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) 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
Key Terms and Concepts Abstinence syndrome Dependence Depressant (neural depressant) Dorsal mesostriatal (nigrostriatal) Drug abuse Drug sensitization Drug tolerance Mesocortical Mesolimbic Naloxone Nigrostriatal Sensitization Stimulants Tolerance Ventral mesostriatal (mesolimbic) Ventral pallidum 241 -4 KTC
Operant Chamber (Skinner Box) for Delivery of Rewarding Electrical Brain Stimulation (Self-Stimulation) 241 -4. 1
A Cumulative Bar-Pressing Curve for a Self-Stimulating Rat With an Electrode in a Positive Reward Site 241 -4. 2
The Relationship Between Self-Stimulation and Conventional Motivated Behaviors and Reward • 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 241 -4. 3
Some Sites Which Support Intracranial Self. Stimulation in Various Animal Species Brain Area Sites Which Support Self-Stimulation Forebrain Frontal cortex; Olfactory nucleus; Nucleus accumbens; Septal area; Amygdaloid nucleus; Hypothalamus Entorhinal cortex; Caudate nucleus; Entopeduncular nucleus; Hippocampus; Ventral and medial thalamus; Median forebrain bundle; Dorsal noradrenergic bundle Midbrain and brain stem Ventral tegmental area; Substantia nigra; Raphe nuclei; Nucleus coeruleus; Superior cerebellar Periaqueductal gray matter peduncle; Mesencephalic nucleus of trigeminal nerve Cerebellum Deep cerebellar nuclei Medulla Motor nucleus of trigeminal nerve; Nucleus of tractus solitarius Other cerebellar areas 241 -4. 4
Neuroanatomy of Brain Reward and Punishment Systems 241 -4. 5
Theories of Self-Stimulation • Automatistic behavior • Hedonic (Olds) • Dual activation of drive and reward pathways (Deutsch; Gallistel) • Consummatory behavior (Glickman & Schiff) • Incentive motivation (Trowill, Panksepp & Gandelman) 241 -4. 6
Lines of Evidence Supporting the Idea that Catecholamines (CAs) Mediate Rewarding Brain Stimulation Larry Stein (Circa 1966) • • Drugs that facilitate self-stimulation release CAs (e. g. , amphetamine). • 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. Drugs that inhibit self-stimulation deplete CAs (reserpine, -methyl-ptyrosine). 241 -4. 7
Horizontal and Lateral Representations of Ascending Noradrenaline and Dopamine Pathways 241 -4. 8
Dopaminergic Pathways in the Rat Brain 241 -4. 9
The Four Major DA Pathways in the Brain 241 -4. 10
Brain Dopamine Systems Ultrashort • • Retina – interplexiform amacrine-like neurons Olfactory bulb – periglomerular dopamine cells Intermediate Length • • • Tuberohypophyseal Incertohypothalamus Medullary periventricular Long Length • • • Nigrostriatal Mesolimbic Mesocortical 241 -4. 11
The Dopamine Synapse 241 -4. 12
Six Types of Postsynaptic Dopamine Receptors D 1 and D 5 D 2 a D 2 b D 3 and D 4 Molecular structure Seven membranespanning regions Effect on cyclic AMP Increases Decreases Increases phosphoinositide turnover ? Agonists Dopamine Apomorphine Full agonist (weak) Partial agonist (weak) Full agonist (potent) Antagonists Phenothiazines Thioxanthenes Butyrophenones Clozapine Potent Weak Inactive Potent Weak Potent 241 -4. 13
The Rotometer 241 -4. 14
Investigation of the Actions of Dopamine in the Nigrostriatal System: Drug-Induced Rotational Behavior in Rats with Unilateral Nigrostriatal Lesions 241 -4. 15
