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I. Introduction II. Neural and Neurochemical Bases of Reward and Action

31:241 Behavioral and Cognitive Neuroscience Professor A.K. Johnson Fall 2012 Outline Reward and Addiction 10/30; 11/1. I. Introduction II. Neural and Neurochemical Bases of Reward and Action A. Discovery of rewarding electrical brain stimulation (self-stimulation)

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I. Introduction II. Neural and Neurochemical Bases of Reward and Action

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  1. 31:241 Behavioral and Cognitive NeuroscienceProfessor A.K. JohnsonFall 2012 OutlineReward and Addiction10/30; 11/1 I. Introduction II. Neural and Neurochemical Bases of Reward and Action A. Discovery of rewarding electrical brain stimulation (self-stimulation) B. Rewarding brain stimulation and conventional motivation and reward C. A punishment system D. Theories of self-stimulation E. Neural and neurochemical substrates of self-stimulation F. Dopamine systems G. The relationship between self-stimulation and drug self-administration (i.e., drugs which act as reinforcers) H. Conditioned place preference: use for assessing reinforcing properties of drugs I. Neural substrates of drug addiction J. Neurochemistry and neuropharmacology of reward systems K. Relation of motivation and reward systems to motor pathways: from motivation to action III. Overview of Drug Abuse, Addition and Dependence A. Definitions B. Toxicity of drugs of abuse C. Origins of abuse and dependence D. DSM-IV and ICD-10 criteria E. Variables associated with abuse and addiction F. Theories of addiction IV. Treatments for Drug Dependence A. Detoxification B. Maintenance of abstinence C. Strategies and therapeutics 241-4.0

  2. Key Terms and Concepts Mesolimbic Naloxone Nigrostriatal Sensitization Stimulants Tolerance Ventral mesostriatal (mesolimbic) Ventral pallidum Abstinence syndrome Dependence Depressant (neural depressant) Dorsal mesostriatal (nigrostriatal) Drug abuse Drug sensitization Drug tolerance Mesocortical 241-4 KTC

  3. Operant Chamber (Skinner Box)for Delivery of Rewarding ElectricalBrain Stimulation (Self-Stimulation) 241-4.1

  4. A Cumulative Bar-Pressing Curve for a Self-Stimulating Rat With an Electrode in a Positive Reward Site 241-4.2

  5. •Performance on instrumental tasks - Reward magnitude - Priming - Rapid extinction - Schedules of reinforcement - Chaining of behaviors - Secondary reinforcers • Electrically elicited behaviors (drinking, eating, chewing, hoarding, aggressive reproductive responses) • Aversion/punishment systems The Relationship Between Self-Stimulation and Conventional Motivated Behaviors and Reward 241-4.3

  6. Brain Area Sites Which Support Self-Stimulation Forebrain Frontal cortex; Entorhinal cortex; Olfactory nucleus; Caudate nucleus; Nucleus accumbens; Entopeduncular nucleus; Septal area; Hippocampus; Amygdaloid nucleus; Ventral and medial thalamus; Hypothalamus Median forebrain bundle; Dorsal noradrenergic bundle Midbrain and Ventral tegmental area; Substantia nigra;brain stem Raphe nuclei; Nucleus coeruleus; Superior cerebellar Periaqueductal gray matter peduncle; Mesencephalic nucleus of trigeminal nerve Cerebellum Deep cerebellar nuclei Other cerebellar areas Medulla Motor nucleus of trigeminal nerve; Nucleus of tractus solitarius Some Sites Which Support Intracranial Self-Stimulation in Various Animal Species 241-4.4

  7. Neuroanatomy of Brain Rewardand Punishment Systems 241-4.5

  8. •Automatistic behavior • Hedonic (Olds) • Dual activation of drive and reward pathways (Deutsch; Gallistel) •Consummatory behavior (Glickman & Schiff) • Incentive motivation (Trowill, Panksepp & Gandelman) Theories of Self-Stimulation 241-4.6

