Drugs of Abuse

Americans Views of the Seriousness

of Health Problems
% saying very serious problem

(Top 10 of 36 Problems)
Drug abuse

82%

Cancer

78%

Drunk driving

75%

Heart disease

74%

HIV/AIDS

73%

Violence
Child abuse
Smoking

71%
69%

68%

Alcohol abuse

65%

Stress

65%

Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000

Two Decades of Neurobiological

Research Have
Brought Us A New Understanding of
Drug Abuse and Addiction, Their
Complexity and their Solutions

For Example

We Know That Despite

Their Many Differences, Virtually
All Abused Substances Enhance
Dopamine (neurotransmitter) Activity
(particularly related to pleasure,
motor, and cognitive function

Other pathways also involved!

Dopamine Pathways
striatum
frontal
cortex

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

hippocampus

substantia
nigra/VTA

Serotonin Pathways

nucleus
accumbens
raphe

Functions
mood
memory
processing
sleep

Neuronal structure
(receiving)

(sending)

stimulation

vesicle

Neuronal terminal
Drug :
transporter
cocaine
ritalin

Vmat

/serotonin

How some drugs of abuse cause dopamine release:

opioids narcotics (activate opioid receptors)
DA/5HT
nicotine (activate nicotine receptors)
marijuana (activate cannabinoid receptors)
caffeine
alcohol (activate GABA receptors; an inhibitory transmitter)

transporter

Vmat

Release DA from vesicles and reverse

transporter
Drug Types:
Amphetamines
-methamphetamine
-MDMA (Ecstasy)

serotonin/

DA/5HT

Accumbens

1100
1000
900
800
700
600
500
400
300
200
100
0

AMPHETAMINE
Much greater
DA
Activity thanDOPAC
any
HVA
Other drug of abuse
-causes neurotoxicity

% of Basal Release

400

250

Accumbens
Caudate

150
100

% of Basal Release

200

DA
DOPAC
HVA

100

250

NICOTINE

COCAINE

200

5 hr

Accumbens

300

Time After Amphetamine

% of Basal Release

% of Basal Release

Effects of Drugs on Dopamine Release

2
3
4
Time After Cocaine

Accumbens

5 hr

ETHANOL
Dose (g/kg ip)

200

0.25
0.5
1
2.5

150

100

0
0

3 hr

Time After Nicotine

Source: Di Chiara and Imperato

1
2
3
Time After Ethanol

4hr

Natural Rewards Elevate Dopamine Levels

200

% of Basal DA Output

NAc shell
150

100
Empty
50

Box Feeding

SEX
200

150

100

15
10
5

0
0

60

120

Time (min)

180

ScrScr
BasFemale 1 Present
Sample 1 2 3 4 5
Number

6 7 8

Scr

Scr
Female 2 Present

9 10 11 12 13 14 15 16 17
Mounts
Intromissions
Ejaculations

Source: Di Chiara et al.

Source: Fiorino and Phillips

Copulation Frequency

DA Concentration (% Baseline)

FOOD

Implication:
Elucidation of the mechanism of
drug addiction will help to
understand other addictive and
motivational behaviors/disorders

Addiction and tolerance can be synonymous

Pharmacodynamic mechanism
of Tolerance

Induction of Tolerance to Morphine

Brain Circuits Involved in

Drug Addiction
INHIBITORY
CONTROL
OFC

PFC
ACG
Hipp

SCC

MOTIVATION/
DRIVE
(saliency)

REWARD

NAcc
VP
Amyg

MEMORY/
LEARNING

Reward Pathways:
Role of Opioids

HOW DOES ADDICTION

OCCUR?

 Principles of Behavior Dynamics

Behavior Tracts Compete for Expression
Prefrontal
Cortex

A
B
C

behavior
expressed

C
B

dopamine initiated

Orbitofrontal cortex

Expression is Determined by (i) Dominance of Tracts,

(ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or
saliency (orbitofrontal cortex)
Activation of Dopamine reward pathway initiates a behavior
track
(Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167)

 Principles of Behavior Dynamics

Prefrontal
Cortex

Orbitofrontal cortex

C
A
Addiction
B
B
BB behavior
expressed

dopamine

How does a behavior become

an addiction?

