Dependence (a.k.a. Addiction)       & Withdrawal
Addiction or Drug Dependence• Is addiction a disease?• What does addiction as a disease imply?• What is implied if addicti...
Addiction as A Disease• How do you qualify or disqualify addiction  is a disease?• Is cancer a disease?• Are mental illnes...
Addiction as A Disease• Define Diseasedis·ease [dih-zeez] noun, verb, -eased, -eas·ing.noun1. a disordered or incorrectly ...
Addiction as A Disease•  Definitionnoun, plural: diseasesAn abnormal condition of an organism which interrupts the normal ...
Dependence, Addiction, and Self Administration  • History of Addiction Research    – Addiction as a Disease: background   ...
Dependence, Addiction, and Self Administration  • History of Addiction Research    – Addiction as a Disease: background   ...
Dependence, Addiction, and Self Administration • Theories in Support of Disease Model   – Predisposition: congenital or ac...
Dependence, Addiction, and Self Administration • Defining Addiction • What is drug dependence / addiction?   – Uncontrolla...
Dependence, Addiction, and Self Administration • How do we diagnose substance dependence   and substance abuse?   – Both a...
Physiological Dependence & Withdrawal• Addiction as Physiological Dependence  – Background     • Autotoxin: hypothetical o...
Dependence, Addiction, and Self Administration • Characterization of Two Primary Types of   Dependence:   – Physiological ...
Physiological Dependence & Withdrawal• Abstinence Syndrome  – Withdrawal: physiological changes that occur    when the use...
Physiological Dependence & Withdrawal• Why do withdrawal symptoms occur?  – Compensatory mechanisms (i.e., tolerance    me...
Physiological Dependence & Withdrawal• Relationship between duration and intensity of drugs effects,  duration and intensi...
Physiological Dependence & WithdrawalSHORT Half-LifeA, B, C: Same drugwith different self-administration patternsA&B: Vari...
Physiological Withdrawal &          Psychological Dependence• Secondary Psychological Dependence  – Person’s fear or anxie...
Dependence, Addiction, and Self Administration • Psychological Dependence    – Primary Psychological Dependence       • Dr...
Dependence, Addiction, and Self Administration   • The Neuroanatomy of Motivation and     Reinforcement     – Olds and Mil...
Dependence, Addiction, and Self Administration • Psychological Dependence   – Mesocorticolimbic dopamine system & natural ...
Dependence, Addiction, and Self Administration• Psychological Dependence  – Mesocorticolimbic dopamine system     • Incons...
Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA   system: •   Which...
Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA   system: •   Which...
Dependence, Addiction, and Self Administration • The Neuroanatomy of Motivation and   Reinforcement    – “Wanting” Versus ...
Dependence, Addiction, and Self Administration • Incentive Sensitization Theory; Robinson &   Berridge • Drug Craving (wan...
Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA   system: • What is...
Neuroanatomy of Motivation and       Reinforcement
Dependence, Addiction, and Self Administration • The Neuroanatomy of Motivation and   Reinforcement   – Reinforcing Effect...
Defining Abuse Liability                           FDA Definition‘‘The term ‘abuse liability’ refers to the likelihood tha...
Determining Abuse LiabilityBehavioral data the FDA requests for preclinical abuseliability assessment: reinforcing, discri...
Determining Abuse LiabilityReinforcing: will your drug maintain extra-therapeutic drug seeking anddrug takingDiscriminativ...
Dependence, Addiction, and Self Administration • Positive Reinforcement:    • What is it?       •   Positive reinforcing s...
Dependence, Addiction and the Self-Administration of Drugs Drug Self-Administration in Animals
Dependence, Addiction, and Self Administration • Measuring the Reinforcing Value of Drugs   – Rate of Responding:      – l...
Dependence, Addiction, and Self Administration – Choice • 2 levers; one has   consequences • Drug A delivered by   pressin...
Dependence, Addiction, and Self Administration   – Place Conditioning: Animal will spend time in     area of reinforcement
Dependence, Addiction, and Self Administration • Self-Administration in Humans & non-Humans   • Operant tasks in a token s...
