Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine

点击翻译按钮获取中文摘要

Project Summary/Abstract Risky choice is one facet of impulsivity that is observed in several psychiatric disorders, including substance use disorders. Understanding the shared neurobiology of risk-taking behavior and drug abuse is important for designing effective pharmacotherapies for individuals that are at risk for developing substance use disorders. The neurotransmitter glutamate is considered to be involved in drug addiction, and recent research has shown that the N-methyl-D-aspartate (NMDA) glutamate receptor is involved in risky choice. Considering NR2B- selective antagonists lack the psychotomimetic side effects observed with NMDA receptor channel blockers (such as MK-801 and ketamine), these drugs may provide a novel therapeutic approach to treating individuals predisposed to engaging in risky behaviors. The NR2B subunit antagonist ifenprodil is effective in blocking the rewarding effects of morphine, an opiate that has high abuse potential. Because ifenprodil has high affinity for adrenergic receptors, additional research with highly selective NR2B subunit antagonists is needed to determine if this subunit is a potential molecular target for treating disorders characterized by excessive risk. The highly selective NR2B antagonist Ro 63-1908 decreases risky choice, as measured in probability discounting, in rats; however, this effect is only observed when the probability of obtaining a large reward increases across the session, raising issues about the validity of this task to measure risky choice. Thus, the first goal of this proposal is to further elucidate the role of the NR2B subunit of the NMDA receptor in risky decision making by testing the effects of Ro 63-1908 in the risky decision task (RDT), in which rats choose between a small, safe reward and a large, risky reward (i.e., paired with foot shock). Using the RDT is ideal because performance in this task is predictive of cocaine self-administration. The second goal is to determine if blocking NR2B-containing NMDA receptors is efficacious in attenuating cocaine self-administration in rats displaying increased risky choice. The third goal of the proposal is to determine if cocaine exposure differentially alters NR2B subunit distribution (via receptor autoradiography) in high and low risk-taking rats and to determine if Ro 63-1908 can reverse cocaine-induced alterations in NR2B subunit distribution.