1 neuroscience of addiction study workshop: overcoming barriers to engagement with difficult and...

Neuroscience of Addiction

Study Workshop: Overcoming Barriers to Engagement withDifficult and Different Clients

Introductions*

1. What type of work do you do?

2. What do you hope to gain from this workshop?

Acknowledgement of Slides• NIDA teaching slides

– www.nida.gov

Arturo E. Morales MD• University of Connecticut School of Medicine,

Nora Volkow • NIH

Glen R. Hanson, Ph.D., D.D.S.• Utah Addiction Center

Beatriz Luna, Ph.D.• Western Psychiatric Institute and Clinic

Other slides include source information

Difficult Patients*

• Who are they?

• What makes them difficult?– Behaviors– Attitudes– Response to treatment

CRAVING

SEEKING

Map your difficult patients to workshop goals:

Identifying vulnerabilitiesAppreciating drug effects on brainUnderstanding cravingDiscuss correlates of compulsionUnderstand cognitive aspects of

drug use

Neuroscience of Addiction

• Advances in understanding over last few years

• New technologies to visualize brain activity

Addiction is Complex

• Psychological

• Social

• Spiritual

• Biological

Brain is Complex• Compared to other organs:

– Many different types of cells– Less accessible for imaging or biopsy– More active changes (expressing genes)

as a result of hormones, drugs, development and experience (learning)

• A moving target!

Addiction

“Addiction at its core is a biological process”Biological AgentBiological Substrate Nestler and Aghajanian, 1997

Overview of Workshop/ Goals

• Part 1 Neuroscience of Addiction– Brain structures and circuits– Reward circuit– Changes from drug use– Who gets addicted?

• Genetics• Environment• Vulnerable groups

Overview of Workshop/ Goals

• Part 2 Applied Neuroscience of Addiction– Understanding craving– Correlates of compulsion– Cognitive aspects of drug use– Emerging pharmacology for treatment of

addiction

Overall Goal

• Understanding the neuroscience of addiction will allow you to treat your clients’ addictions in a new way

Other Housekeeping

• Exercises

• Breaks

• Lunch

• Evaluations

General

• Time outs

• Repetition– Review– Build up understanding– Integrate different materials

Exercises

• Reinforce

• Make abstract information more concrete

• Resources

• Involvement

• Your experience and expertise

Defining Key Terms for Workshop

• Addiction

• Dependence

• Tolerance

Define Addiction

• Loss of control over intense urges

• Drug use despite adverse consequences

Addiction

• Impaired control

• Craving and compulsive use

• Continued use despite negative consequences

Physical Dependence

• State of adaptation

• Expected result of use (opioids, BZD’s)

• Drug class specific withdrawal syndrome– Abrupt decrease/ discontinuation

Tolerance

• State of adaptation

• Drug effects lessen over time

• Increase in dose needed for same effect

Pseudoaddiction

• Unrelieved pain

How do you define addiction?*

• How do you know when someone has crossed that line?

Part 1 Neuroscience

– Review brain– Reward circuit– Changes from drug use– Who gets addicted?

• Genetics• Environment

Brain and Beyond

• Brain

• Structures

• Neuron

• Transmission

• Neurotransmitters

The Brain

• An Adult brain weighs about 3 pounds and has billions of cells– Neurons– Glial cells

The Brain

• Organ of thinking, behavior, homeostasis

• Different areas of the brain regulate different functions

• Complex tasks are split up into specialized areas– Damage to these areas leads to specific

deficits

• “Division of labor” allows for Parallel Processing

Major Brain Regions

• “Primitive” Brain– Brainstem– Cerebellum

– Limbic System

• “Evolved” Brain– Cortex

Midbrain

• Deep brain structures

• “Is it a treat or a threat”

• Receive sensory information from more highly evolved sensory cortical areas

• Send information to many parts of the brain and body

Brain Imaging in Psychiatry

• PET and fMRI: View function (Blood flow)• Computerized Tomography (CT)

– Anatomical Changes

• Magnetic Resonance Imaging (MRI)– Refined Anatomy- Size of structures

Functional Divisions: Cut Brain View

Brain and Beyond

• Brain

• Structures

• Neuron

• Transmission

Structures

• Ventral Tegmental Area (VTA) – More on this later

• Nucleus Accumbens– Center Stage for drug response

• Amygdala

• Prefrontal Cortex

OFCOFCSCC

NAcc VPVP

PFCPFC

ACGACG

HippHipp

AmygAmyg

Brain Structures Involved in Drug Addiction

Structures: Amygdala

Amygdala

• Key for sensing emotional meaning of things

• Reward?

