Principle and Biological Basis of Substance Abuse and Dependence

Question 1

DSM-IV

Answer 1

1994
Defined substance abuse separate from substance dependence.
3 of the 7 criteria met for dependence.
1 of 4 criteria met for abuse.
Difficulty in diagnosis and properly ID individuals and their substance problems.
Substance abuse: A diagnosis which is applied when the person does not meet the criteria for a diagnosis of “substance dependence” but does persistently use the substance in a way which is “potentially harmful”, either to themselves or to others.
Substance abuses criteria: failure to fulfill major role obligation, physically hazardous, legal problems, use despite social or interpersonal problems.
A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by one (or more) of the criteria occurring within a 12 month period.

Question 2

DSM-V

Answer 2

Addressed the problems in DSM-IV.
Combines substance abuse and substance dependence from DSM-IV into a single disorder (Substance Abuse Disorder) for each substance.
Graded clinical severity.
2 criteria required to make a diagnosis.

Question 3

Variables that influence the likelihood that a beginning drug user will lose control and develop an addiction

Answer 3

Agent (drug)
Host (user)
Environment

Question 4

Reinforcement- Agent variable

Answer 4

Drugs that reliably produce euphoria are more likely to be taken repeatedly.
Capacity of drugs to produce effects that make the user wish to take them again.
Stronger reinforcing a drug is the greater likelihood that the drug will be abused.
Associated with drug capacity to increase neuronal activity in critical brain areas: increase DA levels in the ventral striatum (nucleus accumbens); smaller increases in DA in the nucleus accumbens also are observed.
Drugs that block DA receptors generally produce dysphoric effects.
Causal relationship between DA and euphoria/dysphoria has not been established.

Question 5

Abuse Liability (addictive potential)- Agent variable

Answer 5

Enhanced by rapidity of onset= increased desire to use.
Effects that occur soon after administration, more likely to start events that leads to loss of control over drug taking.
PK variables: influence the time it takes a drug to reach critical receptor sites in the brain where you see the effect; fastest onset through IV injection and inhalation/smoking.

Question 6

Genetic influences in Alcoholism- Host variable

Answer 6

Children of alcoholics are more likely to develop alcoholism, even when adopted at birth and raised by nonalcoholic parents.
Not 100% determinism; polygenic disorder that has multiple determinants.
Identical twins don’t have 100% concordance when one twin is an alcoholic, the rate for identical is much higher than for fraternal.
Abuse of alcohol and other drugs tends to have some familial characteristics-suggests a common mechanism.

Question 7

Innate Tolerance to Alcohol- Host variable

Answer 7

Genetically determined lack of sensitivity to a drug that is observed the first time.
Measured by level of response to alcohol administered under experimental conditions.
Biological traits that contributes to the development of alcoholism.
Tolerance- need to take more drug 2nd time than first time to get the same effect.
Impaired metabolism may protect; Asian, native american, eskimo populations have decreased levels of acetaldehyde DH=increased levels of acetaldehyde, which is toxic and makes you feel sick and flush, they are less likely to become alcoholic. less innate tolerance.; homozygous for the gene variant.
North Europeans have higher levels of enzymes responsible for metabolizing ethanol, less likely to get hangovers, so they can drink more and not wake up drunk, all of the ethanol is being metabolized at a higher rate.
Individuals who inherit a gene associated with slow nicotine metabolism; may experience unpleasant effects when beginning to smoke and have a lower chance of becoming nicotine dependent.

Question 8

Psychiatric Disorders- Host variable

Answer 8

Drugs may produce immediate, subjective, effects that receive preexisting symptoms like anxiety, depression, shyness.
Comorbid condition- drugs make you feel better.
Apparent beneficial effects are transient. repeated use of the drug may lead to tolerance, eventually compulsive uncontrolled drug use.
Psychiatric symptoms are seen commonly in drug abusers; most of these symptoms begin after the person starts abusing drugs- drugs of abuse appear to produce more psychiatric symptoms than they relieve.

