dep add sa

Drugs & Behavior

Dependence (a.k.a. Addiction)
& Withdrawal

Addiction or Drug DependenceIs addiction a disease?

What does addiction as a disease imply?

What is implied if addiction is not a disease?

Addiction as A DiseaseHow do you qualify or disqualify addiction is a disease?

Is cancer a disease?

Are mental illnesses, such as schizophrenia, major depressive disorder, etc., diseases?

Addiction as A DiseaseDefine Disease

disease [dih-zeez] noun, verb, -eased, -easing. noun 1. 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

Definition

noun, plural: diseases An 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/DiseaseAddiction as A Disease

History of Addiction ResearchAddiction as a Disease: background

1870 American Association for the Cure of InebriatesAddiction/intemperance/inebrietyMedical Profession involved in Problems with Morphine & Opium (laudenum)

Mid-20th Century Alcoholics AnonymousE.M. Jellinek: Alcohol Addiction

1951 WHOAlcoholism declared a disease

1953 American Medical AssociationAddiction as Disease

Dependence, Addiction, and Self Administration

History of Addiction ResearchAddiction as a Disease: background

American Psychiatric AssociationDisease / Disorder Model DSM IVSubstance AbuseSubstance Dependence

WHO, International Classification of DiseasesICD-10Harmful UseDependence SyndromeIncludes: chronic alcoholism and drug addiction


Theories in Support of Disease Model

Predisposition: congenital or acquired; addiction develops after usingJellinek, first to propose alcoholism is not caused by alcohol, but rather it is inheritedGenetic predispositionMetabolic differences increase/decrease sensitivity to drug

Exposure: addiction is a disease caused by repeated exposure to a drugAlan Leshner, NIDA OOPS Phenomenonhttp://www.nida.nih.gov/Published_Articles/Oops.html


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-injuriousDo we agree with this reasoning?What person in control of their behavior (in a non-diseased state) would choose to harm themselves?


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


Physiological Dependence & WithdrawalAddiction as Physiological DependenceBackground

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

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 discomfortPrimary & Secondary


Physiological Dependence & WithdrawalAbstinence SyndromeWithdrawal: 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 cant 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

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 actionAnxiety, sleep-disturbances, convulsions

Opiates: constipation, dry nasal passage, sleep-induction, reduced sex-drive, analgesiaDiarrhea, runny nose, sleep-disturbances, spontaneous ejaculation or orgasm, hyperalgesia

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 effectsInfrequent 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 effectsDue 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



SHORT Half-Life

A, B, C: Same drug with different self- administration patterns

A&B: Variation in frequency

C: Increased doseLONG Half-Life

D & E: Variation in frequency

Physiological Withdrawal & Psychological DependenceSecondary Psychological DependencePersons 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

Psychological Dependence

Primary Psychological DependenceDrug taking becomes habitual (not the same as habituation)Primarily the result of learning and memory processesAffective states underlying it are influenced by contextCounterpart to Context-Specific Tolerance Drug taking is regularly followed by rewarding effects of drugReliable 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?


The Neuroanatomy of Motivation and ReinforcementOlds and Milner (1954) ExperimentReinforcement CentersMotivation Control System of the BrainVentral tegmental area (VTA)Nucleus accumbensMesolimbic dopamine systemMotor loopLearning and memory system



Mesocorticolimbic dopamine system & natural rewardFeelings of pleasure including sex, chocolate, falling in love, monetary reward, winning money

Brain Stimulation Reward Studies & MicroinjectionsDelivery of electrical stimulation or microinjection of drug to mesolimbic system reinforces various behaviors



Mesocorticolimbic dopamine system Inconsistent results found in NucAcc

DA antagonists and depletionImpairs performance on appetitive and aversively motivated tasksNatural Rewards: food, water, sexStressful Stimuli: anxiety provoking drugs, tail-pinch, foot-shock, immobilizationFood reinforcement, motivation, appetite left in tact

Not all drugs of abuse enhance DA system in same wayBenzodiazepines reduce DA in NucAcc; moderate dependence liability

Other human compulsive behaviors; gambling, overeating, sex addiction, compulsive shoppingBrain of OCD and Addiction Similar?


