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      Impaired Response Inhibition in the Rat 5 Choice Continuous Performance Task during Protracted Abstinence from Chronic Alcohol Consumption

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      PLoS ONE
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          Abstract

          Impaired cognitive processing is a hallmark of addiction. In particular, deficits in inhibitory control can propel continued drug use despite adverse consequences. Clinical evidence shows that detoxified alcoholics exhibit poor inhibitory control in the Continuous Performance Task (CPT) and related tests of motor impulsivity. Animal models may provide important insight into the neural mechanisms underlying this consequence of chronic alcohol exposure though pre-clinical investigations of behavioral inhibition during alcohol abstinence are sparse. The present study employed the rat 5 Choice-Continuous Performance Task (5C-CPT), a novel pre-clinical variant of the CPT, to evaluate attentional capacity and impulse control over the course of protracted abstinence from chronic intermittent alcohol consumption. In tests conducted with familiar 5C-CPT conditions EtOH-exposed rats exhibited impaired attentional capacity during the first hours of abstinence and impaired behavioral restraint (increased false alarms) during the first 5d of abstinence that dissipated thereafter. Subsequent tests employing visual distractors that increase the cognitive load of the task revealed significant increases in impulsive action (premature responses) at 3 and 5 weeks of abstinence, and the emergence of impaired behavioral restraint (increased false alarms) at 7 weeks of abstinence. Collectively, these findings demonstrate the emergence of increased impulsive action in alcohol-dependent rats during protracted alcohol abstinence and suggest the 5C-CPT with visual distractors may provide a viable behavioral platform for characterizing the neurobiological substrates underlying impaired behavioral inhibition resulting from chronic intermittent alcohol exposure.

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          Most cited references43

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          Varieties of impulsivity.

          J Evenden (1999)
          The concept of impulsivity covers a wide range of "actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes". As such it plays an important role in normal behaviour, as well as, in a pathological form, in many kinds of mental illness such as mania, personality disorders, substance abuse disorders and attention deficit/hyperactivity disorder. Although evidence from psychological studies of human personality suggests that impulsivity may be made up of several independent factors, this has not made a major impact on biological studies of impulsivity. This may be because there is little unanimity as to which these factors are. The present review summarises evidence for varieties of impulsivity from several different areas of research: human psychology, psychiatry and animal behaviour. Recently, a series of psychopharmacological studies has been carried out by the present author and colleagues using methods proposed to measure selectively different aspects of impulsivity. The results of these studies suggest that several neurochemical mechanisms can influence impulsivity, and that impulsive behaviour has no unique neurobiological basis. Consideration of impulsivity as the result of several different, independent factors which interact to modulate behaviour may provide better insight into the pathology than current hypotheses based on serotonergic underactivity.
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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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              The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry.

              The developmental history and application of the 5-choice serial reaction time task (5CSRTT) for measuring effects of drugs and other manipulations on attentional performance (and stimulus control) in rats is reviewed. The 5CSRTT has been used for measuring effects of systemic drug treatments and also central manipulations such as neurochemical lesions on various aspects of attentional control, including sustained, selective and divided attention--and is relevant to the definition of neural systems of attention and applications to human disorders such as attention deficit/hyperactivity disorder (ADHD) and Alzheimer's disease. The 5CSRTT is implemented in a specially designed operant chamber with multiple response locations ('nine-hole box') using food reinforcers to maintain performance on baseline sessions (about 100 trials) at criterion levels of accuracy and trials completed. The 5CSRTT can be used for measuring various aspects of attentional control over performance with its main measures of accuracy, premature responding, correct response latencies and latency to collect earned food pellets. The data reviewed include studies mainly of systemic and intra-cerebral effects of adrenoceptor, dopamine receptor, serotoninergic receptor and cholinergic receptor agents. These are compared with investigations of effects of selective chemical neurotoxins and excitotoxins applied to discrete parts of the forebrain, in order to define the neural and neurochemical substrates of attentional function. Furthermore, these results are integrated with findings from in vivo microdialysis in freely moving rats or metabolic studies. The monoaminergic and cholinergic systems appear to play separable roles in different aspects of performance controlled by the 5CSRTT, in neural systems centred on the prefrontal cortex, cingulate cortex and striatum. These conclusions are considered in the methodological and theoretical context of other psychopharmacological studies of attention in animals and humans.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 October 2014
                : 9
                : 10
                : e109948
                Affiliations
                [1]Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California, United States of America
                University of Chicago, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LP CI. Performed the experiments: CI RT TQ. Analyzed the data: CI LP. Wrote the paper: CI LP.

                Article
                PONE-D-14-15360
                10.1371/journal.pone.0109948
                4198178
                f4aa11db-a680-4fe3-b373-ad6bdc3e1f33
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 April 2014
                : 10 September 2014
                Page count
                Pages: 15
                Funding
                LP received funding from National Institute of Alcohol Abuse and Alcoholism (R01 AA022249 and P60 AA006420). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Brain
                Prefrontal Cortex
                Neuroscience
                Behavioral Neuroscience
                Psychology
                Addiction
                Alcoholism
                Behavioral Addiction
                Substance Addiction
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the Supporting Information files.

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                Uncategorized

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