Dependence, Addiction, and Self Administration • Positive Reinforcement Paradox:    • How can self-administration of a dru...
Dependence, Addiction, and Self Administration  • Factors That Alter the Reinforcing Value    of Drugs    – Reinforcing Va...
Dependence, Addiction, and Self Administration  • Factors that Alter the Reinforcing Value of    Drugs    – Other Deprivat...
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  1. 1. Dependence (a.k.a. Addiction) & Withdrawal
  2. 2. Addiction or Drug Dependence• Is addiction a disease?• What does addiction as a disease imply?• What is implied if addiction is not a disease?
  3. 3. Addiction as A Disease• How do you qualify or disqualify addiction is a disease?• Is cancer a disease?• Are mental illnesses, such as schizophrenia, major depressive disorder, etc., diseases?
  4. 4. Addiction as A Disease• Define Diseasedis·ease [dih-zeez] noun, verb, -eased, -eas·ing.noun1. a disordered or incorrectly functioning organ, part, structure, or system of the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional deficiency or imbalance, toxicity, or unfavorable environmental factors; illness; sickness; ailment.2. any abnormal condition in a plant that interferes with its vital physiological processes, caused by pathogenic microorganisms, parasites, unfavorable environmental, genetic, or nutritional factors, etc.3. any harmful, depraved, or morbid condition, as of the mind or society: His fascination with executions is a disease.4. decomposition of a material under special circumstances: tin disease.Dictionairy.com
  5. 5. Addiction as A Disease• Definitionnoun, plural: diseasesAn abnormal condition of an organism which interrupts the normal bodily functions that often leads to feeling of pain and weakness, and usually associated with symptoms and signs.A pathologic condition in which the normal functioning of an organism or body is impaired or disrupted resulting in extreme pain, dysfunction, distress, or death.http://www.biology-online.org/dictionary/Disease
  6. 6. Dependence, Addiction, and Self Administration • History of Addiction Research – Addiction as a Disease: background • 1870 American Association for the Cure of Inebriates – Addiction/intemperance/inebriety – Medical Profession involved in Problems with Morphine & Opium (laudenum) • Mid-20th Century Alcoholics Anonymous • E.M. Jellinek: Alcohol Addiction • 1951 WHO • Alcoholism declared a disease • 1953 American Medical Association • Addiction as Disease
  7. 7. Dependence, Addiction, and Self Administration • History of Addiction Research – Addiction as a Disease: background • American Psychiatric Association • Disease / Disorder Model – DSM IV » Substance Abuse » Substance Dependence • WHO, International Classification of Diseases • ICD-10 • Harmful Use • Dependence Syndrome • Includes: chronic alcoholism and drug addiction
  8. 8. Dependence, Addiction, and Self Administration • Theories in Support of Disease Model – Predisposition: congenital or acquired; addiction develops after using • Jellinek, first to propose alcoholism is not caused by alcohol, but rather it is inherited • Genetic predisposition • Metabolic differences increase/decrease sensitivity to drug – Exposure: addiction is a disease caused by repeated exposure to a drug • Alan Leshner, NIDA “OOPS Phenomenon” • http://www.nida.nih.gov/Published_Articles/Oops.html
  9. 9. Dependence, Addiction, and Self Administration • Defining Addiction • What is drug dependence / addiction? – Uncontrollable and unpleasant mood states leading to compulsive drug seeking and taking despite negative consequences (ICD-10 and DSM) • Out of control and self-injurious – Do we agree with this reasoning? – What person in control of their behavior (in a non-diseased state) would choose to harm themselves?
