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不良决策和高风险有关。高风险可能会导致成瘾和不良的生活结果，使个人更有可能从事药物使用和其他危险行为。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男性和女性药物使用相关的高风险行为的行为和神经机制。对这一长期目标至关重要的是，对一种新型大鼠风险决策模型的初步研究表明，高风险行为的升高预示着随后的可卡因自我服用，而长期可卡因自我服用反过来又会导致风险行为的持续升高，这表明风险行为与可卡因使用之间存在双向关系。另外的初步数据表明，未使用药物的大鼠的高风险与纹状体D2受体表达水平较低有关，激活这些受体可以降低风险。在这些初步发现的基础上，本提案的目的是充分表征高风险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多巴胺受体信号的改变介导。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，要么是预先存在的条件，要么是长期自我服用可卡因的结果。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。我们采用一种综合方法，将冒险行为评估与可卡因自我给药与药理学、分子和解剖学分析结合起来，我们将通过以下方法验证我们的中心假设：1)在男性和女性中描述冒险行为升高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

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.