Question 9

Environmental Variables

Answer 9

Societal norms and peer pressure.

1. Taking drugs initially- form of rebellion against authority.
2. Drugs users and dealers in some communities; role models, young people emulate them, lower SES, not al to of other options for pleasure.

Question 10

Positive Reinforcement-Early Use

Answer 10

The drug makes you “feel good.”

Produces a high.

Question 11

Negative Reinforcement- Early Use

Answer 11

The drug makes you feel “less bad.”

The drug ameliorates pre-exiting unpleasant feelings.

Question 12

Long Term Use

Answer 12

1. Tolerance develops and a persons can’t get high; the dose required to get high produces intolerable side effects, is too expensive, but the person continues to use compulsively and spend all their money.
2. The person can continue to get high; continue compulsive drug use even though it is totally destroying their life.
   Why compulsive drug use- it hurts but continue to use?
   Fear of physical and/or physiological withdrawal symptoms; but, withdrawal effects from some drugs are not that serious, and people who have already gone through withdrawal start using again.
   Pathologically high level of the substances “incentive salience” or craving; increased incentive salience DOES NOT tolerate out, but gets stronger with continued use.
   This incentive salience is not the same as liking the pleasurable effects of the substance; this pathological wanting seems to be very important component of addiction.

Question 13

Chemical Reinforcement-Primary Reinforcers

Answer 13

1. “Strength” or intensity of each reinforcement; greater effect is more likely to gain control over your behavior-substance makes you feel really good or really less bad.
2. Frequency of reinforcement; higher frequency gives more power of control over behavior.

Question 14

Chemical Reinforcement- Secondary Reinforcers

Answer 14

Factors associated with drug use which after many repetitions begin to take on some of the reinforcing properties of the drug itself.
Exposure to secondary reinforcers increased wanting of the drug even in the absence of intent to take the drug.
1. Seeing, tasting, or smelling the drug or similar substance.
2. The ritual associated with using the drug.
3. The environment associated with drug taking.
4. The people with whom I usually take the drug.

Question 15

IV “self-administration” test

Answer 15

Test to test the reinforcing power and subjective effects of a potential new drug to produce abuse and dependence.
Used with rates and monkeys.
If the animal will “work” (press a lever) to obtain an IV injection of a drug, the drug is reinforcing.
Apparatus: Skinner box, lever, implant/pump system.
Press lever, get cocaine.
If you cut the dose on half from what the rat was trained on, it will double up on the amount of times it presses the lever for the drug.
Raising the unit dose decreases the number of infusions.
Adding a DA antagonist also increases the number of self administered infusions, but the rat cannot get the effect.
Breakpoint determination: can measure the drugs reinforcing potency; all drugs except hallucinogenics are active in this model.
With varying doses, the amount of responses the animal gave before it was too much work to push the lever for the drug, so they stopped.

Question 16

Drug Discrimination

Answer 16

Does not tell us anything about reinforcing potency.
It DOES tell you whether the internal sensation produced by a test drug is similar to that produced by a reference standard.
T-maze apparatus; electrified grid, safe areas to the left and right that can be made not to provide a shock.
Inject rat with reference drug and place it on the electrified grid: the rat runs around and finds it can escape shock by going into right hand safe box.
Next day, the rat is injected with saline and the safe box is moved to the left side.
The rate eventually learns… when it feels like the reference drug, it goes to the right side; when it fees like something else (or nothing), it goes to the let side.
Then, inject the test drug and see which way the rat runs.

Question 17

Conditioned Place Preference Test

Answer 17

Tells us whether the drug is reinforcing, but it doesn’t not tell us how potent the drug is.
Apparatus: various forms, but always involves two areas which differ radically in some respect.
Each chamber is separated by a door that can be opened or closed during different phases of the conditioning and testing.
Inject rat with test drug and put in red box for several hours; door is closed to rest of box and do this for several days.
Inject the rat with saline and repeat this procedure in blue box.
Put rat in gray area, open both doors, and see which box the rat spends the most time in; if the test drug is reinforcing the rat will strongly prefer the red box.