• Threat?

Exercise: Cut Brain Image**

• For review and reference :Label and color (if you wish)– VTA– Nucleus Accumbens– Amygdala– Hippocampus– Prefrontal Cortex

Brain and Beyond

• Brain

• Structures

• Neuron

• Transmission

The Neuron

• Basic signaling unit of the brain

• Precise connections allow for different actions– Neurons– Sensory

receptors– Muscles

Identify Parts of the Neuron **• Cell Body

– Nucleus– Metabolic center

• Dendrites– Input from other

neurons

• Axon– Carry messages away

from neuron– High speed– Branches into

presynaptic terminals

Photo of Neuron

Neuron Aglow

The Synapse

• End of axon• Typical

neuron has 1000 synapses with other neurons

• Intercellular space between neurons– Synaptic cleft

The Synapse

Receptors

• Proteins on many types of cells

• Receive and bind specific chemicals

• Neuronal receptors – Neurotransmitters– Drugs

Receptor Numbers and Function

• Cell can Increase or decrease to stay in balance

Cell Receptors• Molecules that bind a receptor are

AGONISTS• Molecules that also bind to a receptor and

block it are ANTAGONISTS– Naloxone

Synapses are Dynamic

• Neurons can strengthen synaptic connections

• New synapses form (protein synthesis)• Synapses can be lost• Responses to life experiences (and

aging)• Cellular basis of learning

Brain and Beyond

• Brain

• Structures

• Neuron

• Transmission

Synaptic Transmission

• Neurons communicate via electrical and chemical signals– Electrical signal converted to a chemical

signal– a neurotransmitter

• How the brain communicates among the millions of neurons

• Basis of perception, consciousness, basic regulation (HR, temp, sleep)

• Neurotransmission is how we have thoughts, feelings, actions

• At the axon terminal, the electrical impulse leads to release of a neurotransmitter

• Stored in vesicles which fuse with the neuron’s membrane and release the neurotransmitter into the cleft

• Neurotransmitters diffuse into intercellular space

• Bind to receptors on dendrite of another cell– Postsynaptic cell

– Receptors are specific– Dopamine receptors will only bind dopamine

• Chemical binding of transmitter with receptor leads to changes in the post-synaptic cell– May generate an

action potential

– Post-synaptic cell may use a different neurotransmitter to communicate “down stream”

Reuptake of Neurotransmitter

• Allow for fast and precise signaling

• Sometimes enzymes in the synapse also clear the transmitter

Synapse**

• Label and color (if you like)

• Presynaptic neuron

• Postsynaptic neuron

• Vesicles

• Receptors

• Reuptake pumps

Dopamine

• Key role in animal attraction

• Allows for the intense focus for “drives”– Food, water– Elevated brain levels associated with

passionate love

• Neurotransmitter of addiction

• Many other functions in human brain

Dopamine binding to receptors and uptake pumps in the nucleus accumbens

Dopamine receptors: Distribution

Dopamine

• Dopamine and Dopamine receptors are center stage for multiple stages of addiction– Initial euphoria– Addiction Vulnerability– Compulsive behaviors– Craving and relapse

Dopamine

• Dopamine receptors come in various forms

• D2 receptor in addictions:– D2 receptors persistently low in patients

addicted to cocaine, alcohol, methamphetamine, opioids and those with morbid obesity

– Chicken or the egg?

D2 receptors Decreased in Obesity

normal subject

cocaine abuser (1 month post)

cocaine abuser (4 months post)

Effect of Cocaine Abuse on Dopamine D2 Receptors

Dopamine and Functional Imaging

• PET Scans– How much binding, how many receptors– Dopamine, D2 receptors

• Functional MRI (fMRI)– How much blood flow– How much brain activity

Drugs Disrupt Neurotransmission

– Bind to brain receptors that they match by coincidence

– Produce feelings of pleasure in the reward system by altering neurotransmission of dopamine neurons in reward circuit in central brain

– Other effects (pain relief, hallucinations) due to action at other areas in the brain

