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      Behavioral phenotypes revealed during reversal learning are linked with novel genetic loci in diversity outbred mice


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          Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, genome-wide corrected <0.1). Candidate genes were prioritized ( 2900076A07Rik, Wdr73 and Zscan2) based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.

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          Impulsivity as a determinant and consequence of drug use: a review of underlying processes.

          Impulsive behaviors are closely linked to drug use and abuse, both as contributors to use and as consequences of use. Trait impulsivity is an important determinant of drug use during development, and in adults momentary 'state' increases in impulsive behavior may increase the likelihood of drug use, especially in individuals attempting to abstain. Conversely, acute and chronic effects of drug use may increase impulsive behaviors, which may in turn facilitate further drug use. However, these effects depend on the behavioral measure used to assess impulsivity. This article reviews data from controlled studies investigating different measures of impulsive behaviors, including delay discounting, behavioral inhibition and a newly proposed measure of inattention. Our findings support the hypothesis that drugs of abuse alter performance across independent behavioral measures of impulsivity. The findings lay the groundwork for studying the cognitive and neurobiological substrates of impulsivity, and for future studies on the role of impulsive behavior as both facilitator and a result of drug use.
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            Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex

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              Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement.

              Stimulant addiction is often linked to excessive risk taking, sensation seeking, and impulsivity, but in ways that are poorly understood. We report here that a form of impulsivity in rats predicts high rates of intravenous cocaine self-administration and is associated with changes in dopamine (DA) function before drug exposure. Using positron emission tomography, we demonstrated that D2/3 receptor availability is significantly reduced in the nucleus accumbens of impulsive rats that were never exposed to cocaine and that such effects are independent of DA release. These data demonstrate that trait impulsivity predicts cocaine reinforcement and that D2 receptor dysfunction in abstinent cocaine addicts may, in part, be determined by premorbid influences.

                Author and article information

                Addict Neurosci
                Addict Neurosci
                Addiction neuroscience
                1 January 2023
                December 2022
                4 November 2022
                26 January 2023
                : 4
                [a ]Department of Psychology, Binghamton University, Binghamton, NY, USA
                [b ]Center for Systems Neurogenetics of Addiction at The Jackson Laboratory, Bar Harbor, ME, USA
                [c ]The Jackson Laboratory, Bar Harbor, ME, USA
                [d ]Department of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA
                [e ]Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA
                Author notes
                [* ]Corresponding author at: Department of Psychology, Binghamton University, Binghamton, NY, USA., jbagley@ 123456binghamton.edu (J.R. Bagley).

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/)


                impulsivity,addiction,genetics,reversal learning,diversity outbred


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