The mechanisms underlying the progression from voluntary use to the compulsive drug-seeking/taking behavior that define addiction remain largely unknown. The ultimate goal of this translational P20 is to take advantage of combined behavioral and neurobiological studies in rats, non-human primates (NHP), and humans to test the hypothesis that dissociable forms of impulsivity contribute to the development of compulsive drug-seeking/taking behavior. We have hypothesized that impulsivity resulting from frontostriatal dysfunction is central to addiction but the precise relationship between impulsivity and compulsivity has not been defined. Our data show that prior cocaine (COC) exposure can selectively disrupt inhibitory control functions mediated by the orbitofrontal cortex (OFC) while at the same time altering limbic-striatal function. We have also identified persistent region-specific alterations in the synaptic proteome after COC exposure in monkeys, including widespread changes in proteins involved in coordinating synaptic plasticity. While these COC-induced deficits are associated with altered DA-regulated signaling within cortico-limbic-striatal regions the interaction between pre-existing and COC-induced individual variability in inhibitory control processes and "addictive-like" behavior has not been elucidated. Here we will examine two forms of impulsivity: impulsive action and impulsive decision-making using stop signal task (SST) and inter-temporal choice task (ITCT). These two tests likely depend on the dorsomedial and ventral striatum, respectively. Individual differences in impulsivity on these tasks will be investigated in rats that will be divided into balanced groups based on their level of performance. Rats with "low" vs. "high" impulsive performance will be tested daily during repeated COC or SAL injections given 6 hours after behavioral testing for 30 days. Animals will then be tested on acquisition COC self administration (SA) and COC-seeking behavior measured by cue-induced reinstatement. Assessment of level and forms of impulsivity with post-exposure performance will be determined and correlated with post-mortem biochemical measures of alterations in D1/D2/D3 receptors in cortico-striatal regions. We hypothesize that individual differences in D2/D3-regulated signaling in the ventral striatum (nucleus accumbens, NAc) will predict performance on the ITCT whereas the level of D2-regulated signaling in the dorsomedial striatum (dmS) will correlate with performance on the SST. Mechanistic tests will utilize regional viral-vector mediated overexpression of the transcription factor Sp1 to prevent the development of impulsive behavior. Sp1 was identified as a COC-regulated target from our previous proteomic data and is known to regulate many of the synaptic proteins reduced by COC. Our recent studies have confirmed COC-induced alterations in Sp1 and several of its downstream targets, including D2/D3 receptors, in both cortical and striatal regions. These findings are consistent with observations made in human addicts. We hypothesize that multiple forms of impulsivity that involve anatomically distinct regions contribute to addiction vulnerability that, together with COC-induced dysfunction, synergize to produce compulsive drug-seeking behaviors that characterize addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory Grants (P20)
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Special Emphasis Panel (ZDA1-MXS-M)
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Yale University
New Haven
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