Hijacking the Dopamine-Fueled Reward System

Part 1 Neuroscience

Reward Circuit

• Ancient brain mechanism to help negotiate environment for survival

• Still active in today’s environments

How do patients describe their first drug use?*

Reward Pathway• Specialized brain areas for producing

and regulating PLEASURE– Ventral Tegmental Area– Nucleus Accumbens– Prefrontal Cortex– Areas of Limbic system– amygdala,

hippocampus, hypothalamus

Reward Circuit

• Drugs hijack this circuit– Give false signal of fitness/ well-being– Override rational thought– Take over voluntary behavior

Reward Circuit: What are Your Natural Rewards?**

Reward Circuit: Evolved

• Grip attention

• Motivate survival behavior

• Disregard dangers

• Compel behavior towards survival goals

Animal Experiments*

• Direct electrical stimulation of brain reward areas with level press.

• What happens?

Reward Circuit

• “Addiction is a disease of brain reward centers that ensure the survival of organisms and species”

• Dackis & O’Brien, 2005

Dopamine Pathways

Functions•reward (motivation)•pleasure,euphoria•motor function (fine tuning)•compulsion•perserveration•decision making

Reward Circuit

• Currency of reward circuit is dopamine

• All abused drugs have a common end point:– Increased dopamine levels in the shell of

the nucleus accumbens

• Drugs activate the pathway with force and persistence not seen with natural rewards

Dopamine Levels around Nucleus Accumbens and Reported “High”

Reward Circuit and Dopamine

• Natural rewards elevate dopamine levels– Food, sex, water– Dopamine release in nucleus accumbens

correlates with “meal pleasantness”

• Drug induced euphoria linked to dopamine (D2) receptor binding

Dopamine and Reward

• Dopamine is the neurotransmitter in the reward center

• Increased dopamine levels correspond with reward

• Nucleus accumbens is the end point for dopamine action

100100

150150

200200

00 6060 120120 180180

Time (min)Time (min)

NAc shellNAc shell

EmptyEmpty

BoxBox FeedingFeeding

Source: Di Chiara et al.Source: Di Chiara et al.

FOODFOOD

Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine

100100

150150

200200D

MountsMountsIntromissionsIntromissionsEjaculationsEjaculations

SampleNumberSampleNumber

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

ScrScrScrScrBasBasFemale 1 PresentFemale 1 Present

ScrScrFemale 2 PresentFemale 2 Present

ScrScr

Source: Fiorino and PhillipsSource: Fiorino and Phillips

SEXSEX

Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine Natural Rewards Elevate DopamineNatural Rewards Elevate Dopamine

Sex and Food on Dopamine• Evolution: linking pleasurable feelings to

food and sex is important in continuing the species

00100100200200300300400400500500600600700700800800900900

1000100011001100

00 11 22 33 44 5 hr5 hr

Time After AmphetamineTime After Amphetamine

DADADOPACDOPACHVAHVA

AccumbensAccumbens AMPHETAMINEAMPHETAMINE

100100

200200

300300

400400

00 11 22 33 44 5 hr5 hrTime After CocaineTime After Cocaine

DADADOPACDOPACHVAHVA

AccumbensAccumbensCOCAINECOCAINE

100100

150150

200200

250250

00 11 22 3 hr3 hr

Time After NicotineTime After Nicotine

AccumbensAccumbensCaudateCaudate

NICOTINENICOTINE

Source: Di Chiara and ImperatoSource: Di Chiara and Imperato

Effects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine ReleaseEffects of Drugs on Dopamine Release

100100

150150

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250250

00 11 22 33 4hr4hrTime After EthanolTime After Ethanol

0.250.250.50.5112.52.5

AccumbensAccumbens

Dose (g/kg ip)Dose (g/kg ip)

ETHANOLETHANOLETHANOLETHANOL

Addiction Cycle

Part 1 Neuroscience

Effects of Drug Use on the Brain

• Short term

• Long term

Short Term (Acute) Effects of Drug Use

• Drug specific receptors

• Dopamine is common final pathway

• Nucleus Accumbens is “final stop”

