Animal Models for the Study of Human Disease || Animal Models of Drug Abuse

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    What are Conditioned Taste Aversions? 693


    problems resulting in severe emotional, financial, and

    approximately two-thirds of these costs are associated

    with self-discipline. For example, a federally funded

    physical costs to the addicted individual, the indi-viduals family, and the community.2 The economiccosts (e.g. healthcare costs, crime-related costs, andloss of productivity) of drug dependence in the UnitedStates exceed $600 billion annually; interestingly,

    study examining cocaines influence on risky sexualbehavior in quail was recently included in a senatorsWastebook, a document detailing how the US federalgovernment wastes tax dollars on research on drugaddiction.6SHOULD WE STUDY IT?

    Drug addiction is defined as a chronically relapsingdisorder, characterized by (1) the compulsion to seekout and take the drug, (2) loss of control in limitingdrug intake, and (3) the emergence of a negativeemotional state, reflecting a withdrawal syndromewhen drug access is prevented.1 Addictions to licit(e.g. alcohol and nicotine) and illicit (e.g. marijuana,cocaine, and heroin) substances are pervasive societal

    with use of the licit drugs nicotine and alcohol (citedin Ref. 2). Substance use and abuse are also associatedwith other public health issues, including the spreadof infectious diseases (e.g. HIV and hepatitis C) andimpaired driving.3,4 Despite the myriad costs to individ-uals and society, justifying the need for animal models ofsubstance abuse and dependence can be a difficult taskfor researchers given that drug addiction is perceivedby a large portion of the general public to result frommoral weakness, a lack of willpower, and/or problems


    hand Conditioning Apparatus 689Advantages of the Place-Conditioning ProcedurePlace Conditioning: Experimental Protocol687

    A Brief History of Place Conditioning 685The Place-Conditioning ProcedureWhat are Conditioned Place Preferences?684684nima

    ttp://ersive Drug Effects 6Av 83ward and Reinforcement 6Re 82Study it? 6we 8168l Models for the Study of Human Disease 1ferences 7Re 03knowledgments 7Ac 03nclusion 7Co 03Protocol and Conditioning Apparatus 699Advantages of the CTA ProcedureConditioned Taste Aversion: Experimental696

    A Brief History of Taste Aversion Learning 694What is Drug Addiction and why ShouldO U T L I N E

    The Flavor-Conditioning Procedure 693C H A


    Animal ModelsPlace and Tast

    CatherineDepartment of Psychiatry and Behavioral Scienc

    University School of MediT E R

    of Drug Abuse:Conditioning. Davis

    , Division of Behavioral Biology, Johns Hopkins

    ne, Baltimore, MD, USACopyright 2013 Elsevier Inc. All rights reserved.

  • In the scientific community, however, substance abuse In the current chapter, two popular methods used in

    gencies are positively reinforced; in other words, they

    28. ANIMAL MODELS OF DRUG ABUSE: CPP AND CTA682and dependence are viewed as a disease of the brain thatwarrants the same type of investments in research andtreatment strategies as those given to diseases likeautism, schizophrenia, andAlzheimers and Parkinsonsdiseases.5 Furthermore, drug abuse researchers employthe same strategies as researchers investigating theseother diseases: animalmodels are developed to representsomecharacteristic of the disorder and then studied,withthe understanding that every detail of the disorder ismost often not completely reproducible in a laboratoryanimal, but that an understanding the disease processandwhat factors contribute to this process can be gained.For example, schizophrenic or autistic rats and micedo not exist,7 although there are rats andmice that exhibitbehaviors characteristic of schizophrenia, autism, oreven obsessive-compulsive disorder8,9 these animalmodels are used to further our understanding of themolecular, cellular, and genetic components of a specificdisorder and how these deficiencies translate into quan-tifiable behavioral symptoms.

