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(Top 10 of 36 Problems)
82%
Drug abuse
Cancer
78%
Drunk driving
75%
Heart disease
74%
73%
HIV/AIDS
Violence
Child abuse
Smoking
71%
69%
68%
Alcohol abuse
65%
Stress
65%
For Example
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
transporter
Vmat
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
% of Basal Release
% of Basal 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
1
2
3
Time After Ethanol
4hr
% 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
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
Copulation Frequency
DA Concentration (% Baseline)
FOOD
Implication:
Elucidation of the mechanism of
drug addiction will help to
understand other addictive and
motivational behaviors/disorders
Pharmacodynamic mechanism
of Tolerance
PFC
ACG
Hipp
SCC
MOTIVATION/
DRIVE
(saliency)
REWARD
NAcc
VP
Amyg
MEMORY/
LEARNING
Reward Pathways:
Role of Opioids
A
B
C
behavior
expressed
C
B
dopamine initiated
Orbitofrontal cortex
Prefrontal
Cortex
Orbitofrontal cortex
C
A
Addiction
B
B
BB behavior
expressed
dopamine
AND
We Have Evidence That
These Changes Can Be Both
Structural and Functional
BRAIN IMAGING
Positron Emission Tomography
Decreases in Metabolism
in Orbito Frontal Cortex (OFC)
control
cocaine abuser
Comparison Subject
METH Abuser
Delayed recall
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???
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)
17
r-SA
r-candidate
22
Complex genetics
VULNERABILITY to What?
Starting Drug Use?
Liking Drugs More?
Continuing Drug Use?
Becoming Addicted?
Specific to A Particular Drug?
Genetics
Gene/
Environment
Interaction
Environment
PET Images:
Dopamine Receptor Density
More
likely
to selfadminister
Cocaine
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?)
Drug
Cocaine and Methamphetamine
Disorder
Schizophrenia, paranoia,
anhedonia, compulsive
behavior
Stimulants
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
Mental
Disorder
Comorbid
Disorders
Addictive
Disorder
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
STRESS
CRF
Anxiety
Anxiety
Prolonged
What
DRUG
USE
RELAPSE
Abstinence
Cocaine-trained rats
100
80
60
40
Alcohol-trained rats
Inactive Lever
Active Lever
*
*
20
0
Saline
Cocaine Footshock
Responses
Nicotine-trained rats
100
80
60
40
20
0
Saline
Nicotine
Footshock
Saline
Heroin Footshock
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
30
Objectives of Intervention:
Rearrange dominance of behavior tracks
contingency management (vouchers)
motivational enhancement
therapeutic communities
Prefrontal
Cortex
A
B
C
behavior
expressed
dopamine initiated
Orbitofrontal cortex
C
B
Prefrontal
Cortex
A
B
C
behavior
expressed
dopamine initiated
Orbitofrontal cortex
C
B
Prefrontal
Cortex
A
B
C
behavior
expressed
dopamine initiated
Orbitofrontal cortex
C
B
Prefrontal
Cortex
A
B
C
behavior
expressed
dopamine initiated
Orbitofrontal cortex
C
B
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
DA
Psychostimulants
Enhancing GABA-ergic inhibition
(baclofen-muscle relaxant; anti-seizureTiagabine)
Cannabinoid antagonist (rimonabant)
Prefrontal
Cortex
behavior
expressed
dopamine initiated
Orbitofrontal cortex
C
B
CRF
Abstinence
RELAPSE
No cure