• Pleasure, reward, euphoria are the common final effects

• Positive reinforcement

Acute Effect of Drugs on Reward Circuit

• Cocaine

• Alcohol

• Methamphetamine

• Ecstasy

• Nicotine

• Caffeine

• Opioids

Cocaine binding to uptake pumps; inhibition of dopamine uptake

Sex 200, Cocaine 350

100100

200200

300300

400400

00 11 22 33 44 5 hr5 hr

Time After CocaineTime After Cocaine

DOPACDOPAC

HVAHVA

AccumbensAccumbens

COCAINECOCAINE

Drug effects on neurotransmission

• Alcohol, heroin, nicotine excite the dopamine neurons in the VTA to increase dopamine release

Drug effects on neurotransmission: Methamphetamine

• Amphetamines cause release of dopamine from vesicles independently of action potentials

• Meth also blocks dopamine transported from taking dopamine back into the cell

• Quick and prolonged increase in synaptic dopamine levels– (Pleasure)

Sex 200, Amphetamine 1050

100100

200200

300300

400400

500500

600600

700700

800800

900900

10001000

11001100

00 11 22 33 44 5 hr5 hr

Time After AmphetamineTime After Amphetamine

DOPACDOPAC

HVAHVA

AccumbensAccumbensAMPHETAMINEAMPHETAMINE

Marijuana

THC Binds in Nucleus Accumbens

THC• Binding in nucleus accumbens

increases dopamine release

• THC binds to receptors specific for a natural brain chemical (anandamide)

Drug Effects On Neurotransmission: Ecstasy

• Binds to reuptake pumps

• REVERSES the pumps

• Also inhibits dopamine transporters

• Stimulates cell body in VTA to increase number of action potentials and dopamine release

• Also binds to receptors on axon terminals in nucleus accumbens to release more dopamine each time

Drug Effects On Neurotransmission: Nicotine

Sex 200, Nicotine 235

100100

150150

200200

250250

00 11 22 3 hr3 hr

Time After NicotineTime After Nicotine

AccumbensAccumbens

CaudateCaudate

NICOTINENICOTINE

Drug Effects On Neurotransmission: Caffeine

• Mild Stimulant

• Increases dopamine in the nucleus accumbens

• Prevents another chemical (adenosine) from binding to its receptor (antagonist)– Adenosine is a natural sleep

inducer

Drug Effects On Neurotransmission: Alcohol

• Excites dopaminergic neurons in VTA– Inhibitory–

decreases the activity of GABA (inhibitory) neurons

– Takes off the “brake” for dopamine transmission

Sex 200, Alcohol 200

100100

150150

200200

250250

00 11 22 33 4hr4hr

Time After EthanolTime After Ethanol

0.250.25

0.50.5

2.52.5

AccumbensAccumbens

Dose (g/kg ip)Dose (g/kg ip)

ETHANOLETHANOLETHANOLETHANOL

Short Term Effects: Endogenous Opioids

Brain pathways involved in:

• Pain

• Pleasure

• Appetite

• Sexual function

• Natural drive states

Opioids

• Multiple and complicated roles in addiction

• Natural opioids (endorphins) released by some drugs of abuse

• Drugs of abuse (heroin, codeine) bind to natural endorphin receptors

Binding Sites in the Brain

Endogenous Opioids: Endorphins

Alcohol: reward is mediated by endogenous opioids and influenced by genetic factors affecting opioid function– Alcohol acutely increases opioid activity– Especially for animals bred to prefer

alcohol

Opiates Binding to Receptors

Opioids

• Alcohol opioid effect is blocked by drug naltrexone (antagonist)

• Naltrexone pretreatment extinguishes alcohol self-administration in monkeys

• Basis for Revia® and Vivitrol®

Other Drug Effects

• Substances may bind to multiple brain sites

• Different effects at different sites– Methamphetamine

• Reward pathway: high• Other dopamine areas: hallucinations

Write a Test Question Exercise*

• Break into groups of 2

• Review content on acute drug effects

• Write a test question (True/ False or Multiple Choice) for use with your clients

Addiction Cycle

Long Term (Chronic) Effects of Drug Use

• Adaptations/ alterations within the brain

• Longer term aspects of addiction– Craving– Relapse– Cellular level

Effects of Chronic Drug Use

• Long lasting

• Involve multiple brain circuits– Reward– Motivation– Learning– Inhibitory control– Executive functioning

Comparison Subject METH AbuserComparison Subject METH Abuser

Dopamine Transporter Loss AfterHeavy Methamphetamine Use

(PET analysis)

Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

Addiction Cycle

• Becomes more uncontrollable as brain becomes more addicted– Frequency of drug use– Route of drug use– Chronicity of drug use

Addiction Cycle

• Behavior transition from voluntary actions (executive functioning- frontal lobe) to

• Habitual drug seeking (midbrain– nucleus accumbens)

• No marker for when this line is crossed

Chronic Drug Use on Dopamine• Individual neurons facing avalanche of

dopamine as a result of drug

• Neurons decrease (“down regulate”) number of dopamine receptors

• Recalibration of reward system– Brain dependent on drug to make up the

difference– Drug is required to feel “normal”– Normal rewards do not register ($20 bill, natural

rewards are eclipsed)– Variable: genetics, experience, environment

Implications for Recalibration*

How/ Why do cells change like this?

• Changes in how the cell works INSIDE

• Changes in cell size, shape and receptors

Addiction is a form of drug-induced neural plasticity

• Changes in intracellular pathways– Occurs in response to chronic

administration of drugs– Changes the types of and amounts of

receptors the cell “builds” to bind dopamine

– Results in tolerance and dependency

Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

Drug Effects on Cell• Drugs of abuse

all directly or indirectly increase dopamine binding to post synaptic receptor with acute behavioral effects

• Chronically, this increases cAMP levels and leads to a cascade of changed cell activity

Drug Effects on Cell

• Increased cAMP levels• Activation of transcription factor CREB and

changes in gene expression– Changes in synapses, cell structure and function

• The resulting intracellular changes appear to be the molecular and cellular basis of addiction (persistent behavioral abnormalities)

Nestler Am J Addiction 2001; 201-217

Drug Effects on Cell and Learning

• Intracellular changes for addiction the same as for learning– Both activities share intracellular signaling

cascades (cAMP) and depend on activity of CREB (protein that leads to building of receptors and other proteins)

Drug Effects on Cell and Learning

• Learning and addiction show similar changes in neuron morphology

• Similar changes at the level of the synapse

• Multiple similar changes in the neuron– Long term changes– Addiction is long term

– Nestler 2001 Science 292 (5525) pp 2266-67

Basis for Plasticity: Summary

• Drugs enter the brain and bind to an initial protein target

• Binding alters synaptic transmission which in turn cause the acute behavioral effects of the drug

• Acute effects of the drug do not explain addiction by themselves

• Addiction produces a change in brain structure and function (adaptation to the drug)

• Molecular and cellular changes in particular neurons change brain circuits

• This leads to changes in behavior consistent with addicted states

• Addiction is therefore a form of drug induced neural plasticity

Basis for Plasticity: Summary

Other Chronic Drug Effects

• Cell Death (“Neurotoxicity”)– Neurons don’t grow back– Alcohol, ecstasy, methamphetamine

• Effect memory, mood, learning (Part 2 topics)

Chronic Effects (Ecstasy)

Chronic Effects (Cocaine) • Over time, brain

activity as measured by PET trends towards normal

• Neuropsychological function may never normalize

Chronic Effects of Drug Use

• Disrupt reward circuits– Cells decrease dopamine receptors to

recalibrate– Normal rewards insufficient for pleasure

• Dysphoric states replace euphoria– Withdrawal– Craving– Negative reinforcement replaces positive

reinforcement

Day 1 Neuroscience

What makes a drug addictive

• Onset of action

• Subjective effect

• Half life

Drug Ingestion

Rapid Onset Increases Risk of Addiction

Half Life

• Rapid discontinuation of effects leads to “negative reinforcement”– Repeated use to avoid withdrawal/rebound

effects

Neuroimaging and Drug Effects

• Increased dopamine in the nucleus accumbens not enough

• Fast drug uptake into the brain associated with high/ rush/ euphoria– IV not oral methylphenidate– Drug users and non-users

Who Gets Addicted?

