1. Drugs of Abuse

2. Americans’ Views of the Seriousness of Health Problems (Top 10 of 36 Problems)
65%
68%
69%
71%
73%
74%
75%
78%
82%
Stress
Alcohol abuse
Smoking
Child abuse
Violence
HIV/AIDS
Heart disease
Drunk driving
Cancer
Drug abuse
% saying “very serious problem”
Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000
Drug abuse
Cancer
Drunk driving
Heart disease
HIV/AIDS
Violence
Child abuse
Smoking
Alcohol abuse
Stress

3. Two Decades of Neurobiological Research Have
Brought Us A New Understanding of
Drug Abuse and Addiction, Their
Complexity and their Solutions

4. Their Many Differences, Virtually All Abused Substances Enhance
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!

5. Dopamine Pathways Serotonin Pathways Functions mood memory processing
nucleus
accumbens
hippocampus
striatum
frontal
cortex
substantia
nigra/VTA
raphe
Functions
reward (motivation)
pleasure,euphoria
motor function
(fine tuning)
compulsion
perserveration
decision making
Serotonin Pathways
Functions
mood
memory
processing
sleep
cognition

6. Neuronal structure
(receiving)
(sending)

7. /serotonin Neuronal terminal Drug : cocaine ritalin transporter Vmat
vesicle
Neuronal terminal
Drug :
cocaine
ritalin
stimulation
transporter
Vmat
/serotonin
How some drugs of abuse cause dopamine release:
opioids narcotics (activate opioid receptors)
nicotine (activate nicotine receptors)
marijuana (activate cannabinoid receptors)
caffeine
alcohol (activate GABA receptors; an inhibitory transmitter)
DA/5HT

8. transporter
Vmat
serotonin/
Release DA from vesicles and reverse
transporter
DA/5HT
Drug Types:
Amphetamines
-methamphetamine
-MDMA (Ecstasy)

9. Effects of Drugs on Dopamine Release
100
200
300
400
500
600
700
800
900
1000
1100 1 2 3 4
5 hr
Time After Amphetamine
% of Basal Release DA
DOPAC
HVA
Accumbens
AMPHETAMINE
100
200
300
400 1 2 3 4
5 hr
Time After Cocaine
% of Basal Release DA
DOPAC
HVA
Accumbens
COCAINE
Much greater
Activity than any
Other drug of abuse
-causes neurotoxicity
100
150
200
250 1 2
3 hr
Time After Nicotine
% of Basal Release
Accumbens
Caudate
NICOTINE
100
150
200
250 1 2 3
4hr
Time After Ethanol
% of Basal Release
0.25
0.5
2.5
Accumbens
Dose (g/kg ip)
ETHANOL
Source: Di Chiara and Imperato

10. Natural Rewards Elevate Dopamine Levels50
100
150
200 60
120
180
Time (min)
% of Basal DA Output
NAc shell
Empty
Box
Feeding
Source: Di Chiara et al.
FOOD
100
150
200
DA Concentration (% Baseline)
Mounts
Intromissions
Ejaculations 15 5 10
Copulation Frequency
Sample
Number 1 2 3 4 6 7 8 9 11 12 13 14 16 17
Scr
Bas
Female 1 Present
Female 2 Present
Source: Fiorino and Phillips
SEX

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

12. Addiction and tolerance can be synonymous

13. Pharmacodynamic mechanism
of Tolerance

14. Induction of Tolerance to Morphine

15. Brain Circuits Involved in
Drug Addiction
PFC
ACG
INHIBITORY
CONTROL
OFC
Hipp
Amyg
MEMORY/
LEARNING
SCC
NAcc VP
REWARD
MOTIVATION/
DRIVE
(saliency)

16. Reward Pathways:
Role of Opioids

17. HOW DOES ADDICTION
OCCUR?

18. B C A B C Principles of Behavior Dynamics
Behavior Tracts Compete for Expression
Prefrontal
Cortex A B
behavior
expressed C
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated
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)

19. B How does a behavior become an addiction? C A B B B B
Principles of Behavior Dynamics C
Prefrontal
Cortex A B
Addiction
behavior
expressed B B B B
Orbito-
frontal cortex
dopamine
How does a behavior become
an addiction?

20. Prolonged Drug Use Changes
We Have Generated A Lot of
Evidence Showing That…
Prolonged Drug Use Changes
the Brain and
In Fundamental
and Long-Lasting Ways

21. These Changes Can Be Both Structural and Functional
We Have Evidence That
These Changes Can Be Both
Structural and Functional

22. Positron Emission Tomography
BRAIN IMAGING
Positron Emission Tomography
Magnetic Resonance Imaging

23. Decreases in Metabolism in Orbito Frontal Cortex (OFC)
control cocaine abuser
Volkow et al. Am. J. Psychiatry 148, 621

24. 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 , October 15, 1998.

25. 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 , 2001.

26. Dependence of Verbal Memory on Striatal DAT
Interference recall
Delayed recall
Compromises Cognitive Functions
R = 0.70
p < 0.005
R = 0.64
p < 0.01
Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp , 2001.

