Koob, George F

Digital Commons@Becker

Washington University School of MedicineDigital Commons@BeckerPresentations 2006: Alcohol and Tobacco Dependence: fromBench to Bedside2006Addiction: Reward, motivation and stressGeorge F. KoobScripps Research InstituteFollow this and additional works at: http://digitalcommons.wustl.edu/guzepresentation2006Part of the Medicine and Health Sciences CommonsThis Presentation is brought to you for free and open access by the 2006: Alcohol and Tobacco Dependence: from Bench to Bedside at DigitalCommons@Becker. It has been accepted for inclusion in Presentations by an authorized administrator of Digital Commons@Becker. For moreinformation, please contact engeszer@wustl.edu.Recommended CitationKoob, George F., "Addiction: Reward, motivation and stress" (2006). Presentations. Paper 2 Samuel B. Guze Symposium onAlcoholism.http://digitalcommons.wustl.edu/guzepresentation2006/2Addiction: Reward, Motivation and StressGeorge F. Koob, Ph.D.ProfessorMolecular and Integrative Neurosciences Department The Scripps Research InstituteLa Jolla, CaliforniaThe Neurocircuitry of Drug Addiction: Neuroadaptive Mechanisms from the ―Dark Side‖• What is Addiction?1. Conceptual framework2. The ‘dark side’ of compulsivity• Animal Models for the Motivational Effects of Dependence1. Brain stimulation reward2. Place aversion3. Anxiogenic-like responses in the plus maze and defensive burying tests4. Escalation in drug self-administration with prolonged access • A Role for Corticotropin-Releasing Factor in Drug Addiction1. Cocaine2. Nicotine3. Heroin4. Alcohol • Future Directions1. Development of CRF1 antagonists for treatment of addiction2. The neurocircutry  of emotional behaviortemplate"Absinthe Drinker"Pablo Picasso (1910)Key DefinitionsDrug Addiction — Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented (here, defined as the “dark side” of addiction)Extended Amygdala — Forebrain macrostructure composed of central medial amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbensCorticotropin-Releasing Factor — 41 amino acid polypeptide “brain stress” neurotransmitter that controls hormonal, sympathetic, and behavioral responses to stressorsDrug addiction is conceptualized as a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcementDrug AddictionFrom: Koob GF, Alcohol Clin Exp Res, 2003, 27:232-243.Stages of the Addiction CycleAnimal Models for the Motivational Components of DependenceAnimal Models for the Withdrawal/Negative Affect Stage1. Brain stimulation reward2. Place aversion3. Anxiogenic-like responses in elevated plus maze anddefensive buryingAnimal Models for the Transition to Addiction1. Drug taking in selected lines of drug preferring animals 2. Withdrawal-induced drug taking3. Escalation in drug self-administration with prolongedaccess4. Drug taking despite aversive consequencesCocaine Self-AdministrationFrom: Caine SB, Lintz R and Koob GF. in Sahgal A (ed) Behavioural Neuroscience: A Practical Approach, vol. 2, IRL Press, Oxford, 1993, pp. 117-143.Neurochemical Circuitry in Drug RewardPotential Substrates in the Extended Amygdala for the Motivational Effects of Drug DependenceHeimer L and Alheid G, Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas PW and Hanin I (Eds), The Basal Forebrain: Anatomy to Function (series title: Advances in ExperimentalMedicine and Biology, Vol. 295), Plenum Press, New York, 1991, pp. 1-42.Modified from:Equilibrium State for a Homeostatic Regulatory System in a Nondependent and Dependent OrganismFrom: Martin WR, A homeostatic and redundancy theory of tolerance to and dependence on narcotic analgesics.in Wikler A (Ed.), The Addictive States (series title: Its Research Publications, vol. 46), Williams and Wilkins, Baltimore, 1968, pp. 206-225.Standard Pattern of Affective Dynamics Producedby Novel and Repeated Unconditioned StimulusFrom: Solomon RL, American Psychologist, 1980, 35:691-712.Mood Changes Associated with Plasma Levelsof Cocaine During Coca Paste SmokingFrom: Van Dyke C and Byck R, Cocaine, Scientific American, 1982, 246:123-141. Sampling of Interstitial Neurochemicalsby in vivo Microdialysis• Allows sampling of neurochemicals in conscious animals (correlate brain chemistry with behavior).• Implanted so that semi-permeable probe tip is in specific brain region of interest.• Substances below the membrane MW cutoff diffuse across membrane based on concentration gradient.