Question 18

Intracranial self stimulation test

Answer 18

Tells us whether a drug has reinforcing properties and it relative reifying potency.
Rat implanted with stimulating electrode positioned somewhere in the pleasure pathway.
Rat learns to press a lever to receive a brief electrical stimulation of the pathway, which is rewarding to the animal, called wireheads.
Injects a drug in the rat and then repeat the test.
If the drug has reinforcing properties, intensity of the electrical stimulate needed to support self stimulation is lowered.
If the drug is not reinforcing, the threshold will not change.
The extent of lowering is proportional to the reinforcing potency of the drug.

Question 19

Human Studies

Answer 19

1. Self-administation: Insert a temporary line, see how avidly humans will perform some task to get drug injections, data look exactly like rat data.
2. Subjective rating: simple and common approach, give injections of a drug, rate subjective effects on pleasurable scales, variation of this is to give injections to experiences drug abusers.

Question 20

Psychological Dependence

Answer 20

A state produced by repeated administration of a substance in which continued use of the substance is required for psychological well being.
Factors affecting development of dependence:
-Substance
-Dose
-Frequency of use
-Route of administration
-User
Magnitude of dependence
Powerful- capable of maintaining a strong drug habit; incentive salience “craving;” most difficult aspect of drug dependence to treat and is the usual cause of relapse.
All abused substance can produce psychological dependence, the likelihood depends on the particular drug.
Psychological dependence does not necessarily mean drug abuse.

Question 21

Physical Dependence

Answer 21

An altered physiological state, produced by repeated administration of a substance, in which continued use of the substance is required to prevent the appearance of abstinence (withdrawal) syndrome.
Progressive pharmacological adaptation to the drug in neurons resulting in tolerance.
Involved neurons in CNS and ENS.
Abrupt removal of the drug-withdrawal syndrome occurs; adaptive responses are now unopposed by the drug; withdrawal symptoms are opposite to the original drug effects and the CARDINAL SIGN of “physical dependence.”
The state of physical dependence is a normal response; treatable by tapering the drug dose, not in itself a sign o addiction!!!
Importance:
Causes no direct harm or discomfort to the user; ONLY THE ABSTINENCE SYNDROME is potentially dangerous or discomforting.
Physical dependence cannot be directly detected by the user or by anyone else, it is inferred though the development of the abstinence syndrome following drug removal.
Fear of abstinence syndrome motivates continued drug use.
Physical dependence does not mean drug abuse.

Question 22

Intensity and Rate of Development of Physical Dependence

Answer 22

Dependent on sustained high level of drug in the nervous system-constancy of drug action in the nervous system, the occasional use of drugs will not produce physical dependency.
Magnitude of drug action in the nervous system; frequent use of low doses of drug is unlikely to produce significant physical dependence.
Constancy and magnitude depend on dose, frequency, and route of administration- how quickly it gets to place of action and is at elevated level.

Question 23

Physical Dependence in Substance Abuse

Answer 23

Substances that can cause psychological and physical dependence, psychological dependence usually develops first: EXCEPTION, when the substance is used for legit medical reasons psychological dependence may not ever develop, like with opioids and benzo long term medical use.
All classes of substances of abuse can cause psychological dependence.
All classes can cause physical dependence except cocaine, amphetamine-like stimulants, psychedelics, and PCP do not cause physical dependence.

Question 24

Abstinence (Withdrawal) Syndrome

Answer 24

Older literature-associated with physical dependence.
Now, associated with all types of withdrawal effects, whether or not physical dependence is present.
Withdrawal of the drug can result in symptoms which are entirely psychological (absence physical dependence); the craving is always present, irritability, anxiety, depression.
Psychological symptoms are intrinsic to physical withdrawal syndrome (presence of physical dependence).
Psychological symptoms of physical dependent are specific to that abstinence syndrome for a particular drug.
If psychological dependence is also present, additional psych symptoms may occur, but may be overshadowed by the more intense psych symptoms of physical withdrawal; which is more powerful depends on the agent and the host.
Psych dependence symptoms: anxiety, irritability, craving.
Physical dependence symptoms: irritability, delusional thinking, hallucinations.
Both capable of producing abstinence (withdrawal) syndromes.