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 rewardsAddiction: withdrawal-induced anhedonia - dopamine down-regulation

Reward-Learning (Schultz & Dickinson, 2000)Addiction: abnormal neural learningExaggerated predictions about reward or excessive drug-taking habits



Which hypotheses have been proposed to explain addiction?

Incentive-Salience (Robinson & Berridge, 2001)DA modulates incentive value of reward stimuliDA results in rewards being more wanted, not necessarily more likedAddiction: sensitization of mesolimbic system; excessive wanting to consume drugs

DA involved in Generalized FunctionsAttention MotivationIntegration of sensory and motor activities, which are involved in mediating both aversive and rewarding stimuli


The Neuroanatomy of Motivation and ReinforcementWanting Versus Liking in ReinforcementPleasure 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 valuethe 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


Incentive Sensitization Theory; Robinson & BerridgeDrug Craving (wanting)The desire to experience the effect(s) of a previously experienced psychoactive substance.Subjective stateDesire is excessive in addicted personsCravings result from sensitization of DA system to effects of drugsSensitization leads to stronger reinforcement and greater incentive value



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 NucAccGABAergic system of NucAcc and VTA that normally suppress DA firing


Neuroanatomy of Motivation and Reinforcement

The Neuroanatomy of Motivation and ReinforcementReinforcing Effects of DrugsGlutamate, GABA, Dopamine Mediated via VTA and Nucleus AccumbensSame system of natural rewards but natural reinforcers have a satiating mechanism that terminates their reinforcing effectImmediacy of reward and strength of drugs ability to activate DA system greater than in natural rewards

Stress and ReinforcementStress, both present and in the past, increases the strength for reinforcing stimulus.Glucocorticoid hormones cause release of DA in Nuc Acc


The term abuse liability refers to the likelihood that a drug with anabolic, psychoactive or central nervous system (CNS) effects will sustain patterns of non-medical self administration (SA) that result in disruptive or undesirable consequencesN.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72Defining Abuse LiabilityFDA Definition

Determining Abuse LiabilityBehavioral data the FDA requests for preclinical abuse liability assessment: reinforcing, discriminative, and physical-dependence producing properties of the drugN.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72

Determining Abuse Liability

Reinforcing: will your drug maintain extra-therapeutic drug seeking and drug taking

Discriminative: how similar are the interoceptive stimulus effects (i.e., the sense of physiological condition of the body) of your drug to other psychoactive compounds, including those currently marketed for the intended indication

Physical-dependence assessments: provide data on the effects of abrupt drugwithdrawal after chronic use, which are important both for determining whether a gradual drug cessation regimen should be designed for clinical use and forconsidering whether a withdrawal syndrome might contribute to extra-therapeutic drug useN.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72

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 BehaviorAnimals will work to shut off stimulus that predicts LSD, antipsychotics, and some antidepressants


Dependence, Addiction and the
Self-Administration of DrugsDrug Self-Administration in Animals

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 drugsCan the animal physically respond or does the drug cause over-responding due to stimulant properties

Schedule of ReinforcementFixed Ratio, Fixed Interval, Progressive Ratio, Variable Ratio, Variable Interval

Progressive RatioStart with FR10 and increase up to FR100Breaking pointOrganism will stop responding because demand is too high


Choice2 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

Dependence, Addiction, and Self AdministrationChoose between levers will determine which drug is more reinforcing

Place Conditioning: Animal will spend time in area of reinforcement


Self-Administration in Humans & non-Humans

Operant tasks in a token society?


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 DelayConsequence has diminished ability to control behavior.The reinforcement value of the available drug is perceived as greater than any value of future eventsGuides our choices


Factors That Alter the Reinforcing Value of DrugsReinforcing Value of Different DrugsAbuse potentialAbuse liabilityDose of DrugGenetic DifferencesRelief of Unpleasant SymptomsTask DemandsStress


Factors that Alter the Reinforcing Value of DrugsOther Deprivations and MotivationsHungerPrevious Experience with Other DrugsPrevious Experience with the Same DrugPhysical Dependence (withdrawal)Priming (relapse)Conditioned ReinforcementSecond-Order SchedulesEnvironmental Stimuli (CSs) trigger craving, relapse, conditioned withdrawal and conditioned tolerance


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