Risk taking and cocaine use: interactions, mechanisms, and therapeutic targets

描述（由申请人提供）：药物成瘾与男性和女性的决策能力差和风险增加有关。冒险行为的增加可能会导致成瘾和不良的生活结果，使个人更有可能从事毒品使用以及其他危险行为。药物使用和高风险之间的因果关系，以及可能介导这种关系的神经机制尚不清楚。然而，更好地理解这些机制可能会导致治疗成瘾的新方法。这项研究计划的长期目标是了解与男性和女性吸毒相关的高风险行为和神经机制。重要的是这个长期的目标，初步工作与一种新的大鼠模型的风险决策表明，风险承担是预测随后的可卡因自我管理，而长期可卡因自我管理反过来又会导致持续的风险承担，表明风险承担和可卡因使用之间的双向关系。此外，初步数据表明，未用药大鼠的冒险行为增加与纹状体D2受体表达水平降低有关，这些受体的激活可以减少冒险行为。基于这些初步研究结果，本提案的目的是充分表征风险增加和可卡因自我管理之间的关系，并确定这些关系是否是由D2和D3多巴胺受体信号传导的改变介导的。我们的中心假设是，高风险是由低水平的纹状体D2受体和高水平的纹状体D3受体介导的，无论是作为一个预先存在的条件或导致慢性可卡因自我管理。我们进一步预测，使这些受体的活性或表达正常化将有效地减少冒险行为。使用一种综合方法，其中我们将风险行为评估与可卡因自我管理和药理学，分子和解剖学分析相结合，我们将通过以下方式测试我们的中心假设：1）描述男性和女性中高风险行为与可卡因自我给药之间的双向关系，并确定可卡因诱导的冒险行为增加是否与纹状体D2和D3受体的改变有关; 2）确定纹状体D2和D3受体的改变是否足以导致风险升高 3）确定纹状体D2和D3受体的慢性环境或药理学正常化是否可以逆转可卡因诱导的风险承担的升高。更好地了解纹状体多巴胺信号在冒险中的作用，将为制定针对高风险行为的干预策略以减少药物使用提供必要的基础知识。

DESCRIPTION (provided by applicant): Drug addiction is associated with poor decision making and elevated risk taking in both males and females. Elevated risk taking may contribute to addiction and poor life outcomes by rendering individuals more likely to engage in drug use as well as other risky behaviors. The causal relationships between drug use and elevated risk taking, as well as the neural mechanisms which might mediate such relationships, are unclear. However, a better understanding of these mechanisms could lead to novel approaches for treating addiction. The long- term goal of this research program is to understand the behavioral and neural mechanisms underlying elevated risk taking associated with drug use in both males and females. Important to this long-term goal, preliminary work with a novel rat model of risky decision making shows that elevated risk taking is predictive of subsequent cocaine self-administration, and that chronic cocaine self-administration in turn causes lasting elevations in risk taking, indicating a bidirectional relationship between risk taking and cocaine use. Additiona preliminary data indicate that elevated risk taking in drug-na�ve rats is associated with lower levels of striatal D2 receptor expression, and that activation of these receptors can reduce risk taking. Building on these preliminary findings, the objective of this proposal is to fully characterize the relationships between elevated risk taking and cocaine self-administration, and to determine whether these relationships are mediated by alterations in D2 and D3 dopamine receptor signaling. Our central hypothesis is that elevated risk taking is mediated by low levels of striatal D2 receptors and high levels of striatal D3 receptors, either as a pre-existing conditin or resulting from chronic cocaine self-administration. We further predict that normalizing the activity or expression of these receptors will be efficacious for reducing risk taking. Using an integrative approach in which we combine behavioral assessment of risk taking with cocaine self-administration and pharmacological, molecular, and anatomical assays, we will test our central hypothesis by: 1) characterizing the bidirectional relationship between elevated risk taking and cocaine self-administration in both males and females, and determining if cocaine-induced increases in risk taking are associated with alterations in striatal D2 and D3 receptors; 2) determining if alterations in striatal D2 and D3 receptors are sufficient to cause elevated risk taking, and if acute targeting of these receptors can reverse cocaine-induced elevations in risk taking; 3) determining if chronic environmental or pharmacological normalization of striatal D2 and D3 receptors can reverse cocaine- induced elevations in risk taking. A better understanding of the role of striatal dopamine signaling in risk taking will provide foundational knowledge necessary to develop intervention strategies targeting elevated risk taking in order to reduce drug use.