• Animal models

• Genetics

• Developmental

• Environment

• Mental illness

Animal Models

• Animals of many species seek intoxicants in the wild

• In the laboratory, animals exposed to drugs quickly learn to develop drug-seeking behaviors

• Drugs that are addictive to humans are also voluntarily self-administered by lab animals

» Ref: Gardner E. Addiction and Animal Models of Self Administration. Am J Addictions 9:285-313 2000

Animal Models of Relapse

• “Drug Seeking Behavior”

• Stimulated by:– Exposure to the drug– Cues associated with prior drug exposure– Stress

Animal Strains

• Different readiness to self-administer drugs

• Different cellular and molecular responses to chronic drug exposure

Lewis Rats• High vulnerability for self-administration of

alcohol and cocaine• Learn alcohol/cocaine self administration

more readily• Work harder for IV cocaine or opioid self-

administration

Ref: Lepore M Studies on the neurobiological interrelationship between vulnerability to depression and vulnerability to drug abuse in animal models. Behav Pharmacol 1995;6(suppl1):82-84

Lewis Rats

• Dopamine surges in response to a variety of addictive drugs (opiates, THC, nicotine, cocaine) are much more pronounced in Lewis rats

Ref: Lepore M Studies on the neurobiological interrelationship between vulnerability to depression and vulnerability to drug abuse in animal models. Behav Pharmacol 1995;6(suppl1):82-84

Who Gets Addicted?

• Animal models

• Genetics

• Developmental

• Environment

Genetics

• Variability to drug experimentation– Risk/ novelty seeking traits

• Variability to acute drug response– How pleasurable was drug

• Variability to chronic drug response– What types of adaptations

• Variability to stress response

Genetics *

• 40-60% of addiction attributable to genetic factors

• What are some other genetically influenced diseases?

Genetics Plays a Role in– Ovarian cancer^– Breast cancer^– Bipolar disorder^– Sickle cell anemia*– High cholesterol*– Obesity^– Alzheimer’s Disease*^– Huntington’s Disease*– Many many other physical and mental

diseases– *= predictable ^=multifactorial

Genetics of High Cholesterol

The faulty copy of the LDLR gene that causes predisposition to hypercholesterolaemia is represented by "D". Its expression overrides the correct copy of the gene, represented by "d". A person who inherits a faulty copy of the LDLR gene from a parent is at increased risk for developing cardiovascular disease during their life.

How Do Separate Nature and Nurture?

• Twin studies– Compare identical (100% shared genes) with

non-identical (50%) shared genes

• Adoption studies

• Animal studies– Genetically similar animals- compare different

environments

Effect of Genetics on Addiction

• Twin Studies– Smoking, alcohol, response to MJ all

increased in identical vs non-identical twins

• Nestler 2000 Nature Genetics Vol 26 277-281– http://genetics.nature.com

GENETICS• TWIN STUDIES

– Smoking, alcohol, response to MJ all increased in identical vs non-identical twins

• Nestler 2000 Nature Genetics Vol 26 277-281– http://genetics.nature.com

• Kaj (1960) concordance rate for alcoholism was greater in male identical twins than non-identical twins-60% versus 39%

• Kendler, et al. (1992) large sample of female twin pairs- identical twins had higher concordance for alcoholism

GENETICS

• ADOPTION STUDIES• Schuckit, et al. (1972) studied

individuals who had been raised apart from biological parents, but who had a biological or surrogate parent with alcoholism

• subjects with a biological parent with alcoholism were more likely to have alcoholism themselves than if their surrogate parent were alcoholic

GeneticsGeneticsGeneticsGenetics

EnvironmentEnvironmentEnvironmentEnvironment

Gene/Gene/EnvironmentEnvironmentInteractionInteraction

Genetics and Alcoholism

• Genetic predisposition to alcoholism experience more pleasure from alcohol– Lower baseline blood beta endorphin

levels– Greater beta-endorphin response as a

result of alcohol ingestion– Greater experience of euphoria from this

Relative sensitivity of different mouse strains to opioids

(Pasternak, 2004)

Genetics: What Else Predicts Drug Response?

• D2 Receptor levels vary in population

• Low levels D2 receptors associated with significantly more pleasure from drugs in non-addicted people

• Monkeys with low D2 receptors are more likely to self-administer cocaine

Genetics: D2 Receptors

• High levels of D2 receptors may protect against addiction– Increase the number of D2 receptors in

rats with a experimental technique– Alcohol ingestion significantly reduced

• Genetics/ D2 receptor density may help explain variability in liking drug effect

unpleasant response

pleasant response

DA Receptor Levels and Response to methylphenidate In People

Low receptor levels MPH pleasant

High receptor levels MPH unpleasant

Ref: Volkow, ND, Wang, G-J, Fowler, JS, Logan, J, Gatley, SJ, Gifford, A, Hitzemann, R, Ding, Y-S, Pappas, N. Brain dopamine D2 receptor levels predict reinforcing responses to psychostimulants in humans. Am J Psychiatry, September 1999.