• Both neurochemical sampling and localized drug delivery are possible.Collaborators: Dr. Friedbert Weiss, Dr. Larry Parsons, Dr. Emilio Merlo-Pich, Dr. Regina RichterExtracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration and WithdrawalFrom: Parsons LH, Koob GF and Weiss F, J Pharmacol Exp Ther, 1995, 274:1182-1191.Withdrawal from chronic drugs of abuse produces a reward (motivational) dysregulation as measured by thresholds for intracranial self-stimulationDrug WithdrawalIntracranial Self-Stimulation (ICSS)Threshold ProcedureAdapted from: Markou A and Koob GF, Physiol Behav, 1992, 51:111-119.Elevations in ICSS Reward Thresholds During WithdrawalReward Transmitters Implicated in the Motivational Effects of Drugs of AbuseDopamine … ―dysphoria‖Opioid peptides ... painSerotonin … ―dysphoria‖GABA … anxiety, panic attacksDopamineOpioid peptidesSerotoninGABAPositive Hedonic Effects Negative Hedonic Effectsof WithdrawalCNS Actions ofCorticotropin-Releasing Factor (CRF)Major CRF-Immunoreactive Cell Groups andFiber Systems in the Rat BrainFrom: Swanson LW, Sawchenko PE, Rivier J and Vale W, Neuroendocrinology, 1983, 36:165-186.CRF Produces Arousal, Stress-like Responses,and a Dysphoric, Aversive StateParadigm CRF Agonist CRF AntagonistAcoustic startle Facilitates startle Blocks fear-potentiated startleElevated plus maze Suppresses exploration Reverses suppression of explorationDefensive burying Enhances burying Reduces buryingFear conditioning Induces conditioned fear Blocks acquisition of conditioned fearCued electric shock Enhances freezing Attenuates freezingTaste / Place Conditioning Produces place aversion Weakens drug-induced place aversionChronic cocaine administration produces a dependence syndrome that is reversed by blockade of CRF function.CocaineDefensive Burying: Active Anxiety-Like BehaviorHabituation• Two 45-min sessions in test cage• No shock probe presentTesting• Electrified shock probe present• Probe delivers a single, < 1 sec, 1.5 mA shock on contact• Probe is shut off after shock• Defensive burying scored for 10 minEndpoints• Latency to bury• Duration of burying• Duration of other active behaviorsEffect of CRF Antagonist D-Phe-CRF12-41Administered ICV on Anxiogenic-Like Effect Following Chronic Cocaine AdministrationFrom: Basso AM, Spina M, Rivier J, Vale W and Koob GF, Psychopharmacology, 1999, 145:21-30.Extracellular CRF Levels in the Central Nucleus of the Amgydala During Cocaine Self-Administration and Subsequent WithdrawalFrom: Richter RM and Weiss F, Synapse, 1999, 32:254-261.Protocol for Drug EscalationAll Rats (n=24):2-hr SA sessionFixed Ratio 10.25 mg cocaine/injection1) Initial Training PhaseShort Access (n=12)22 x 1-hr SA session2) Escalation PhaseLong Access (n=12)22 x 6-hr SA sessionDose-response forneuropharmacologicalprobes3) Testing PhaseProtocol from: Ahmed SH and Koob, Science, 1998, 282:298-300.Change in Brain Stimulation Reward Thresholds in Long-Access (Escalation) vs. Short-Access (Non-Escalation) RatsFrom: Ahmed SH, Kenny PJ, Koob GF and Markou A, Nature Neurosci, 2002, 5:625-627.Dose-Dependent Decrease of Cocaine Intakewith Administration of a CRF1 AntagonistFrom: Specio SE, Zorrilla EP, O’Dell LE and Koob GF, unpublished results.Pieter BruegelChronic alcohol exposure produces a dependence syndrome that is reversed by blockade of CRF function.AlcoholElevated Plus Maze• Unconditioned approach/avoidance behavior• 3 underlying factors: anxiety, activity, assessment of risk• Predictive validity for anxiolytic and anxiogenic drugsCompetitive CRF Antagonist -Helical CRF9-41Injected into Central Nucleus of the AmygdalaBlocks the Anxiogenic Effects of Alcohol WithdrawalFrom: Rassnick S, Heinrichs SC, Britton K and Koob GF, Brain Res, 1993, 605:25-32. Extracellular CRF Levels in the CentralAmygdala During Ethanol WithdrawalFrom: Merlo-Pich E, Lorang M, Yeganeh M, Rodriquez de Fonseca F, Koob GF and Weiss F, J Neurosci, 1995,15:5439-5447.Protocol for Initiation of Lever Pressing forOral Ethanol Self-Administration in the RatInitiation of the free-choice operant task: ethanol (10%) and waterRats trained to lever press on a FR-1 scheduleEthanol added to the saccharin solutionAccess to ethanol and water or ethanol + saccharin and water1-34-91011-12131415-16718+DaysDaysDayDaysDayDayDaysDayDay0.2%0.2%-0.2%-0.2%-0.2%-0%5%5%5%5%8%8%10%10%****Training Saccharin (w/v) EtOH (w/v)From: Rassnick S, Pulvirenti L and Koob