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，在青少年时期，酗酒行为、吸烟和内侧前额叶皮层的持续发育之间存在交集。这些事件的同时发生可能对神经传递、药物使用以及成年后的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，已知影响中脑边缘和皮质区域的神经元活动，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涉及乙醇和尼古丁自我给药的关键部位。目前的方法将测试这样一个假设，即在青春期前后同时自愿摄入乙醇和尼古丁会对成年期乙醇和尼古丁的自我给药行为以及中皮质边缘谷氨酸神经传递产生深远的影响。选择性繁殖的酒精偏好(P)大鼠将用于该项目的这一部分，因为在这条线上已经证明了个体和同时自愿摄入乙醇和尼古丁。对照组单独饮用乙醇、尼古丁或水，也将被用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测试，以确定本应用中所有实验结果的性别差异，并对成年后初次接触乙醇和尼古丁的大鼠进行研究，以确定青春期前后开始服用药物的具体变化。为了评估青春期前后乙醇和尼古丁同时暴露的长期后果，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的自我给药（包括渴望和复发的测量）。同时，微透析-高效液相色谱方法也将在成年动物中进行，以测量青少年时期乙醇和尼古丁摄入如何影响关键中皮质边缘脑回路中谷氨酸的细胞外水平，这与酒精和药物滥用有关。总之，这些研究代表了一种新的方法来研究青少年时期乙醇和尼古丁的共同使用对神经生物学的影响以及成年期对乙醇和尼古丁的易感性。预计这一应用将为制定针对酗酒和尼古丁成瘾等重大公共卫生问题的早期（青少年）和晚期（成人）治疗和/或预防战略提供重要信息。

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.