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

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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.