    Similar to many of these other human disease states,drug addiction is a uniquely human phenomenon;thus, any attempt to study it in the laboratory inevitablyconstrains its reproducibility. Investigators must keepthis in mind when designing and employing animalmodels of drug addiction. Some models have verygood face validity, such as the drug self-administrationprocedure in which an animal emits a response (e.g.lever press) to receive a drug injection reinforcer. Elegantexperiments using the self-administration procedure tostudy in rats the diagnostic criteria of addiction (out-lined in the Diagnostic and Statistical Manual of MentalDisorders, 4th ed., or DSM-IV-TR) have been reportedand arguably provide new, more realistic approachesto study the neurobiology of addiction.1013 For othermethods, the connection to human drug abusers is notas evident, but the procedures nonetheless allowresearchers to examine some aspect of addiction that isimportant to its overall etiology. Given these issues,the specific question under investigation undoubtedlyinfluences the procedure employed; great care must betaken to understand each procedures strengths andlimitations and how these factors affect the interpreta-tion of the results of the study. Even with these caveats,preclinical animal models have been instrumental infurthering our understanding of the characteristics ofaddiction, including drug taking, physical dependence,tolerance, drug craving, and the factors that mightincrease the likelihood of relapse. These models haveadded greatly to our understanding of drug addiction;however, there is still much to learn and numerousreasons to continue refining our current models, in addi-tion to developing new models as various techniquesbecome even more sophisticated.VIII. BEHserve as appetitive stimuli that increase the emission ofthe instrumental response; stimuli associated with drugintake in these situations can also become conditionedreinforcers, a process by which they acquire incentive-motivational properties (which are considered to becomepathological in addiction), and when these stimuliare presented in the absence of the drug, they elicitwanting or craving responses (for a review, seeRef. 25; see also Refs 2628). (2) Drugs acting as rein-forcers increase the associative strength of specificstimulusresponse contingencies, which results in anincreased probability of the instrumental responseoccurring; reinforcers thus serve to enhance informationstorage about the situations in which they occur,the drug abuse field, place conditioning (primarilyfocused on conditioned place preference, or CPP) andconditioned taste aversion (CTA), will be discussed.Both procedures have been used extensively to studythe rewarding and aversive effects associated with drugexposure. With each of these procedures comes a ratherlarge literature base that includes, but is not limited to,variations in procedural details, equipment, and studydesign; debates on data analysis and interpretation; andexcellent reviews commenting on the strengths, weak-nesses, and controversies surrounding each procedure.Although many of these factors will be discussed in thecurrent chapter, readers are encouraged to accessthese resources for additional information.1423


    When beginning any discussion of animal models ofdrug addiction, the distinction between reward and rein-forcement should be made and include what these termsmean in the context of drug abuse research. Drugs ofabuse are considered reinforcers and, in a Skinnerianview, are thus defined as events that follow an instru-mental response and influence the probability of thatresponse occurring in the future. Regardless of thevalence (i.e. positive or negative), reinforcement willincrease the probability of behavioral output in anorganism, in order for the organism to earn an appetitivereinforcer or to avoid experiencing an aversive one. Inter-estingly at different stages of the addictionprocess, drugsof abuse are thought to differently reinforce drug-takingbehavior, with positive reinforcement occurring in theearly stages of drug use and negative reinforcementinvolved predominantly following more chronic drugtaking. Sanchis-Sugura and Spanagel24 argues that, inthis context, drugs of abuse serve as reinforcers in threedistinct ways: (1) Drugs serve as primary motivators(i.e. positive reinforcement) where behavioral contin-AVIOR

  • a process that can bias response choiceswhen those situ-

    ated independently, such that a drug has some levelof rewarding and/or aversive effects and each effectfunctions to impact overall drug acceptability (datadescribed in this chapter argue for these independenteffects). The perceived balance of these effects thendictates drug intake, where a drug perceived as moreaversive is self-administered less than a drug that isperceived as more rewarding. Importantly, these aver-sive drug effects are considered distinct from those thatnegatively reinforce drug taking following withdrawal;aversive drug effects in this context are experiencedfollowing acute administration and could serve a protec-tive function by limiting (or eliminating) future intake.Thus, aversive drug effects could decrease the likelihoodthat a drug will be abused. Interestingly, the two proce-dures reviewed in this chapter have been used indepen-dently and in combination to demonstrate that a drugsrewarding and aversive effects are measurable simulta-neously in individual subjects following a single drugadministration. Furthermore, these procedures haveshown that not all manipulations and subject variables,including drug history, strain and other genetic differ-ences, sex, and stress, alter these effects in the samemanner (e.g. decreased aversion and increased reward),which makes these p


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