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

青少年冒险、多巴胺信号传导和可卡因：恶性循环

• 批准号: 8316867
• 负责人: Marci R Mitchell
• 金额: $ 1.42万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2012-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316867
• 关键词: Adolescence; Adolescent; Adolescent Development; Adult; Animal Experimentation; Animal Model; Behavior; Behavioral; Brain; Brain region; Chronic; Clinical; Cocaine; Cocaine Users; Cognitive; Corpus striatum structure; Data; Decision Making; Development; Dopamine; Dorsal; Drug Addiction; Drug Delivery Systems; Drug usage; Drug user; Environment; Epidemiology; Etiology; Fostering; Future; Goals; Health behavior; Human; In Situ Hybridization; Individual; Individual Differences; Laboratories; Link; Literature; Mediating; Messenger RNA; Microinjections; Modeling; Motivation; Nature; Neurobiology; Pharmaceutical Preparations; Probability; Process; Publishing; Punishment; Rattus; Regulation; Relapse; Research; Research Project Grants; Rewards; Risk; Risk Behaviors; Risk-Taking; Role; Science; Scientist; Self Administration; Self-Administered; Signal Transduction; Social Policies; System; Testing; Time; Training; addiction; adverse outcome; cocaine use; cognitive function; dopamine transporter; experience; insight; interest; mRNA Expression; neurobiological mechanism; novel; prevent; receptor; research study; skills; young adult

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.

描述（由申请人提供）：冒险行为与药物使用密切相关;然而，冒险行为与药物使用之间关系的性质尚未明确。本提案的总体目标是使用大鼠模型来确定a）冒险和药物使用之间的潜在双向关系，以及B）多巴胺信号在介导这些关系中的作用。特别是，该提案中的实验将重点关注青春期的冒险行为，因为一些人类研究将这一时期的危险行为与未来吸毒的可能性增加联系起来。将使用风险决策任务评估青春期大鼠的风险承担，在该任务中，大鼠在伴随不同惩罚风险的小“安全”奖励和大“风险”奖励之间进行选择（该任务是一种条件模型，其中高度奖励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都容易做出错误的决策，往往未能充分评估可能产生的不良后果和（或）采取行动。目标1下的实验将确定青少年冒险行为的个体差异是否能预测成年期可卡因的自我管理。目标1还将调查成年期长期自我服用可卡因是否会导致风险决策的持续增加（从而导致风险行为和药物使用的“恶性循环”）。目标2和3下的实验将研究多巴胺信号传导在介导青少年冒险行为和可卡因使用之间的关系中的作用，特别关注D2样受体和多巴胺转运蛋白，这些受体和转运蛋白在初步和先前发表的数据中与冒险行为和可卡因使用有关。具体来说，目标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受体的mRNA表达，以及多巴胺转运蛋白，特别关注纹状体。目标3下的实验将测试在初步数据和目标2中确定的风险决策和多巴胺能标记物之间的关系的功能相关性，使用脑内显微注射靶向这些标记物的药物在感兴趣的脑区域，如背侧纹状体。这项研究的结果将提供深入了解冒险行为和药物使用之间的因果关系的方向，以及多巴胺能调节风险决策。从临床、流行病学和社会政策的角度来看，这些信息可能有助于制定治疗和预防吸毒的战略。 公共卫生关系：青少年和吸毒者都倾向于从事危险行为，这可能会增加开始和复发吸毒的倾向;然而，青少年冒险和吸毒之间的关系的性质还没有很好地确定。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型成瘾治疗方法。