  9. • Drugs that facilitate self-stimulation release CAs (e.g., amphetamine). • Drugs that inhibit self-stimulation deplete CAs (reserpine, -methyl-p- tyrosine). • Drugs that block adrenergic transmission (chlorpromazine) inhibit self-stimulation. • Protection of CAs with monoamine oxidase inhibitors or block reuptake (e.g., imipramine) enhances the facilitatory effect of amphetamine on self-stimulation. • Depletion of brain CAs with reserpine or -methyl-p-tyrosine decreases the facilitatory effects of amphetamine on self-stimulation. • A large component of the medial forebrain bundle (MFB), a “hot-spot” for self-stimulation, is catecholaminergic. • Rewarding stimulation of the MFB causes release of norepinephrine into the amygdala and hypothalamus. Lines of Evidence Supporting the Idea that Catecholamines (CAs) Mediate Rewarding Brain StimulationLarry Stein(Circa 1966) 241-4.7

  10. Horizontal and Lateral Representations of Ascending Noradrenaline and Dopamine Pathways 241-4.8

  11. Dopaminergic Pathways in the Rat Brain 241-4.9

  12. The Four Major DA Pathways in the Brain 241-4.10

  13. Ultrashort •Retina – interplexiform amacrine-like neurons • Olfactory bulb – periglomerular dopamine cells Intermediate Length • Tuberohypophyseal •Incertohypothalamus • Medullary periventricular Long Length • Nigrostriatal •Mesolimbic • Mesocortical Brain Dopamine Systems 241-4.11

  14. The Dopamine Synapse 241-4.12

  15. D1 and D5 D2a D2b D3 and D4 Molecular structure Seven membrane- Seven membrane- Seven membrane- Seven membrane- spanning regions spanning regions spanning regions spanning regions Effect on cyclic AMP Increases Decreases Increases phospho- ? inositide turnover Agonists Dopamine Full agonist (weak) Full agonist (potent) Apomorphine Partial agonist (weak) Full agonist (potent) Antagonists Phenothiazines Potent Potent Thioxanthenes Potent Potent Butyrophenones Weak Potent Clozapine Inactive Weak Weak Potent Six Types of Postsynaptic Dopamine Receptors 241-4.13

  16. The Rotometer 241-4.14

  17. Investigation of the Actions ofDopamine in the Nigrostriatal System:Drug-Induced Rotational Behavior in Rats with Unilateral Nigrostriatal Lesions 241-4.15

  18. Presumed Mechanism Most Prominent Drug of Action Physiological Effects AntagonistsButyrophenones Haloperidol Phenothiazines Receptor blockade Tranquilizer; antipsychotic; antinauseant Chlorpromazine* Agonists Apomorphine Receptor stimulation Antiparkinsonian, emetic Bromocriptine Releasers Amphetamine Releaser Stimulant, appetite suppressant Vesicular Storage Inhibitors Reserpine* Depletion Antihypertensive; tranquilizer; antipsychotic Pump Inhibitors Cocaine Reuptake inhibition Stimulant euphoriant Synthesis Inhibitors Carbidopa Dopa decarboxylase inhibition Adjuvant for central dopa -Methyl-p-tyrosine* Tyrosine hydroxylase inhibition Depressant; akinesia Monoamine Oxidase Inhibitors Iproniazid* Broad-spectrum MAO inhibition Antidepressant COMT Inhibitors Tropolone, pyrogallol*, COMT inhibition Minimal effects rutin, quercetin False Transmitters -Methyldopamine* Antihypertensive Toxin 6-Hydroxydopamine* Destruction of cells Experimental PrecursorsDopa Stimulates transmitter production Antiparkinsonism and mild stimulant *Also has prominent norepinephrine or epinephrine action, or both Some Prototypic Dopamine Agonists and Antagonists 241-4.16

  19. The Medial Forebrain Bundle is One of the "Hottest" Brain Pathways for Self-Stimulation 241-4.17

  20. Blockade of Medial Forebrain Bundle Self-Stimulation by Dopamine Receptor Antagonist Infused Into the Nucleus Accumbens 241-4.18

  21. Effects of Electrical Self-Stimulationof the Ventral Tegmental Area on Extracellular Dopamine in the Nucleus Accumbens 241-4.19

