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

描述(由申请者提供)：男性和女性的吸毒成瘾都与糟糕的决策和高风险有关。冒险程度的提高可能会使个人更有可能从事毒品使用和其他危险行为，从而导致成瘾和不良的生活结果。药物使用和风险增加之间的因果关系，以及可能调节这种关系的神经机制，目前尚不清楚。然而，对这些机制的更好理解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男性和女性与药物使用相关的风险增加背后的行为和神经机制。对这一长期目标非常重要的是，一种新的高风险决策大鼠模型的初步工作表明，风险承担增加预示着随后的可卡因自我管理，而长期的可卡因自我管理反过来会导致风险承担的持久上升，表明风险承担和可卡因使用之间存在双向关系。此外，初步数据表明，药物NA�VE大鼠的风险承担增加与纹状体D2受体表达水平降低有关，这些受体的激活可以降低风险承担。在这些初步发现的基础上，这项建议的目标是充分描述风险增加和可卡因自我给药之间的关系，并确定这些关系是否由D2和D3多巴胺受体信号的变化所介导。我们的中心假设是，冒险行为的增加是由纹状体D2受体的低水平和纹状体D3受体的高水平介导的，无论是作为一种预先存在的条件素，还是由于长期服用可卡因。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降低风险。使用一种综合的方法，我们将风险行为评估与可卡因自我管理以及药理学、分子和解剖学分析相结合，我们将通过以下方法检验我们的中心假设：1)表征男性和女性风险增加和可卡因自我管理之间的双向关系，并确定可卡因诱导的风险承担增加是否与纹状体D2和D3受体的变化有关；2)确定纹状体D2和D3受体的变化是否足以导致风险增加 3)确定纹状体D2和D3受体的慢性环境或药物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风险承担中的作用，将为制定针对风险增加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.