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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory Grants (P20)
Project #
5P20DA027844-04
Application #
8507694
Study Section
Special Emphasis Panel (ZDA1-MXS-M)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$137,966
Indirect Cost
$54,602
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yip, Sarah W; Worhunsky, Patrick D; Xu, Jiansong et al. (2018) Gray-matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions. Addict Biol 23:394-402
Yip, Sarah W; Potenza, Marc N (2018) Application of Research Domain Criteria to childhood and adolescent impulsive and addictive disorders: Implications for treatment. Clin Psychol Rev 64:41-56
Leeman, Robert F; Nogueira, Christine; Wiers, Reinout W et al. (2018) A Test of Multisession Automatic Action Tendency Retraining to Reduce Alcohol Consumption Among Young Adults in the Context of a Human Laboratory Paradigm. Alcohol Clin Exp Res 42:803-814
Worhunsky, Patrick D; Potenza, Marc N; Rogers, Robert D (2017) Alterations in functional brain networks associated with loss-chasing in gambling disorder and cocaine-use disorder. Drug Alcohol Depend 178:363-371
Fauth-B├╝hler, Mira; Mann, Karl; Potenza, Marc N (2017) Pathological gambling: a review of the neurobiological evidence relevant for its classification as an addictive disorder. Addict Biol 22:885-897
Yip, Sarah W; Morie, Kristen P; Xu, Jiansong et al. (2017) Shared microstructural features of behavioral and substance addictions revealed in areas of crossing fibers. Biol Psychiatry Cogn Neurosci Neuroimaging 2:188-195
Ren, Yudan; Fang, Jun; Lv, Jinglei et al. (2017) Assessing the effects of cocaine dependence and pathological gambling using group-wise sparse representation of natural stimulus FMRI data. Brain Imaging Behav 11:1179-1191
Worhunsky, Patrick D; Matuskey, David; Gallezot, Jean-Dominique et al. (2017) Regional and source-based patterns of [11C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D2 and D3 receptor availability in cocaine-use disorder. Neuroimage 148:343-351
Worhunsky, Patrick D; Dager, Alecia D; Meda, Shashwath A et al. (2016) A Preliminary Prospective Study of an Escalation in 'Maximum Daily Drinks', Fronto-Parietal Circuitry and Impulsivity-Related Domains in Young Adult Drinkers. Neuropsychopharmacology 41:1637-47
Natarajan, Annamalai; Angarita, Gustavo; Gaiser, Edward et al. (2016) Domain Adaptation Methods for Improving Lab-to-field Generalization of Cocaine Detection using Wearable ECG. Proc ACM Int Conf Ubiquitous Comput 2016:875-885

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