1 neuroscience of addiction study workshop: overcoming barriers to engagement with difficult and...
Post on 20-Dec-2015
214 views
TRANSCRIPT
1
Neuroscience of Addiction
Study Workshop: Overcoming Barriers to Engagement withDifficult and Different Clients
2
Introductions*
1. What type of work do you do?
2. What do you hope to gain from this workshop?
3
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
4
Difficult Patients*
• Who are they?
• What makes them difficult?– Behaviors– Attitudes– Response to treatment
5
CRAVING
SEEKING
USE
6
Map your difficult patients to workshop goals:
Identifying vulnerabilitiesAppreciating drug effects on brainUnderstanding cravingDiscuss correlates of compulsionUnderstand cognitive aspects of
drug use
7
Neuroscience of Addiction
• Advances in understanding over last few years
• New technologies to visualize brain activity
8
Addiction is Complex
• Psychological
• Social
• Spiritual
• Biological
9
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!
10
Addiction
“Addiction at its core is a biological process”Biological AgentBiological Substrate Nestler and Aghajanian, 1997
11
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
12
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
13
Overall Goal
• Understanding the neuroscience of addiction will allow you to treat your clients’ addictions in a new way
14
Other Housekeeping
• Exercises
• Breaks
• Lunch
• Evaluations
15
General
• Time outs
• Repetition– Review– Build up understanding– Integrate different materials
16
Exercises
• Reinforce
• Make abstract information more concrete
• Resources
• Involvement
• Your experience and expertise
17
Defining Key Terms for Workshop
• Addiction
• Dependence
• Tolerance
18
Define Addiction
• Loss of control over intense urges
• Drug use despite adverse consequences
19
Addiction
• Impaired control
• Craving and compulsive use
• Continued use despite negative consequences
20
Physical Dependence
• State of adaptation
• Expected result of use (opioids, BZD’s)
• Drug class specific withdrawal syndrome– Abrupt decrease/ discontinuation
21
Tolerance
• State of adaptation
• Drug effects lessen over time
• Increase in dose needed for same effect
22
Pseudoaddiction
• Unrelieved pain
23
How do you define addiction?*
• How do you know when someone has crossed that line?
24
Part 1 Neuroscience
– Review brain– Reward circuit– Changes from drug use– Who gets addicted?
• Genetics• Environment
25
Brain and Beyond
• Brain
• Structures
• Neuron
• Transmission
• Neurotransmitters
26
The Brain
• An Adult brain weighs about 3 pounds and has billions of cells– Neurons– Glial cells
27
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
28
Major Brain Regions
• “Primitive” Brain– Brainstem– Cerebellum
– Limbic System
• “Evolved” Brain– Cortex
29
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
30
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
31
Functional Divisions: Cut Brain View
32
Brain and Beyond
• Brain
• Structures
• Neuron
• Transmission
• Neurotransmitters
33
Structures
• Ventral Tegmental Area (VTA) – More on this later
• Nucleus Accumbens– Center Stage for drug response
• Amygdala
• Prefrontal Cortex
34
OFCOFCSCC
NAcc
NAcc VPVP
PFCPFC
ACGACG
HippHipp
AmygAmyg
Brain Structures Involved in Drug Addiction
35
Structures: Amygdala
36
Amygdala
• Key for sensing emotional meaning of things
• Reward?
• Threat?
37
Exercise: Cut Brain Image**
• For review and reference :Label and color (if you wish)– VTA– Nucleus Accumbens– Amygdala– Hippocampus– Prefrontal Cortex
38
Brain and Beyond
• Brain
• Structures
• Neuron
• Transmission
• Neurotransmitters
39
The Neuron
• Basic signaling unit of the brain
• Precise connections allow for different actions– Neurons– Sensory
receptors– Muscles
40
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
41
Photo of Neuron
42
Neuron Aglow
43
The Synapse
• End of axon• Typical
neuron has 1000 synapses with other neurons
• Intercellular space between neurons– Synaptic cleft
44
The Synapse
45
The Synapse
46
Receptors
• Proteins on many types of cells
• Receive and bind specific chemicals
• Neuronal receptors – Neurotransmitters– Drugs
47
Receptor Numbers and Function
• Cell can Increase or decrease to stay in balance
48
Cell Receptors• Molecules that bind a receptor are
AGONISTS• Molecules that also bind to a receptor and
block it are ANTAGONISTS– Naloxone
49
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
50
Brain and Beyond
• Brain
• Structures
• Neuron
• Transmission
• Neurotransmitters
51
Synaptic Transmission
• Neurons communicate via electrical and chemical signals– Electrical signal converted to a chemical
signal– a neurotransmitter
52
Synaptic Transmission
• 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
53
Synaptic Transmission
• 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
54
Synaptic Transmission
• Neurotransmitters diffuse into intercellular space
• Bind to receptors on dendrite of another cell– Postsynaptic cell
– Receptors are specific– Dopamine receptors will only bind dopamine
55
Synaptic Transmission
• 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”
56
Reuptake of Neurotransmitter
• Allow for fast and precise signaling
• Sometimes enzymes in the synapse also clear the transmitter
57
58
Synapse**
• Label and color (if you like)
• Presynaptic neuron
• Postsynaptic neuron
• Vesicles
• Receptors
• Reuptake pumps
59
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
60
61
Dopamine binding to receptors and uptake pumps in the nucleus accumbens
62
Dopamine receptors: Distribution
63
Dopamine
• Dopamine and Dopamine receptors are center stage for multiple stages of addiction– Initial euphoria– Addiction Vulnerability– Compulsive behaviors– Craving and relapse
64
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?
