Neural circuits and mechanisms underlying maladaptive risk-taking following cocaine self-administration

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Project Summary: Drug addiction is associated with poor decision-making and elevated risk-taking, which can persist well into abstinence and contribute to relapse. These adverse behavioral changes are particularly evident in cocaine users, who exhibit pronounced elevations in risk-taking both in the laboratory and in real world settings. The majority of preclinical research to date has focused on the mechanisms by which hypersensitivity to reward promotes poor decision-making and continued drug use; however, we have only a rudimentary understanding of the brain circuits that encode the risk of punishment associated with these maladaptive choices. The long term goal of this project is to elucidate the neurobiology of drug-induced maladaptive decision-making involving punishment and, thereby, identify neural targets for therapeutically attenuating risk-taking in substance abusers. Relevant to this goal, our laboratory has established a rat model of risk-taking (the “Risky Decision-Making Task”; RDT) that recapitulates real-life decision-making in that it incorporates both reward and risk of punishment. Using this model, our lab showed that chronic cocaine self- administration causes lasting increases in punished risk-taking behavior and that dopamine D2 receptor (D2R) function in the nucleus accumbens (NAc) plays a critical role in this behavior. Further, preliminary data reveal unique roles in punishment-related decision-making for the basolateral amygdala (BLA) and insular cortex (INS), both of which project to the NAc and are impacted by drugs of abuse. The proposed experiments will build on these findings and test the central hypothesis that cocaine-induced insensitivity to risk of punishment is mediated both by attenuated D2R function in the NAc and by disrupted communication between the NAc and afferent structures that convey essential information regarding anticipation and probability of punishment. This hypothesis will be tested using a combination of in vivo electrophysiology and optogenetics to allow both in vivo manipulation and real-time monitoring of neural activity during decision-making behavior. Aim 1 will determine whether alterations in NAc D2R function mediate cocaine-induced insensitivity to risk of punishment by first testing whether a D2R agonist restores altered neural activity in the NAc during decision-making in rats with a history of cocaine self-administration. In a second experiment, D2R-expressing neurons in the NAc will be optogenetically manipulated during decision-making to test whether inhibition of these neurons reverses cocaine-induced increases in risk-taking. Aim 2 will determine whether dysfunction in the BLA and INS afferents to the NAc contributes to cocaine-induced insensitivity to risk of punishment. These experiments will determine how activation or silencing of these circuits affects risk-taking and neural encoding of risk of punishment following cocaine self-administration. Collectively, these findings will provide insight into how the neural circuitry underlying risk-taking may become compromised by drugs of abuse and, thus, reveal brain targets that could be modulated to reduce maladaptive risk-taking associated with drug addiction.