Question 25

Abstinence (withdrawal) Syndrome Symptoms

Answer 25

The symptoms of a withdrawal syndrome of either psychological or physical dependence tends to be the opposite of the effects of the drug.
Withdrawal syndromes of either type can be rapidly revered by administration of the drug!
1. Drug discontinuation or major dose reduction
2. Administration of a receptor antagonist; opioids, cannabinoids, and benzos only.
3. Physiological antagonist will NOT precipitate abstinence syndromes; with a pharmacological antagonist that acts at the same receptor, you CAN produce withdrawal symptoms.

Question 26

Severity of Abstinence Syndrome

Answer 26

Depends on several factors whether or not physical dependence is present.
These factors more strongly affect physical withdrawal then psychological withdrawal.
Each substance produces its own set of withdrawal symptoms- maximum severity increases with dose.
1. The class of drug- each set produces its own set of abstinence symptoms.
2. The degree of physical dependence present: there does seem to be a maximum severity of withdrawal.
3. The speed and extent of drug deprivation: fast and extensive decrease in drug action (cold turkey) produces a fast onset, severe, but relatively short physical abstinence syndrome; gradual withdrawal of drug in small steps: produce a delayed, mild and prolonged syndrome.
4. Physical and mental status of the person affects the severity of the withdrawal (DTs in alcohol physical withdrawal is much more likely in debilitated persons.

Question 27

Tolerance

Answer 27

The reduction in response to the drug after repeated administration.
There are different types of tolerance.
This is the most common response to repetitive use of the same drug.
As the dose of the drug increases, the observed effect of the drug increases.
Rightward shift in the dose response curve; a higher dose is required to produce the same effect obtained at a lower dose.
Tolerance to some drug effects develops much more rapidly than to other effects.
Example: tolerance develops rapidly to the euphoria produced by opioids such as heroin; addict tend to increase their dose in order to re-experience the high.
Tolerance develops more slowly to the GI effects of opioids; also slow for respiration and BP-can lead to fatal overdoses in sedative abusers, trying to re-experience the euphoria they recall from earlier use.

Question 28

Acquired Tolerance

Answer 28

PK: also called dispositional tolerance; changes in the distribution or metabolism of a drug after repeated administrations; the given dose produces a loser blood concentration than the same dose did initially.
Most common mechanism is an increase rate of drug metabolism (barbiturates).
PD: Adaptive changes that have taken place within systems affected by the drug; response to a given concentration of the drug is reduced; example: drug-induced changes in receptor density or efficiency of receptor coupling, decreased coupling, need more of the drug to get the same effect.

Question 29

Learned Tolerance

Answer 29

A reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences.
Behavioral: skills that can be developed through repeated experiences, attempting to function despite a state of mild to moderate intoxication (learning to walk a alright line despite the motor impairment produced by alcohol); at higher levels of intoxication behavioral tolerance is overcome.
Conditional: environmental cues such as sights, smells, or situations; paired with the administration of a drug, usually reflexive counteraction or adaptation in the direction opposite the drug-not done at a cognitive level; prevents the full manifestation of the drugs effects.

Question 30

Acute Tolerance

Answer 30

Rapid tolerance developed with repeated use on a single occasion such as a “binge.”

Question 31

Reverse Tolerance (sensitization)

Answer 31

Can occur with stimulants such as cocaine or amphetamine.

Increase in response with repetition of the same dose of the drug; shift to the left of the dose response curve.

Question 32

Cross Tolerance

Answer 32

Repeated use of a drug in a given category.
Confers tolerance not only to that drug, but to other drugs in the same structural and mechanistic category with the same mechanism/receptors; does not typically cross drug categories.

