。