  10. 10. Dependence, Addiction, and Self Administration • How do we diagnose substance dependence and substance abuse? – Both are maladaptive patterns of substance use leading to clinically significant impairment or distress – Dependence requires 3 criteria be met within 12 month period whereas abuse requires 1 or more be met within 12 month period • What is the differential diagnosis between the two? – Tolerance, withdrawal, persistent desire or unsuccessful efforts to cut down, and time spent in activities necessary to obtain the drug
  11. 11. Physiological Dependence & Withdrawal• Addiction as Physiological Dependence – Background • Autotoxin: hypothetical opium metabolite to explain sickness • Withdrawal or Abstinence Syndrome: avoidance of withdrawal still used to explain compulsive drug taking • Physical or Physiological Dependence: described state in which cessation or reduction of drug taking caused withdrawal • Dependence: to describe physiological dependence and compulsive drug taking • Tolerance: necessary condition for physical dependence
  12. 12. Dependence, Addiction, and Self Administration • Characterization of Two Primary Types of Dependence: – Physiological Dependence: precipitation of abstinence syndrome which is characterized by physical disturbances when drug usage stops after a period of prolonged use or actions of drug are halted by antagonist – Psychological Dependence: strong compulsion or desire to experience effects of drug that produces pleasure or reduces psychic discomfort • Primary & Secondary
  13. 13. Physiological Dependence & Withdrawal• Abstinence Syndrome – Withdrawal: physiological changes that occur when the use of a drug is stopped or when dosage is decreased • Expression of the adjustment the body has made to a drug (i.e., tolerance) • You can’t have withdrawal without tolerance but you can have tolerance without withdrawal• Cross-dependence: when a drug of the same family is administered and can stop withdrawal symptoms
  14. 14. Physiological Dependence & Withdrawal• Why do withdrawal symptoms occur? – Compensatory mechanisms (i.e., tolerance mechanisms) to drug last after drug usage stops• What do withdrawal symptoms usually look like? – Opposite of drugs effects – Barbiturates: calming, sleep-inducing, anticonvulsant action • Anxiety, sleep-disturbances, convulsions – Opiates: constipation, dry nasal passage, sleep- induction, reduced sex-drive, analgesia • Diarrhea, runny nose, sleep-disturbances, spontaneous ejaculation or orgasm, hyperalgesia
  15. 15. Physiological Dependence & Withdrawal• Relationship between duration and intensity of drugs effects, duration and intensity of abstinence syndrome, and pattern of self-administration• Short half-life (i.e. 4 hrs) intense but short lasting behavioral effects – Infrequent use followed by cessation will likely not lead to abstinence syndrome – Frequent use and increased dosage followed by cessation will likely lead to fairly intense but short lasting abstinence syndrome• Long half-life (i.e., 24 hrs) weak but long lasting behavioral effects – Due to a longer half-life, while the drug is still in the system, cessation produces relatively milder abstinence syndrome – The duration of syndrome can be longer when administration of drug was more frequent
  16. 16. Physiological Dependence & WithdrawalSHORT Half-LifeA, B, C: Same drugwith different self-administration patternsA&B: Variation infrequencyC: Increased dose LONG Half-Life D & E: Variation in frequency
  17. 17. Physiological Withdrawal & Psychological Dependence• Secondary Psychological Dependence – Person’s fear or anxiety of experiencing abstinence syndrome after physical dependence has already developed• This is not a fully accepted notion to explain withdrawal and dependence. Why? – Many drugs of abuse that people compulsively take do not lead to abstinence syndrome, or withdrawal is short lived – Relapse in drug taking behavior with drugs that only cause mild physical dependence, or after withdrawal is over – People often quit drugs that cause physical dependence
  18. 18. Dependence, Addiction, and Self Administration • Psychological Dependence – Primary Psychological Dependence • Drug taking becomes habitual (not the same as habituation) • Primarily the result of learning and memory processes • Affective states underlying it are influenced by context – Counterpart to Context-Specific Tolerance • Drug taking is regularly followed by rewarding effects of drug – Reliable prediction about reward or expectation of reward – What motivates a person to take drugs? • Enhance mood or performance, stress, socialize, conform, expand experiential awareness – Which of these motives are predictive of excessive use and problems?