We Have Generated A Lot of

Evidence Showing That

Prolonged Drug Use Changes

the Brain and
In Fundamental
and Long-Lasting Ways

AND

We Have Evidence That

These Changes Can Be Both
Structural and Functional

BRAIN IMAGING
Positron Emission Tomography

Magnetic Resonance Imaging

Decreases in Metabolism
in Orbito Frontal Cortex (OFC)

control

cocaine abuser

Volkow et al. Am. J. Psychiatry 148, 621

METH Suppresses Expression of DAT

(note: duration of use/3-20 yrs; abstinent/ 1-4 yrs)

Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998.

Dopamine Transporter Loss After

Heavy Methamphetamine Use
(PET analysis)

Comparison Subject

METH Abuser

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

Dependence of Verbal Memory on Striatal

DAT
Interference recall

Delayed recall

Compromises Cognitive Functions

R = 0.70
p < 0.005

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

R = 0.64
p < 0.01

MOTOR FUNCTION
Slowed gait
Impaired balance

Impairment correlates with damage

to dopamine system

Implication:
Brain changes resulting from
prolonged use of psychostimulants,
such as methamphetamine
may be reflected in compromised
cognitive and motor functioning

Is There Recovery?
Good News: After 2 years some
of the dopamine deficits are
recovering
Bad News: Functional deficits
persist
What does this mean???

Reward System in Addiction

More

Cocaine

Alcohol

Food

treated

METH

Ability to Experience
Rewards Is Damaged

Less

Their Brains

Get Rewired
by Drug Use

INHERITED FACTORS
(genetic vulnerability-not
inevitability)

Common strategy to investigate

are Twin Studies

In General: Inheritability for Drug

Abuse Ranges From 40-60%

Some Variability Between Drugs

Some Gender Variability

Chromosomal Locations for Substance Abuse Vulnerability Loci

17

r-SA

3 samples, > 2 labs

4 samples, > 3 labs

r-candidate

>2 samples, >2 labs

Uhl et al Tr Genetics, updated June 03

22

Complex genetics

Complex phenotypes (expressions)

(Relation to Risk Factors?)

VULNERABILITY to What?
Starting Drug Use?
Liking Drugs More?
Continuing Drug Use?
Becoming Addicted?
Specific to A Particular Drug?

For ExampleContribution of Genetic Factors to:

NicotineLiability to initiate=56%
Transition to dependence=70%
Smoking persistence= >50%
(Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)

Genetics May Influence How

Neurobiology Interacts With
Environment

Genetics
Gene/
Environment
Interaction

Environment

PET Images:
Dopamine Receptor Density

More
likely
to selfadminister
Cocaine

Addictive Disorders Often Co-Exist with

or Predispose to Mental Disorders
DSM IV Manual:
Devotes ~ 100 pages to describing
addiction and dependence disorders
Discusses substance abuse as a
confound to diagnosis and Tx

National Comorbidity
Survey (NCS)
Nearly half of individuals with a past year
substance use disorder also had a mental
disorder
Mental disorders found to be most prevalent
included affective disorders, anxiety disorders,
personality disorders, and psychotic disorders
(Note: can we have parity for mental health without considering drug abuse?)

Common Underlying Neurobiological

Factors Can Be:
Neurochemical (imbalance of
neurotransmitters)
Structural/anatomical (same regions
and pathways)
Genetic (inherited factors that
compromise function)

Because of this overlap, drugs of abuse

can cause symptoms that mimic
most forms of mental illness

Drug
Cocaine and Methamphetamine

Disorder
Schizophrenia, paranoia,
anhedonia, compulsive
behavior

Stimulants

Anxiety, panic attacks,

mania and sleep disorders

LSD, Ecstasy & psychedelics

Delusions and hallucinations

Alcohol, sedatives, sleepaids

& narcotics
PCP & Ketamine

Depression and mood

disturbances
Antisocial behavior

Some drugs of abuse have a

mechanism of action similar to
that of drugs used as
psychotherapeutic agents
Significance: rationale for
self-administration

Synaptic vesicle

Serotonin/dopamine synaptic
terminal
transporter
Prozac,
Ritalin, &
Cocaine
block