  22. Apparatus for Producing andMeasuring a Conditioned Place Preference 241-4.20

  23. Place Conditioning With Dopamine AgonistsInfused Into the Nucleus Accumbens 241-4.21

  24. Intravenous Self-Administration of Drugs of Abuse 241-4.22

  25. Alcohol Marijuana Amphetamines Methadone Apomorphine Methyl phenidate Barbiturates Morphine Benzodiazepines Nicotine Chlorphentermine Nitrous oxide Chloroform Pentazocine Clortermine Phencyclidine Cocaine Phenmetrazine Codeine Pipradrol Diethylpropion Procaine Ether Propiram Lacquer, thinners Propoxyphene *Animals will voluntarily self-administer these drugs after suitable priming, depending on dose, schedule, route of administration, and species. Routes of administration include: intravenous, intramuscular, inhalation, intracerebral, intragastric tube, and oral. Animal species include: rat, monkey, ape, baboon, dog, and others. Some Drugs Which Act asReinforcers* in Animal Species 241-4.23

  26. Mediation of the Rewarding Effects of Drugs of Abuse by Dopamine (DA) Action in the Nucleus Accumbens 241-4.24

  27. Hypothesized Sites of Action of Drugson Brain-Reward Circuitry in the Rat 241-4.25

  28. Changes in Dopamine Detected in the Extracellular Fluid of the Nucleus Accumbens of Rats After Daily Intraperitoneal Cocaine Injections (10 mg/kg) 241-4.26

  29. Tetrahydrocannabinol (THC)-Induced Enhancementof Dopamine Efflux in the Nucleus Accumbens 241-4.27

  30. Two Systems Responsible for theInitiation of Movements (Actions):One Involves Cognitive Processes and the Other Involves Those in Response to Basic Motivations (Drives) and Emotions Caudate N. (Neostriatum) Globus Pallidus N. Accumbens (Ventral Striatum) Cerebral Cortex Limbic Structures DAA10 VTA MotorSystem 241-4.28

  31. Locomotion Occurs When Inhibitory GABA-Secreting Synapses on Neuronsin the Globus Pallidus Decrease Their Activity 241-4.29

  32. The Motive Circuit "Translates" thePerception of a Reward Into Locomotion 241-4.30

  33. Simplified Diagram of CentralPathways Controlling Locomotion Thalamus NRP NRP Spinal Pattern Generator Caudate N.(Neostriatum) Mesencephalic Locomotor Region(Pedunculo Pontine Nucleus) Globus Pallidus Cerebral Cortex VentromedialMedulla N. Accumbens (Ventral Striatum) Limbic Structures MotorSystem VTA VTA, ventral tegmental area; NRG, nucleus reticularis gigantocellularis; NRP, nucleus reticularis pontis oralis 241-4.31

  34. Drug Abuse = a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences to repeated use of substances. Dependence • Drug dependence is a state whereby an individual either psychologically or physically requires a drug in order to feel well in the absence of medical indications. • Discontinuation of the drug will produce a characteristic group of withdrawal symptoms. • Physiological dependence = adverse physiological reactions (e.g., stomach cramps) in the absence of drugs. • Primary psychological dependence = produces pleasure and/or reduces "psychic" discomfort (drug craving). • Secondary psychological dependence = fear or anxiety as a result of a lack of drug. Drug Dependence and Abuse 241-4.32

  35. Drug Addiction = Substance Dependence 1. Compulsion to seek and take a drug. 2. Loss of control in limiting intake. 3. Emergence of negative emotional state (e.g., dysphoria, anxiety, irritability) when access to drug is prevented. 4. Chronic relapsing disorder. 241-4.33

  36. Opiates and Opioids• Morphine, codeine, heroin, meperidine, hydromorphone, and other opioid agonists Stimulants• Cocaine, amphetamines, methylphenidate, nicotine, caffeine Depressants• Barbiturates, non-barbiturate sedatives, benzodiazepines, and ethanol Hallucinogens• D-lysergic acid diethylamide (LSD), mescaline, methylenedioxymethamphetamine (MDMA), phencyclidine, marijuana Inhalants Categories of Drugs of Abuse 241-4.34

  37. Classification of Drug Use 1. Occasional, controlled, social use 2. Abuse or harmful use 3. Addiction 241-4.35

  38. Drug Use, Abuse and Dependencein U.S. Adults At Some Point in Their Lifespan • 15.6% engage in illicit drug use • 3.1% engage in abuse • 2.9% develop dependence 241-4.36