  19. 19. Dependence, Addiction, and Self Administration • The Neuroanatomy of Motivation and Reinforcement – Olds and Milner (1954) Experiment • Reinforcement Centers – Motivation Control System of the Brain • Ventral tegmental area (VTA) • Nucleus accumbens • Mesolimbic dopamine system • Motor loop • Learning and memory system
  20. 20. Dependence, Addiction, and Self Administration • Psychological Dependence – Mesocorticolimbic dopamine system & natural reward • Feelings of pleasure including sex, chocolate, falling in love, monetary reward, winning money – Brain Stimulation Reward Studies & Microinjections • Delivery of electrical stimulation or microinjection of drug to mesolimbic system reinforces various behaviors
  21. 21. Dependence, Addiction, and Self Administration• Psychological Dependence – Mesocorticolimbic dopamine system • Inconsistent results found in NucAcc • DA antagonists and depletion – Impairs performance on appetitive and aversively motivated tasks » Natural Rewards: food, water, sex » Stressful Stimuli: anxiety provoking drugs, tail-pinch, foot-shock, immobilization – Food reinforcement, motivation, appetite left in tact 4.Not all drugs of abuse enhance DA system in same way – Benzodiazepines reduce DA in NucAcc; moderate dependence liability • Other human compulsive behaviors; gambling, overeating, sex addiction, compulsive shopping – Brain of OCD and Addiction Similar?
  22. 22. Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA system: • Which hypotheses have been proposed to explain drug addiction? – Hedonia (Wise, 1998) • DA mediates sensory pleasure of food, drugs, and other rewards • Addiction: withdrawal-induced anhedonia - dopamine down- regulation – Reward-Learning (Schultz & Dickinson, 2000) • Addiction: abnormal neural learning • Exaggerated predictions about reward or excessive drug-taking habits
  23. 23. Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA system: • Which hypotheses have been proposed to explain addiction? – Incentive-Salience (Robinson & Berridge, 2001) • DA modulates incentive value of reward stimuli • DA results in rewards being more wanted, not necessarily more liked • Addiction: sensitization of mesolimbic system; excessive wanting to consume drugs – DA involved in Generalized Functions • Attention • Motivation • Integration of sensory and motor activities, which are involved in mediating both aversive and rewarding stimuli
  24. 24. Dependence, Addiction, and Self Administration • The Neuroanatomy of Motivation and Reinforcement – “Wanting” Versus “Liking” in Reinforcement • “Pleasure Centers” resulted because people “liked” stimulus but this is misleading and subjective • Presentation of the stimuli will actually come to activate the DA system rather than the stimuli themselves; • stimuli acquire incentive value • the stimuli themselves become wanted (i.e., attractive motivational properties of a lever) • Pleasure is a subjective by-product of activating a “do-it- again” system (DA system) • Wanting opposed to liking
  25. 25. Dependence, Addiction, and Self Administration • Incentive Sensitization Theory; Robinson & Berridge • Drug Craving (wanting) • The desire to experience the effect(s) of a previously experienced psychoactive substance. • Subjective state • Desire is excessive in addicted persons • Cravings result from sensitization of DA system to effects of drugs • Sensitization leads to stronger reinforcement and greater incentive value
  26. 26. Dependence, Addiction, and Self Administration • Psychological Dependence and the Mesocorticolimbic DA system: • What is the consensus that has been reached? – The mesocorticolimbic DA system is crucial to motivational incentive functions • What other neurotransmitter systems are involved in psychological dependence or compulsive drug-seeking? – Glutamatergic projections from pre-frontal cortex and AMY to NucAcc – GABAergic system of NucAcc and VTA that normally suppress DA firing
  27. 27. Neuroanatomy of Motivation and Reinforcement
  28. 28. Dependence, Addiction, and Self Administration • The Neuroanatomy of Motivation and Reinforcement – Reinforcing Effects of Drugs – Glutamate, GABA, Dopamine Mediated via VTA and Nucleus Accumbens – Same system of natural rewards but natural reinforcers have a satiating mechanism that terminates their reinforcing effect – Immediacy of reward and strength of drug’s ability to activate DA system greater than in natural rewards – Stress and Reinforcement • Stress, both present and in the past, increases the strength for reinforcing stimulus. • Glucocorticoid hormones cause release of DA in Nuc Acc
