Consequences of voluntary intake of ethanol & nicotine during peri-adolescence

描述（由申请人提供）：越来越多的证据表明，在青春期，酗酒行为、吸烟和内侧前额叶皮质的持续发育之间存在交叉点。这些事件的同时发生可能会对成年后的神经传递、药物使用以及鲁莽和冲动行为产生持久的有害影响。谷氨酸是一种氨基酸神经递质，已知会影响中脑边缘和皮层区域的神经元活动，并与乙醇和尼古丁滥用有关。前额叶皮层既接受谷氨酸输入，又有谷氨酸能投射到参与乙醇和尼古丁自我给药的关键部位。目前的方法将测试的假设，concommittant自愿乙醇和尼古丁的摄入量在青春期导致深远的影响，乙醇和尼古丁自我管理的行为，和mesocorticolimbic谷氨酸神经传递，在成年期。选择性繁殖的酒精偏好（P）大鼠将用于项目的这一部分，因为在该品系中已经证明了乙醇和尼古丁的个体和同时自愿摄入。也将使用单独饮用乙醇、尼古丁或水的对照组来评估同时摄入与单独摄入每种药物相比的影响。重要的是，将对雄性和雌性大鼠进行检测，以确定本申请中所有实验结果的性别差异，还将对成年时初始暴露于乙醇和尼古丁的大鼠进行研究，以确定青春期前后开始吸毒的特定变化。为了评估青春期前后同时暴露于乙醇和尼古丁的长期后果，将在青春期前后自愿摄入乙醇和尼古丁后检查乙醇和尼古丁自我给药（包括渴望和复发的指标）。同时，还将在成年动物中进行微透析-HPLC程序，以测量青春期前后的乙醇和尼古丁摄入如何影响与酒精和药物滥用有关的关键中皮质边缘脑回路中谷氨酸的细胞外水平。总之，这些研究代表了一种新的方法来检查在青春期同时使用乙醇和尼古丁对神经生物学的影响以及成年后对乙醇和尼古丁的易感性。预计该应用程序将为针对酒精中毒和尼古丁成瘾的关键公共卫生问题制定早期（青少年）和晚期（成人）治疗和/或预防策略提供重要信息。

DESCRIPTION (provided by applicant): Accumulating evidence points to an intersection between binge drinking behavior, smoking, and the ongoing development of the medial prefrontal cortex, during adolescence. The concurrence of these events may have lasting detrimental effects on neurotransmission, drug use, and reckless and impulsive behaviors in adulthood. Glutamate is an amino acid neurotransmitter known to influence neuronal activity in mesolimbic and cortical areas and has been implicated in both ethanol and nicotine abuse. The prefrontal cortex both receives glutamate inputs and has glutamatergic projections to key sites involved in ethanol and nicotine self- administration. The current approach will test the hypothesis that concommittant voluntary ethanol and nicotine intake during peri-adolescence leads to profound effects on both ethanol and nicotine self-administration behavior, and mesocorticolimbic glutamate neurotransmission, in adulthood. The selectively bred alcohol- preferring (P) rat will be used in this part of the project because individual and concurrent voluntary intake of ethanol and nicotine has been demonstrated in this line. Control groups drinking ethanol, nicotine, or water alone will also be used to assess the impact of concurrent intake as compared to intake of each drug alone. Importantly, both male and female rats will be tested to identify sex differences in outcomes for all experiments in this application, and rats with initial ethanol and nicotine exposure as adults will be also be studied to identify changes specific to peri-adolescent initiation of drug taking. To assess the long-term consequences of concurrent ethanol and nicotine exposure during peri-adolescence, ethanol and nicotine self-administration (including measures of craving and relapse) will be examined after voluntary ethanol and nicotine intake in peri-adolescence. Concurrently, microdialysis-HPLC procedures will also be conducted in adult animals to measure how peri-adolescent ethanol and nicotine intake affects extracellular levels of glutamate in critical mesocorticolimbic brain circuits which have been implicated in alcohol and drug abuse. Together, these studies represent a novel approach to examine the impact of the co-use of ethanol and nicotine in the peri- adolescent period on neurobiology and the susceptibility to ethanol and nicotine in adulthood. It is anticipated that this application will provide important information for the development of early (adolescent) and late (adult) treatment and/or prevention strategies targeting the critical public health problems of alcoholism and nicotine addiction.