Genetically Altered Animals

Who Gets Addicted?

• Animal models

• Genetics

• Developmental

• Environment

Independence + Irresponsibility=Adolescence

Developmental: Adolescence

• Normal behaviors increase probability of drug experimentation– Risk-taking– Novelty-seeking– Peer pressure– Rebelling against authority

• Brain development incomplete

• Myelination of frontal lobe regions not complete– Frontal lobe: judgment, impulse control,

Maturation of brain age 5-21

Brain Maturation

• Rapid conversion gray to white matter• Maturation back to front: Frontal lobes last

• Growing volume

• Increased organization of brain tracts– Protective myelin coating

Developmental: Brains in Transition

• Brains in transition are vulnerable

• Stress can lead to reverting to a less mature state– Regression of young children when tired

or hungry

• Very young brains need emotional support for proper development– Implications for neglected/ abused

children?

• Neuroadaptations to drugs different than adult brains– Nicotine, alcohol, cannabinoids

• Greater vulnerability to addiction as adults?

Alcohol on Developing Brain

Most people start drug experimentation ages 8-16

• What are the implications?*

Adolescents

• Drug use often starts before they are capable of making informed decisions

• Drug use changes brain function– Impulse control, decision making and

reward system altered

What would an effective prevention program look like?*

Who Gets Addicted?

• Animal models

• Genetics

• Developmental

• Environment

Environmental Aspects of Addiction

• How available is the drug?– Recent drug abuse patterns in the U.S.– What contributes to an “epidemic”?

Environment: The Meth Epidemic

• Rates of methamphetamine addiction fluctuated during 1990’s– Measured by rates of people entering

treatment programs, ER visits, deaths

• Fluctuations corresponded to drug availability and purity

Environment: Viet Nam and Heroin

• 20% soldiers in Viet Nam addicted to heroin

• 1% continued addiction in U.S.

• What are the environmental factors?

Stress Triggers Relapse

Individuals exposed to stress are more likely to abuse alcohol and other drugs or undergo a relapse

Kosten TR et al: A 2.5 year follow-up of depressions life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 1986; 43-733-739

Sinha R et al Psychological stress, drug-related cues, and cocaine craving. Psychopharmacology 2000; 152:140-148

Shaham Y Immobilization stress-induced oral opioid self administration and withdrawal in rats: role of conditioning factors and the effects of stress on relapse to opioid drugs Psychopharmacology.1993:11; 477-485

Environmental Aspects of Addiction

Overlap with genetics/ stressors• Low SES

• Low parental support

What are the alternative rewards/ reinforcers?

Macaque Monkeys

D2 Receptor Review• Low levels of receptors

– Increased self administration in animals

– Increased “pleasantness” of methylphenidate

• High levels of receptors– Decreased “pleasantness” of

methylphenidate– Protective

Monkeys

• First scan monkeys who were housed separately– Scan brains for D2 receptor availability

• Compare after monkeys housed together and social rank became established

• Compare cocaine self administration as well– Macaque monkeys

• Winning fights• Linear hierarchy

– Nader and Czoty, Am J Psychiatry 162:8 August 2005a

Environment and Stress/ Rewards

Social status affects brain Dopamine D2 receptors

– Low social status • Less expression of D2 receptors• Increased cocaine self administration

More likelyMore likelyto self-to self-administeradministerCocaineCocaine

PET Images: Dopamine Receptor Density

Effect of Social Dominance on CocaineEffect of Social Dominance on CocaineSelf -AdministrationSelf -Administration

.003 .01 .03 .1

2.0 TOTAL INTAKE

(mg/kg/session)

Cocaine (mg/kg/injection)

Subordinate

DominantMea

Implications of Monkey Experiments for Addiction

Treatment?*

Addiction Cycle

Summary

• Brain

• Pathways

• Vulnerabilities

Genetics: Exercise in Chocolate*

Part 2

• Part 2 Applied Neuroscience– Understanding craving– Correlates of compulsion– Cognitive aspects of drug use– Emerging pharmacology for treatment of

addiction

1 neuroscience of addiction study workshop: overcoming barriers to engagement with difficult and...

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