  29. 29. Defining Abuse Liability FDA Definition‘‘The term ‘abuse liability’ refers to the likelihood that adrug with anabolic, psychoactive or central nervous system(CNS) effects will sustain patterns of non-medical selfadministration (SA) that result in disruptive or undesirableconsequences’’ N.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72
  30. 30. Determining Abuse LiabilityBehavioral data the FDA requests for preclinical abuseliability assessment: reinforcing, discriminative, andphysical-dependence producing properties of the drug N.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72
  31. 31. Determining Abuse LiabilityReinforcing: will your drug maintain extra-therapeutic drug seeking anddrug takingDiscriminative: how similar are the interoceptive stimulus effects (i.e., thesense of physiological condition of the body) of your drug to otherpsychoactive compounds, including those currently marketed for theintended indicationPhysical-dependence assessments: provide data on the effects ofabrupt drugwithdrawal after chronic use, which are important both for determiningwhether a gradual drug cessation regimen should be designed for clinicaluse and forconsidering whether a withdrawal syndrome might contribute to extra-therapeutic drug use N.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72
  32. 32. Dependence, Addiction, and Self Administration • Positive Reinforcement: • What is it? • Positive reinforcing stimuli will increases rate of response on which it is dependent • Do stimuli that act as positive reinforcers always give us pleasure? • Aversive Stimuli can Increase Incidence of Behavior • Animals will work to shut off stimulus that predicts LSD, antipsychotics, and some antidepressants
  33. 33. Dependence, Addiction and the Self-Administration of Drugs Drug Self-Administration in Animals
  34. 34. Dependence, Addiction, and Self Administration • Measuring the Reinforcing Value of Drugs – Rate of Responding: – long acting drugs may be highly reinforcing but produce lower rates of responding than short-acting drugs – Can the animal physically respond or does the drug cause over-responding due to stimulant properties – Schedule of Reinforcement – Fixed Ratio, Fixed Interval, Progressive Ratio, Variable Ratio, Variable Interval – Progressive Ratio • Start with FR10 and increase up to FR100 • Breaking point – Organism will stop responding because demand is too high
  35. 35. Dependence, Addiction, and Self Administration – Choice • 2 levers; one has consequences • Drug A delivered by pressing left lever, saline delivered by pressing right lever • Drug B delivered by pressing right lever, saline delivered by pressing left lever • Choose between levers will determine which drug is more reinforcing
  36. 36. Dependence, Addiction, and Self Administration – Place Conditioning: Animal will spend time in area of reinforcement
  37. 37. Dependence, Addiction, and Self Administration • Self-Administration in Humans & non-Humans • Operant tasks in a token society?
  38. 38. Dependence, Addiction, and Self Administration • Positive Reinforcement Paradox: • How can self-administration of a drug be both positively reinforcing enough to make people continue to use it, but aversive enough to motivate people to stop? • When do the punishing and painful consequences occur compared to the positive reinforcing effects? • Behavioral Economics Discount of Delay • Consequence has diminished ability to control behavior. • The reinforcement value of the available drug is perceived as greater than any value of future events • Guides our choices
  39. 39. Dependence, Addiction, and Self Administration • Factors That Alter the Reinforcing Value of Drugs – Reinforcing Value of Different Drugs • Abuse potential • Abuse liability – Dose of Drug – Genetic Differences – Relief of Unpleasant Symptoms – Task Demands – Stress
  40. 40. Dependence, Addiction, and Self Administration • Factors that Alter the Reinforcing Value of Drugs – Other Deprivations and Motivations • Hunger – Previous Experience with Other Drugs – Previous Experience with the Same Drug – Physical Dependence (withdrawal) – Priming (relapse) – Conditioned Reinforcement – Second-Order Schedules • Environmental Stimuli (CSs) trigger craving, relapse, conditioned withdrawal and conditioned tolerance

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