Some Prototypic Dopamine Agonists and Antagonists Drug Presumed Mechanism of Action Antagonists Butyrophenones Haloperidol Phenothiazines Receptor blockade Chlorpromazine* Agonists Apomorphine Receptor stimulation Bromocriptine Releasers Amphetamine Releaser Vesicular Storage Inhibitors Reserpine* Depletion Pump Inhibitors Cocaine Reuptake inhibition Synthesis Inhibitors Carbidopa Dopa decarboxylase inhibition -Methyl-p-tyrosine* Tyrosine hydroxylase inhibition Monoamine Oxidase Inhibitors Iproniazid* Broad-spectrum MAO inhibition COMT Inhibitors Tropolone, pyrogallol*, COMT inhibition rutin, quercetin False Transmitters -Methyldopamine* Toxin 6 -Hydroxydopamine* Destruction of cells Precursors Dopa Stimulates transmitter production *Also has prominent norepinephrine or epinephrine action, or both Most Prominent Physiological Effects Tranquilizer; antipsychotic; antinauseant Antiparkinsonian, emetic Stimulant, appetite suppressant Antihypertensive; tranquilizer; antipsychotic Stimulant euphoriant Adjuvant for central dopa Depressant; akinesia Antidepressant Minimal effects Antihypertensive Experimental Antiparkinsonism and mild stimulant 241 -4. 16
The Medial Forebrain Bundle is One of the "Hottest" Brain Pathways for Self-Stimulation 241 -4. 17
Blockade of Medial Forebrain Bundle Self. Stimulation by Dopamine Receptor Antagonist Infused Into the Nucleus Accumbens 241 -4. 18
Effects of Electrical Self-Stimulation of the Ventral Tegmental Area on Extracellular Dopamine in the Nucleus Accumbens 241 -4. 19
Apparatus for Producing and Measuring a Conditioned Place Preference 241 -4. 20
Place Conditioning With Dopamine Agonists Infused Into the Nucleus Accumbens 241 -4. 21
Intravenous Self-Administration of Drugs of Abuse 241 -4. 22
Some Drugs Which Act as Reinforcers* in Animal Species Alcohol Amphetamines Apomorphine Barbiturates Benzodiazepines Chlorphentermine Chloroform Clortermine Cocaine Codeine Diethylpropion Ether Lacquer, thinners Marijuana Methadone Methyl phenidate Morphine Nicotine Nitrous oxide Pentazocine Phencyclidine Phenmetrazine Pipradrol Procaine Propiram 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. 241 -4. 23
Mediation of the Rewarding Effects of Drugs of Abuse by Dopamine (DA) Action in the Nucleus Accumbens 241 -4. 24
Hypothesized Sites of Action of Drugs on Brain-Reward Circuitry in the Rat 241 -4. 25
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
Tetrahydrocannabinol (THC)-Induced Enhancement of Dopamine Efflux in the Nucleus Accumbens 241 -4. 27
Two Systems Responsible for the Initiation of Movements (Actions): Limbic Structures Cerebral Cortex Caudate N. (Neostriatum) N. Accumbens (Ventral Striatum) Globus Pallidus One Involves Cognitive Processes and the Other Involves Those in Response to Basic Motivations (Drives) and Emotions DA A 10 VTA Motor System 241 -4. 28
Locomotion Occurs When Inhibitory GABA-Secreting Synapses on Neurons in the Globus Pallidus Decrease Their Activity 241 -4. 29
The Motive Circuit "Translates" the Perception of a Reward Into Locomotion 241 -4. 30
Simplified Diagram of Central Pathways Controlling Locomotion Thalamus Mesencephalic Locomotor Region (Pedunculo Pontine Nucleus) N. Accumbens (Ventral Striatum) Globus Pallidus Limbic Structures Cerebral Cortex Caudate N. (Neostriatum) NRP Spinal Pattern Generator Ventromedial Medulla Motor System VTA, ventral tegmental area; NRG, nucleus reticularis gigantocellularis; NRP, nucleus reticularis pontis oralis 241 -4. 31
Drug Dependence and Abuse 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. 241 -4. 32
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
Categories of Drugs of Abuse 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 241 -4. 34
Classification of Drug Use 1. Occasional, controlled, social use 2. Abuse or harmful use 3. Addiction 241 -4. 35
Drug Use, Abuse and Dependence in 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
DSM-IV and ICS-10 Diagnostic Criteria for Alcohol and Drug Abuse/Harmful Use 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. 241 -4. 37
DSM-IV and ICD-10 Diagnostic Criteria for Alcohol and Drug Dependence 241 -4. 38
Stages of Drug Addiction/Dependence 241 -4. 39
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-I 0 (World Health Organization) 241 -4. 40
Origins of Abuse and Dependence • 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. 241 -4. 41
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
