Adolescent risk-taking, dopamine signaling, and cocaine: a vicious circle

描述(由申请人提供)：冒险行为与吸毒密切相关；然而，冒险与吸毒之间的关系的性质还没有很好地确定。这项建议的总体目标是使用大鼠模型来确定a)冒险行为和药物使用之间的潜在双向关系，以及b)多巴胺信号在调节这些关系中的作用。特别是，这项提议中的实验将集中在青春期的冒险行为，因为一些对人类的研究已经将这一时期的危险行为与未来使用药物的可能性增加联系在一起。将使用风险决策任务来评估青春期大鼠的冒险行为，在该任务中，大鼠在伴随着不同惩罚风险的小规模“安全”奖励和大额“风险”奖励之间进行选择(这项任务是一种条件模型，在这种情况下，高回报的选择伴随着不利后果的风险)。这类决策与青少年冒险和吸毒问题高度相关，因为青少年和吸毒者往往决策不力，往往未能充分评估和/或对可能产生的不良后果采取行动。目标1下的实验将确定青春期冒险行为的个体差异是否预示着成年后的可卡因自我管理。目标1还将调查成年后长期服用可卡因是否会导致风险决策的持续增加(从而导致危险行为和药物使用的“恶性循环”)。AIMS 2和AIMS 3下的实验将调查多巴胺信号在调节青少年冒险行为和可卡因使用之间的关系中的作用，特别是D2样受体和多巴胺转运体，在初步和之前发表的数据中，这两种受体与冒险行为和可卡因使用都有关。具体地说，AIM 2将使用原位杂交来确定青少年冒险行为和慢性可卡因对冒险行为的影响之间的关系，以及D2、D3和D4受体以及多巴胺转运体的mRNA表达，特别是纹状体。目标3下的实验将测试初步数据和目标2中确定的高风险决策和多巴胺能标志物之间的关系的功能相关性，方法是在脑内微量注射针对这些标志物的大脑区域，如背侧纹状体。这项研究的结果将为深入了解冒险行为和药物使用之间的因果关系的方向(S)以及风险决策的多巴胺能调节提供依据。从临床、流行病学和社会政策的角度来看，这些信息可能对制定治疗和预防药物使用的战略有用。 与公共卫生的相关性：青少年和吸毒者都容易从事危险行为，这可能会增加开始吸毒和吸毒复发的倾向；然而，青少年冒险和吸毒之间的关系的性质尚未很好地确定。这项拟议的研究将使用动物模型在行为和神经生物学水平上研究这些关系，这可能有助于开发新的成瘾治疗方法。

DESCRIPTION (provided by applicant): Risk taking behavior is strongly associated with drug use; however, the nature of the relationship between risk taking and drug use is not well established. The overall goal of this proposal is to use a rat model to determine a) potential bidirectional relationships between risk taking and drug use, and b) the role of dopamine signaling in mediating these relationships. In particular, experiments in this proposal will focus on risk taking during adolescence, as some studies in humans have associated risky behavior during this period with increased likelihood of future drug use. Risk taking will be assessed in adolescent rats using the Risky Decision-making Task, in which rats choose between small "safe" rewards and large "risky" rewards that are accompanied by varying risks of punishment (this task is a model of conditions in which highly rewarding choices are accompanied by risks of adverse consequences). This type of decision making is highly relevant to the issue of adolescent risk taking and drug use, as both adolescents and drug users are prone to poor decision-making and often fail to adequately assess and/or act on the potential for adverse outcomes. Experiments under Aim 1 will determine whether individual differences in adolescent risk taking predict cocaine self-administration during adulthood. Aim 1 will also investigate whether chronic cocaine self-administration in adulthood causes lasting increases in risky decision-making (thus resulting in a "vicious circle" of risky behavior and drug use). Experiments under Aims 2 and 3 will investigate the role of dopamine signaling in mediating the relationship between adolescent risk taking and cocaine use, with particular focus on D2-like receptors and the dopamine transporter, which have been linked to both risk taking and cocaine use in preliminary and previously published data. Specifically, Aim 2 will use in situ hybridization to determine the relationship between both adolescent risk taking and chronic cocaine's effects on risk taking, and expression of mRNA for D2, D3, and D4 receptors, as well as the dopamine transporter, with a particular focus on the striatum. Experiments under Aim 3 will test the functional relevance of relationships identified in the preliminary data and Aim 2 between risky decision-making and dopaminergic markers, using intracerebral microinjections of drugs targeting these markers in brain regions of interest such as dorsal striatum. Results from this research will provide insight into the direction(s) of causality in the relationship between risk taking behavior and drug use, as well as the dopaminergic regulation of risky decision-making. Such information may be useful from clinical, epidemiological, and social policy perspectives for developing strategies to treat and prevent drug use. PUBLIC HEALTH RELEVANCE: Both adolescents and drug users are prone to engage in risky behavior, which may increase propensity to initiate and relapse to drug use; however, the nature of the relationships between adolescent risk taking and drug use is not well established. The proposed research will use an animal model to investigate these relationships at both the behavioral and neurobiological levels, which could aid in the development of novel addiction treatments.