Postsynaptic
target

Causes an effect
Activate transmitter receptors

Mechanism of action
of amphetamine and
cocaine

Chronic use of some of these drugs of

abuse may alter the way the brain
functions, making persons particularly
susceptible to mental illness

People With Comorbid

Mental and Addictive Disorders
Have a Double
Double Brain Disease

Mental
Disorder

Comorbid
Disorders

Addictive
Disorder

Role of Stress and Trauma

The Stress Hormone Cycle

Hypothalamus

CRF
Pituitary
Gland

ACTH
CRF:
Corticotropin
Releasing
Factor

Adrenal
Glands

Kidneys

Stress
Responses
Stress
Responses
Stress
StressResponses
Responses
CORTISOL

Anxiety

DRUG USE
(Self-Medication)

CRF

What Role Does Stress Play

In Initiating Drug Use?

STRESS

CRF

Anxiety

Anxiety
Prolonged
What
DRUG
USE

RELAPSE

Happens When A Person

Stops
CRF Taking A Drug?

Abstinence

Stress Reliably Reinstates Drug Seeking in Rats

Responses

Cocaine-trained rats
100
80
60
40

Alcohol-trained rats

Inactive Lever
Active Lever

20
0

Saline

Cocaine Footshock

Responses

Nicotine-trained rats

Water Alcohol Footshock

Heroin-trained rats

100
80
60
40

20
0

Saline

Nicotine

Footshock

Saline

Heroin Footshock

From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

CRF1 Receptor Antagonist Attenuates

Stress-Induced Reinstatement
of Drug Seeking
Heroin-trained rats

Alcohol-trained rats

45
30

15
0

Responses (3 hr)

60

Responses (1 hr)

60

Cocaine-trained rats
No stress
Intermittent Footshock

45

30

*
*

15

15

30

15

30

15

CP-154,526 Dose (mg/kg, SC)

From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

30

Objectives of Intervention:
Rearrange dominance of behavior tracks
contingency management (vouchers)
motivational enhancement
therapeutic communities

 Principles of Behavior Dynamics

Prefrontal
Cortex

A
B
C

behavior
expressed

dopamine initiated

Orbitofrontal cortex

C
B

 Strengthen prefrontal cortex influence

(change thinking process)
cognitive and cognitive behavioral tx
(unlearn old habits-suppress; learn
new skills)
assertiveness training (suppress and
express)

 Principles of Behavior Dynamics

Prefrontal
Cortex

A
B
C

behavior
expressed

dopamine initiated

Orbitofrontal cortex

C
B

Alter function of orbitofrontal

(saliency) cortex
motivational therapy
family therapies

 Principles of Behavior Dynamics

Prefrontal
Cortex

A
B
C

behavior
expressed

dopamine initiated

Orbitofrontal cortex

C
B

 Recovery of function (frontal and obitofrontal cortex)

all treatments that keep brain away
from drugs for extended time

 Principles of Behavior Dynamics

Prefrontal
Cortex

A
B
C

behavior
expressed

dopamine initiated

Orbitofrontal cortex

C
B

 Alleviate underlying psychiatric

disorder
administer: Antidepressants for depression
Ritalin for ADHD
Sedatives for anxiety

Targets of Medication
Methadone, LAAM and Buprenorphine
Activate opioid receptors
Naloxone
Block opioid receptors
Nicotine gum/patch
Activate nicotinic receptors

stimulation

Vmat

vesicle

Neuronal terminal
transporter

How some drugs of abuse cause dopamine release:

opioids narcotics (activate opioid receptors)
nicotine (activate nicotine receptors)

DA

 Psychostimulants
Enhancing GABA-ergic inhibition
(baclofen-muscle relaxant; anti-seizureTiagabine)
Cannabinoid antagonist (rimonabant)

 Principles of Behavior Dynamics

Prefrontal
Cortex

GABA and cannabinoid

systems critical for
A
function
B
C

behavior
expressed

dopamine initiated

Orbitofrontal cortex

C
B

 Relieve stress-related drug abuse

CRF antagonist
Anxiety
Prolonged
DRUG
USE

CRF

Abstinence

RELAPSE

No cure