Abstinence Syndrome • Physiological and psychological dependencerelated symptoms and signs that arise during withdrawal of a drug. - Relationship with ½ life of drug. 241 -4. 43
Relationship Between the Intensity of a Drug's Effects and the Intensity of the Abstinence Syndrome 241 -4. 44
Differences in Responses to Heroin and Methadone 241 -4. 45
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
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
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
Major Issues for a Comprehensive Understanding of Drug Addiction • Reward mechanisms • Changes in response to the drug (sensitization or tolerance) • Drug craving • Causes for relapse 241 -4. 49
Neuroadaptation Views of Addiction 1. Behavioral Sensitization Berridge & Robinson Conceptually tied to psychomotor sensitization Incentive sensitization Liking and wanting Incentive-salience --Cues associated with drug cues and drug taking become associated through Pavlovian stimulus associative conditioning to enhance motivation 2. Opponent-Process or Counteradaptation Theory Contributors used such theories to account for tolerance and withdrawal: Himmelsbach ('40's) Martin ('60's) Solomon & Corbit ('70's) Koob & Bloom ('80's) --Theorized that the brain uses negative feedback mechanisms to keep affective responses in check --An unconditioned "a" process (positive/pleasurable) is counteracted by a "b" process --The "b" process has a larger latency of onset and duration of action --"b" process grows disproportionally compared to the decreasing "a" process and is associated with an aversive craving state --Solomon argues that the 'b" process "grows" with repeated drug taking 3. Motivational --Drug addicts frequently report that there is minimal pleasure derived from the drug although the craving is great --The threshold for reward becomes elevated when drug is administered --Can be demonstrated by showing that ICSS thresholds are elevated by cocaine administration 4. Plasticity in Second Messenger and Immediate Early Gene Response Systems 5. Allostasis = maintaining apparent reward function stability through changes in brain reward mechanisms Koob & Le Moal Propose: that not only does the opponent-process "b" change with repeated drug consumption but that the drug-reward "set point" also changes 241 -4. 50
Robinson and Berridge's Theory of Incentive Salience and Drug Addiction • Administration of some classes of abused drugs (e. g. , psychostimulants) produce sensitization (i. e. , reverse tolerance). • For example, psychomotor stimulants increase locomotor behavior with spaced, repeated administration in a normal environment. • Robinson and Berridge propose that increased drug craving is the produce of a similar sensitization process where "wanting" the drug is enhanced. 241 -4. 51
Berridge and Robinson's Model Focusing on the Role of Incentive Salience as a Factor Related to Drug Craving and In Turn Relapse 241 -4. 52
The Opponent-Process Theory of Motivation and Emotion 241 -4. 53
Koob and Le Moal's Application of Opponent-Process Theory to Phenomenology Associated with Drug Addiction 241 -4. 54
Koob and Le Moal's Diagram of the Hypothetical Spiraling Distress-Addiction From a Neurobiological Perspective 241 -4. 55
Nestler's Theory of Sensitization as a Result of Drugs that Release Dopamine Causing Increased Fos-Related Antigens (Fra) 241 -4. 56
Behavioral and Cellular/Molecular Changes Associated with Drug Use, Addiction, Withdrawal and Long-Term Abstinence 241 -4. 57
Treatment for Drug Dependence • Will vary with the drug being used and social and cultural factors determining the use. • The management of withdrawal syndromes can be achieved with minimal risk and high probability of success using pharmacological agents. 241 -4. 58
