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
1
2
3
4
% of Basal Release
400
0
250
Accumbens
Caudate
150
100
% of Basal Release
200
DA
DOPAC
HVA
100
250
NICOTINE
COCAINE
200
0
5 hr
Accumbens
300
Time After Amphetamine
% of Basal Release
% of Basal Release
Effects of Drugs on Dopamine Release
0
1
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
1
2
3 hr
0
Time After Nicotine
Source: Di Chiara and Imperato
0
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
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?
B
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
5
6
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:
Nicotine-
•Liability 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
*
0
0
15
30
0
15
30
0
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