Dep add sa

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 addiction is not a
disease?

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?

• Define Disease
dis·ease [dih-zeez] noun, verb, -eased, -eas·ing.
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/Disease

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


• 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


• 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


• 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?


• 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 & 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


• 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


• 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

• 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

• 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

SHORT Half-Life

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

A&B: Variation in
frequency

C: Increased dose

LONG Half-Life

D & E: Variation in
frequency

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


• 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?


• 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


– 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

– 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?

• 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

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

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


• 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


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

Neuroanatomy of Motivation and
Reinforcement

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

Defining Abuse Liability
FDA Definition

‘‘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
consequences’’

N.A. Ator, R.R. Griffiths / Drug and Alcohol Dependence 70 (2003) S55!/S72

Determining Abuse Liability

Behavioral data the FDA requests for preclinical abuse
liability assessment: reinforcing, discriminative, and
physical-dependence producing properties of the drug


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 drug
withdrawal after chronic use, which are important both for determining
whether a gradual drug cessation regimen should be designed for clinical
use and for
considering whether a withdrawal syndrome might contribute to extra-
therapeutic drug use



• 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

Dependence, Addiction and the
Self-Administration of Drugs
Drug 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 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

– 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


– 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 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


• 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


• 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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