Detoxification: Withdrawal of Opioids • Most patients will perceive withdrawal symptoms. • May be possible to reduce the drug. • Methadone is suitable for suppressing withdrawal symptoms. • With methadone substitution in an in-patient setting, symptoms usually aren't worse than "flu-like" syndrome. • Under these "drug weaning" conditions, most patients can be withdrawn in less than 10 days. • Clonidine ( 2 -adrenergic receptor agonist) can suppress some components of opioid withdrawal. • Clonidine suppresses autonomic signs and symptoms (e. g. , nausea, vomiting, diarrhea) then drug craving. 241 -4. 59
Withdrawal of Neurodepressants • Abrupt neurodepressant withdrawal can be fatal. • Pentobarbital can be substituted for any neurodepressant. • Pentobarbital is administered to induce mild intoxication and maintained 24 to 36 hrs and stabilized, then withdrawal can be started. 241 -4. 60
Role of Pharmacological Agents Following Withdrawal • Therapeutics may be used to treat underlying psychological problem (e. g. , anxiety or depression). • Therapeutic agents intended to be a less toxic substitute (e. g. , methadone) may be used. • Drugs to interfere with reinforcing actions of the abused drug (e. g. , naltrexone). 241 -4. 61
Pharmacological Approach to Cocaine and Amphetamine Dependence • Most consistent pharmacotherapy has been obtained with tricyclic antidepressants (e. g. , desipramine). • After 1 to 2 weeks, desipramine appears to reduce craving for cocaine. • It is postulated that the antidepressants increase functional activity in reward systems by altering cocaine-induced supersensitivity at dopamine autoreceptors. 241 -4. 62
Drugs of Abuse and How Their Effects Might Theoretically Be Treated Mechanism Involved Main Neurotransmitter Affected Potential Treatment Action on endogenous receptors for endogenous ligands Opioids Endorphins, enkephalins Alcohol GABA, endorphins Benzodiazepines & barbiturates Nicotine Cannabinoids LSD and related hallucinogens GABA Acetylcholine ? Anandamide 5 -HT Partial agonist (e. g. , buprenorphine) Antagonists (e. g. , naltrexone) Partial agonists (e. g. , bretazenil) Opiate antagonists (e. g. , naltrexone) Partial agonists (e. g. , bretazenil Antagonists (e. g. , flumazenil) Antagonists (? mecamylamine) Antagonists (e. g. , SR 141716 A) 5 -HT 2 receptor antagonists (e. g. , ritanserin) Increasing the release of endogenous neurotransmitters Cocaine Dopamine Solvents ? Noradrenaline Antagonizing the action of natural transmitters Alcohol Glutamate D 2 receptor antagonist* Antagonist of the uptake site (e. g. , SSRI) ? Receptor antagonists NMDA antagonists (e. g. , dizocilpine) *Most typical (e. g. , haloperidol) and atypical (e. g. , sulpiride, tiapride, risperidone) neuroleptics have a high affinity for D 2 receptors. 241 -4. 63
Pharmacotherapy for Drug Abuse Relapse Prevention Drug • Natrexone (Trexan) – opioid and alcohol dependency • Disulfiram (Antabuse) – alcohol dependency • Clonidine (Catapres) – opioid withdrawal • Methadone (Dolophine) – opioid dependency • Buprenorphine (Buprenex) – opioid dependency • Nicotine – patches and gum • Ibogaine (Endabuse) - anticraving • Acamprosate – anti-alcohol craving • Immunization (experimental animals) - Morphine - Cocaine 241 -4. 64
Modification of Behavior After Withdrawal Psychotherapy • Little evidence that traditional individual psychotherapy is of value for compulsive drug user. • Cognitive or expressive psychotherapy has improved poor prognosis patients in methadone programs. • Special forms of group therapy and self-help groups have been demonstrated to reduce relapse. Voluntary Groups and Self-Regulatory Communities • Alcoholic anonymous, narcotics anonymous, Phoenix House, etc. Supervised-Deterrent Approaches • Abstinence during a period in a hospital, prison, or special facility followed by supervision in the community. 241 -4. 65
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