  39. DSM-IV Alcohol and Drug Abuse A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12 month period: 1. Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home. 2. Recurrent substance use in situations in which it is physically hazardous. 3. Recurrent substance-related legal problems. 4. Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the drug. B. The symptoms have never met the criteria for substance dependence for this class of substances. ICD-10 Harmful Use of Alcohol and Drugs A. A pattern of substance use that is causing damage to health. The damage may be physical or mental. The diagnosis requires that actual damage should have been caused to the mental or physical health of the user. B. No concurrent diagnosis of the substance dependence syndrome for same class of substance. DSM-IV and ICS-10 Diagnostic Criteria for Alcohol and Drug Abuse/Harmful Use 241-4.37

  40. DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug Dependence 241-4.38

  41. Stages of Drug Addiction/Dependence 241-4.39

  42. Diagnostic Criteria of Addiction • Shift in emphasis in diagnostic criteria from focus on tolerance and withdrawal to criteria related to compulsive use. • Diagnostic and Statistical Manual of Mental Disorders = DSM-IV (American Psychiatric Association) • International Statistical Classification of Diseases and Related Health Problems = ICD-I0 (World Health Organization) 241-4.40

  43. • Drugs that affect behavior are likely to be taken in excess when the effects are considered pleasurable. • Legal prescription drugs (e.g., barbiturates, morphine, amphetamine), illegal drugs (e.g., heroin and cocaine) and non-prescription drugs (e.g., ethanol and nicotine) are abused and can produce dependence. • Very few individuals begin addiction problems by misuse of prescription drugs. • However, prescribed medications for pain, anxiety and even hypertension commonly produce tolerance and physical dependence. • Tolerance and physical dependence do not imply abuse or addiction. Origins of Abuse and Dependence 241-4.41

  44. Vulnerability to Addiction Individual Differences: •Temperament--Disinhibition--Negative affect--Novelty/sensation seeking •Social Development--Early drug/alcohol exposure •Co-morbidity--Mood disorders--Anxiety disorders--Antisocial personality disorder--Conduct disorders •Genetics--Contributes to ~40% of total variability associated with drug dependence •Protective Factors--Also receives contributions from genetics, personality, and environment 241-4.42

  45. • Physiological and psychological dependence-related symptoms and signs that arise during withdrawal of a drug. - Relationship with ½ life of drug. Abstinence Syndrome 241-4.43

  46. Relationship Between the Intensity of a Drug's Effects and the Intensity of the Abstinence Syndrome 241-4.44

  47. Differences in Responsesto Heroin and Methadone 241-4.45

  48. Medical/Psychological Views of Addiction 1. Dependence ('40's) --Physical dependence the sine qua non of the abstinence syndrome --Evolved to include "psychic" (psychological) dependence --Drug craving 2. Psychiatric --Addiction has aspect of impulse control disorders and compulsive disorders --Impulsive acts preceded by tension or arousal followed by pleasure gratification or relief --Compulsive acts preceded by anxiety and stress followed by relief from stress --Addiction considered to shift from an impulsive disorder to a compulsive disorder --A circle of addiction with 3 stages: preoccupation/anticipation → binge/intoxication → withdrawal/negative affect 3. Psychodynamic --Focuses on developmental difficulties, emotional disturbances, structural (ego) factors, personality organization and building of the self --Associated with a self-medication hypothesis where users are considered to take drugs to cope with painful/threatening emotions --Opiates for anger and rage --Psychostimulants for anhedonia, anergia, and lack of feelings --Neurodepressants for those flooded by or cut off from feelings --Each drug class serves as an antidote for a dysphoric condition or state 4. Social Psychological/Self-Regulation --Failure in self-regulation leads to addiction --Initial lapse in self-regulation leads to large-scale breeder claims in self-regulation due to emotional distress --Each successive lapse brings greater distress and a downward spiral ensues --View can be related to neural processing concepts involving frontal lobe dysfunction 241-4.46

  49. Diagram Representing a Psychiatric View of the Transition of a Problem of Impulse Control to a Problem of Compulsion in the Course of Becoming Addicted and the Nature of Reinforcement (Positive to Negative) 241-4.47

  50. Primary Goal of Neurobiological Addiction Research: To Understand the Neuropharmacological and Neuroadaptive/Neuroplastic Mechanisms Within the neurocircuitry mediating the transition between occasional drug use and the loss of control over drug seeking and taking (i.e., addiction). 241-4.48

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