Question 33

DSM-IV on Substance Dependence

Answer 33

Set of cognitive, behavioral, and physiological symptoms: person has impaired control of psychoactive substance use, person continues use of the substance despite adverse consequences.
Pattern of repeated self-administration: usually results tolerance, withdrawal symptoms if use is suddenly discontinued or reduced, compulsive drug-taking behavior.
Craving- a strong subjective drive to use the substance, not a criteria, likely to be experienced by most, if not all, individuals with substance dependence.

Question 34

DSM-V on Substance Dependence

Answer 34

Combines substance abuse and substance dependence from DSM-IV into a single disorder for each substance- substance use disorder.
Also different than the DSM-IV, in the DSM-V the condition is graded for clinical severity and two criteria are required to make a diagnosis.

Question 35

Addiction according to DSM-IV

Answer 35

Same as substance dependence of DSM-IV.

Confusion over dependence as a normal response and dependence as addiction.

Question 36

Addiction according to DSM-V

Answer 36

Produced by repeated drug use.
Occurs in only a minority of those who initiate drug use.
Leads progressively to compulsive out of control drug use.
DSM-V correct the confusion with the DSM-IV.
Addiction can be defined fundamentally as a form of maladaptive memory.
Begins with the administration of substances or behaviors; directly and intensely active the brain reward circuits; activation of these circuits motivates normal behavior and most humans enjoy the experience without being compelled to repeat it.
For a minority… it produces strong conditioned associations to environmental cues-signals the availability of the drug or the behavior, reflexive activation of reward circuits involuntary and rapid.
Cues acquire strong salience that overwhelms other behaviors.
Individual becomes drawn into compulsive repetition; focus on the immediate pleasure, despite negative long-term consequence, neglect of important social responsibilities.

Question 37

Process of Dependence Development

Answer 37

3 stimuli which are most often responsible for a relapse from abstinence back into drug ins include:
Conditioned cues
Stress
Use of even a small amount of the drug which generalizes to the drug.

Question 38

Complications arising from Use by Injection

Answer 38

One of the most common and serious complications of using drugs by injection are systemic infections, such as HIV/AIDs, hepatitis (mainly B), septicemia, and endocarditis.
Drug abuse by injection is now the most frequent method for transmission of hepatitis and AIDs in major metropolitan areas.

Question 39

Results of Needle Sharing

Answer 39

Method of transmission for most systemic infections.
Hepatits and HIV; needle sharing is the only way that IV drug use results infection.
Septicemia and endocarditis: cause of infection could be contaminated drug or unsterile injection technique.
There is a shortage or clean needles due to laws against the sale except on prescription.
Shooting up at “shooters galleries” using borrowed or rented equipment.

Question 40

Solutions to Sharing Equipment

Answer 40

Education programs regarding the risk and precautions to take and how to disinfect.
Distribution of black disinfection kits.
Needle exchange programs.
Drawing addicts to treatment through this programs!

Question 41

Quality Concerns

Answer 41

Some illicit drugs look exactly like legitimate pharmaceutical products but are actually counterfeit (especially anabolic steroids).
Preparation may not contain the drug it is represented to contain.
The amount of drug in the product may not be what it is represented to be.
The product may be adulterated or contaminated.

Question 42

Dilution (“cutting”)

Answer 42

Very common issue with street drugs, especially heroin and cocaine.
Diluted or “cut” with various substances in order to increase the bulk and thus the profit.
It may have been cut multiple times and by different individuals using different cutting agents.

Question 43

Cutting Agents

Answer 43

Almost any white power can be used as a cutting agent.
Lactose is the most common.
Potentially harmful cutting agents are used; talc is used which is particularly a problem if one is injecting the drug.

Question 44

Adulteration

Answer 44

Intentional impurity:
A cheaper agent is added that still packs a wallop.
Common additives to juice up street drugs are PCP and LSD.
Unintentional contamination of impurity:
Thee can include bacteria, fungi or toxic byproducts of clandestine (secret) synthesis.