27. MOTOR FUNCTION
Slowed gait
Impaired balance
Impairment correlates with damage
to dopamine system

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

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

30. Reward System in Addiction
More
Cocaine
Ability to Experience
Rewards Is Damaged
Activity of Reward System
METH
controls
treated
Alcohol
Less
Food

31. Get Rewired
by Drug Use
Their Brains…

32. (genetic vulnerability-not inevitability)
INHERITED FACTORS
(genetic vulnerability-not
inevitability)
Common strategy to investigate
are Twin Studies

33. In General: Inheritability for Drug
Abuse Ranges From 40-60%
Some Variability Between Drugs
Some Gender Variability

34. Chromosomal Locations for Substance Abuse Vulnerability Loci17 22
r-SA
r-candidate 5 6
3 samples, > 2 labs
4 samples, > 3 labs
>2 samples, >2 labs
Chromosomal Locations for Substance Abuse Vulnerability Loci
Uhl et al Tr Genetics, updated June 03

35. Complex genetics
Complex phenotypes (expressions)
(Relation to Risk Factors?)

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

37. Contribution of Genetic Factors to:
For Example-
Contribution 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)

38. Genetics May Influence How
Neurobiology Interacts With
Environment

39. Gene/ Environment Interaction
Genetics
Gene/ Environment Interaction
Environment

40. Dopamine Receptor Density
PET Images:
Dopamine Receptor Density
More
likely
to self-
administer
Cocaine

41. Devotes ~ 100 pages to describing
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

42. 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 with-
out considering drug abuse?)

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

44. Because of this overlap, drugs of abuse can cause symptoms that mimic
most forms of mental illness

45. Drug Disorder Cocaine and Methamphetamine Schizophrenia, paranoia,
anhedonia, compulsive
behavior
Stimulants
Anxiety, panic attacks,
mania and sleep disorders
LSD, Ecstasy & psychedelics
Delusions and hallucinations
Alcohol, sedatives, sleepaids
& narcotics
Depression and mood
disturbances
PCP & Ketamine
Antisocial behavior

46. Some drugs of abuse have a mechanism of action similar to
that of drugs used as
psychotherapeutic agents
Significance: rationale for
self-administration

47. Causes an effect Serotonin/dopamine synaptic terminal transporter
Synaptic vesicle
Prozac,
Ritalin, &
Cocaine
block
Postsynaptic
target
Causes an effect
Activate transmitter receptors

48. Mechanism of action
of amphetamine and
cocaine

49. Chronic use of some of these drugs of
abuse may alter the way the brain
functions, making persons particularly
susceptible to mental illness

50. Mental and Addictive Disorders
Double
People With Comorbid
Mental and Addictive Disorders
Have a Brain Disease
Mental
Disorder
Addictive
Disorder
Comorbid
Disorders

51. Role of Stress and Trauma

52. The Stress Hormone Cycle
Stress Responses
Hypothalamus
Stress Responses
Stress Responses
Stress Responses
CRF
Pituitary
Gland
CORTISOL
ACTH
Adrenal
Glands
CRF:
Corticotropin
Releasing
Factor
Kidneys

53. DRUG USE (Self-Medication)
Anxiety
DRUG USE (Self-Medication)
What Role Does Stress Play
In Initiating Drug Use?
CRF
CRF
STRESS
Anxiety

54. What Happens When A Person
Anxiety
RELAPSE
Prolonged DRUG USE
What Happens When A Person
Stops Taking A Drug?
CRF
Abstinence

55. Stress Reliably Reinstates Drug Seeking in Rats*
Cocaine-trained rats
Alcohol-trained rats
100 80
Inactive Lever
Responses 60
Active Lever * 40 * 20 *
Saline
Cocaine
Footshock
Water
Alcohol
Footshock
Nicotine-trained rats
Heroin-trained rats *
100 80
Responses 60 * * * 40 20
Saline
Nicotine
Footshock
Saline
Heroin
Footshock
From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

56. CRF1 Receptor Antagonist Attenuates Stress-Induced Reinstatement
of Drug Seeking
Alcohol-trained rats
Heroin-trained rats
Cocaine-trained rats 60 60
No stress 45 45
Intermittent Footshock
Responses (1 hr) * 30
Responses (3 hr) 30 * * * * 15 15 15 30 15 30 15 30
CP-154,526 Dose (mg/kg, SC)
From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

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

58. B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito-
expressed C
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated

59. Strengthen prefrontal cortex influence (change thinking process)
cognitive and cognitive behavioral tx
(unlearn old habits-suppress; learn
new skills)
assertiveness training (suppress and
express)

60. B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito-
expressed C
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated

61. Alter function of orbitofrontal (saliency) cortex
motivational therapy
family therapies

62. B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito-
expressed C
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated

63. Recovery of function (frontal and obito- frontal cortex)
all treatments that keep brain away
from drugs for extended time

64. B C A B C Principles of Behavior Dynamics Prefrontal Cortex Orbito-
expressed C
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated

65. Alleviate underlying psychiatric disorder
administer: Antidepressants for depression
Ritalin for ADHD
Sedatives for anxiety

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

67. How some drugs of abuse cause dopamine release:
vesicle
Neuronal terminal
stimulation
transporter
Vmat
How some drugs of abuse cause dopamine release:
opioids narcotics (activate opioid receptors)
nicotine (activate nicotine receptors) DA

68. Psychostimulants
Enhancing GABA-ergic inhibition
(baclofen-muscle relaxant; anti-seizure-
Tiagabine)
Cannabinoid antagonist (rimonabant)

69. C B GABA and cannabinoid systems critical for function A B C
Principles of Behavior Dynamics
GABA and cannabinoid
systems critical for
function
Prefrontal
Cortex A C
behavior
expressed B
behavior
expressed B C
Orbito-
frontal cortex
dopamine initiated

70. Relieve stress-related drug abuse
CRF antagonist
Anxiety
RELAPSE
Prolonged DRUG USE
CRF
Abstinence

71. No cure