GF, Alcohol, 1993, 10:127-132.Ethanol Dependence InductionFrom: Rassnick S, Heinrichs SC, Britton KT and Koob GF,Brain Res, 1993, 605:25-32.From: Rogers J, Wiener SG and Bloom FE,Behav Neural Biol, 1979, 27:466-486.Enhanced Ethanol Self-AdministrationDuring Withdrawal in Dependent AnimalsFrom: Funk C and Koob GF, unpublished results.Effects of a Competitive CRF Antagonist Injected ICV on Ethanol Self-Administration During Withdrawal in Dependent Rats(60 min session 2 h into withdrawal)From: Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP and Koob GF, Alcohol Clin Exp Res, 2002,26:1494-1501.Effect of CRF Antagonist D-Phe-CRF12-41– Central Nucleus of the Amygdala –From: Funk C, O’Dell LE and Koob GF, unpublished results.Effect of CRF Antagonist D-Phe-CRF12-41– Lateral Bed Nucleus of the Stria Terminalis –From: Funk C, O’Dell LE and Koob GF, unpublished results.Effect of CRF Antagonist D-Phe-CRF12-41– Nucleus Accumbens Shell –From: Funk C, O’Dell LE and Koob GF, unpublished results.CRF1 Specific AntagonistsCRF1 Specific AntagonistsR121919From: Funk C, Zorrilla EP, Lee MJ, Rice KC and Koob GF, unpublished results.Interaction of CRF Antagonists in Animal Models of Protracted Abstinence1. CRF antagonists injected into the extended amygdala block stress-induced reinstatement of drug seekingErb S, Salmaso N, Rodaros D and Stewart J, Psychopharmacology, 2001, 158:360-365Liu X and Weiss F, J Neurosci, 2002, 22:7856-7861Funk D, Li Z, Shaham Y and Le AD, Neuroscience, 2003, 122:1-42. CRF antagonists injected i.c.v. block stress-induced anxiogenic-like responses and excessive drinking during protracted abstinenceValdez GR, Zorrilla EP, Roberts AJ and Koob GF, Alcohol, 2003, 29:55-60.3. CRF1 knockout mice show a blunted anxiogenic-like response to alcohol withdrawal and a blockade of excessive drinking during protracted abstinenceChu K, Koob GF, Cole M and Roberts AJ, submittedThe extended amygdala is a rich substrate for neurochemical and neurocircuitry interactions that produce the ―dark side‖ of motivation.Extended AmygdalaNeurochemical Changes in the Extended Amygdala during the Development of Dependence:Implications for Emotional ProcessingNeurochemical Changes Associated with the Transition from Drug Use to DependenceFrom: Roberts AJ and Koob GF, Alcohol: ethanol antagonists/amethystic agents. in Adelman G and Smith BH (Eds.), Encyclopedia of Neuroscience, 3rd edn, Elsevier, New York, 2003 [http://203.200.24.140:8080/Neuroscience].ConclusionsCRF in the extended amygdala is recruited during the development of dependence and has motivational significance for drug seeking.Compulsive drug taking associated with addiction derives both from decreases in reward neurotransmission and from recruitment of anti-reward systems (―dark side‖ of addiction).Other neurochemical elements in the extended amygdala—such as norepinephrine, NPY and galanin—may have a role in motivational neuroadaptation associated with drug dependence.The common interface in the extended amygdala of the neurochemistry of addiction and pain and fear conditioning pathways provides a heuristic framework for exploring the neural basis of negative emotional states.Neurobiology of Drug AddictionKoob LaboratoryPost-DoctoralFellowsCindy FunkBrendan WalkerTom GreenwellSandy GhozlandNick GilpinChitra MandyamSunmee WeeSpecial thanks to:Mike Arends(Senior Research Assistant)Janet Hightower(Biomedical Graphics Dept)ResearchAssistantsBob LintzRichard SchroederElena CrawfordMolly BrennanMaury ColeTess KimberYanabel GrantRon SmithAdministrativeAssistantsLisa MaturinMellany SantosMarisa GallegoNeurobiology of Drug AddictionCurrent CollaboratorsSupport from:National Institute on Alcohol Abuse and AlcoholismNational Institute on Drug AbuseNational Institute of Diabetes and Digestive and Kidney DiseasesPearson Center for Alcoholism and Addiction ResearchJean RivierCatherine RivierTamas BartfaiGeorge SigginsMarisa RobertoKenner RiceKim JandaLaura O’DellRobert PurdyWalter FrancesconiSheila SpecioMarc AzarFloyd BloomBarbara MasonMichel Le MoalLuis StinusFriedbert WeissAthina MarkouAmanda RobertsLarry ParsonsPietro SannaLuigi PulvirentiEric ZorrillaWylie Vale

Addiction: Reward, motivation and stress

http://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=1001&context=guzepresentation2006

Addiction: Reward, motivation and stress

Abstract

Similar works

Full text

Available Versions

Digital Commons@Becker