Question 45

Polydrug Abuse

Answer 45

Multi drug abuse.
Extremely common when drug abusers use two or more drugs at the same time or at different times.
Usual situation.
The most common “second” drug in the combination is alcohol.
Dependence frequently develops to both drugs and is particularly difficult to treat.

Question 46

Rationale to joint Use

Answer 46

Longer lasting high than either drug alone.
Examples: heroin with cocaine, marijuana with alcohol.
People are looking for a high which is different than their usual experience.
To take the edge off coming down from a stimulant high; alcohol, barbiturates, benzodiazepines, or opioids are frequently used.
To medicate abstinence symptoms in a physically dependent person; benzos are frequently used for opioid or general CNS depressant withdrawal.
Used on the basis of availability.
“Garbage head”- person just uses anything available.
Person actually prefers the actions of several drugs independently.

Question 47

Central Neurobiology of Drugs of Abuse-The Reward Pathway

Answer 47

Composed of highly diversified chemical substances and distinct protein target centrally with distinct biochemical and physiologic effects.
All drugs of abuse share common acute and chronic effects on this pathway.

Question 48

Acute Effects

Answer 48

Drugs of abuse converge on a common circuit; mesolimbic pathway in the limbic system.
Important for acute reward; system used by natural rewards- sex and food.
Activation is necessary but not sufficient to cause addiction.
Drugs are rewarding in their acute effects; leads to repeated drug taking, leads addiction in vulnerable people, loss of control over drug taking.

Question 49

Chronic Effects

Answer 49

Addiction is a disease of the brain reward system.
High frequency, brief burst of dopamine are required for addiction; addiction only occurs if these are high frequency bursts in nucleus accumbens; dopamine release is correlated with the drug high.
Key site in processing saliency: regulates or influences, reward, reward expectation, motivation, emotions, feelings of pleasure.
Common chronic effects: impaired dopamine system; baseline levels of dopamine function are reduced, normal rewarding stimuli are less effective at stimulating dopamine release !!!

Question 50

Beyond the Reward Pathway

Answer 50

Phasic dopamine is necessary to induce conditioning:
to the drug itself, to expectations, to cues.
Neuroadaptive changes occur:
Due to repeated drug exposures, due to repeated perturbations of the reward system; dopamine modulate many systems: motivation/drive, inhibitory control, executive functioning, memory/conditioning.

Question 51

Changes Observed in Addicted Subjects

Answer 51

Hypodopaminergic state; decreased D2 receptor and decreased dopamine released.
Decreased metabolism in prefrontal cortex; anterior cingulate gyrus, orbitofrontol cortex.
Decreased sensitivity to natural rewards.
Reduced striatal D2 receptors linked to impulsivity in rodents.
Decreased dopamine release in addicted and post-addicted subjects; ventral striatum and other stratal areas, blunted pleasurable responses to drug, likely disrupted regulatory system in prefrontal cortex or amygdala.

Question 52

Four Systems Role

Answer 52

Dysfunction can explain the problems seen in addiction.
Influence how an individual makes choices between alternatives; modulated by circuits affecting mood and conscious awareness; directly innervated by dopamine neurons, connected to each other directly or indirectly through glutaminergic paths.

Question 53

The Four Systems Contribution

Answer 53

1. Reward; related to saliency, several nuclei of the basal ganglia (especially in the ventral striatum), nucleus accumbens receives input from the VTA, relays information to the ventral palladum.
2. Motivation/drive: related to internal state, location orbitofrontal cortex, subcallosal cortex, dorsal striatum, motor cortex.
3. Memory/conditioning; related to learned associations; located in amygdala and hippocampus.
4. Planning/control; related to conflict resolution; location in dorsolateral prefrontal cortex, anterior cingulate gyrus, interior frontal cortex.
   Tilt balance away from inhibitory control and towards craving.
   During addiction, enhanced value of the drug in the reward, motivation, and memory circuits overcomes the inhibitory control exerted by the prefrontal cortex.

Question 54

Two Modulatory Systems

Answer 54

Mood; includes stress reactivity.

Interoception; includes awareness of drug craving and mood.