65
D2 receptors Decreased in Obesity
66
normal subject
cocaine abuser (1 month post)
cocaine abuser (4 months post)
Effect of Cocaine Abuse on Dopamine D2 Receptors
67
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
68
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
69
Hijacking the Dopamine-Fueled Reward System
70
Part 1 Neuroscience
– Review brain– Reward circuit– Changes from drug use– Who gets addicted?
• Genetics• Environment
71
Reward Circuit
• Ancient brain mechanism to help negotiate environment for survival
• Still active in today’s environments
72
How do patients describe their first drug use?*
73
Reward Pathway• Specialized brain areas for producing
and regulating PLEASURE– Ventral Tegmental Area– Nucleus Accumbens– Prefrontal Cortex– Areas of Limbic system– amygdala,
hippocampus, hypothalamus
74
Reward Circuit
• Drugs hijack this circuit– Give false signal of fitness/ well-being– Override rational thought– Take over voluntary behavior
75
Reward Circuit: What are Your Natural Rewards?**
76
Reward Circuit: Evolved
• Grip attention
• Motivate survival behavior
• Disregard dangers
• Compel behavior towards survival goals
77
Animal Experiments*
• Direct electrical stimulation of brain reward areas with level press.
• What happens?
78
Reward Circuit
• “Addiction is a disease of brain reward centers that ensure the survival of organisms and species”
• Dackis & O’Brien, 2005
79
Dopamine Pathways
Functions•reward (motivation)•pleasure,euphoria•motor function (fine tuning)•compulsion•perserveration•decision making
80
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
81
Dopamine Levels around Nucleus Accumbens and Reported “High”
82
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
83
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
84
00
5050
100100
150150
200200
00 6060 120120 180180
Time (min)Time (min)
% o
f B
asal
DA
Ou
tpu
t%
of
Bas
al D
A O
utp
ut
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
85
100100
150150
200200D
A C
on
cen
tra
tio
n (
% B
asel
ine)
DA
Co
nce
ntr
ati
on
(%
Bas
elin
e)
MountsMountsIntromissionsIntromissionsEjaculationsEjaculations
1515
00
55
1010
Co
pu
latio
n F
req
ue
nc
yC
op
ula
tion
Fre
qu
en
cy
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
86
Sex and Food on Dopamine• Evolution: linking pleasurable feelings to
food and sex is important in continuing the species
87
00100100200200300300400400500500600600700700800800900900
1000100011001100
00 11 22 33 44 5 hr5 hr
Time After AmphetamineTime After Amphetamine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADADOPACDOPACHVAHVA
AccumbensAccumbens AMPHETAMINEAMPHETAMINE
00
100100
200200
300300
400400
00 11 22 33 44 5 hr5 hrTime After CocaineTime After Cocaine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADADOPACDOPACHVAHVA
AccumbensAccumbensCOCAINECOCAINE
00
100100
150150
200200
250250
00 11 22 3 hr3 hr
Time After NicotineTime After Nicotine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
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
200200
250250
00 11 22 33 4hr4hrTime After EthanolTime After Ethanol
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
0.250.250.50.5112.52.5
AccumbensAccumbens
00
Dose (g/kg ip)Dose (g/kg ip)
ETHANOLETHANOLETHANOLETHANOL
88
Addiction Cycle
89
Part 1 Neuroscience
– Review brain– Reward circuit– Changes from drug use– Who gets addicted?
• Genetics• Environment
90
Effects of Drug Use on the Brain
• Short term
• Long term
91
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
92
93
Acute Effect of Drugs on Reward Circuit
• Cocaine
• Alcohol
• Methamphetamine
• Ecstasy
• Nicotine
• Caffeine
• Opioids
94
Cocaine binding to uptake pumps; inhibition of dopamine uptake
95
Sex 200, Cocaine 350
00
100100
200200
300300
400400
00 11 22 33 44 5 hr5 hr
Time After CocaineTime After Cocaine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADA
DOPACDOPAC
HVAHVA
AccumbensAccumbens
COCAINECOCAINE
96
Drug effects on neurotransmission
• Alcohol, heroin, nicotine excite the dopamine neurons in the VTA to increase dopamine release
97
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)
98
99
Sex 200, Amphetamine 1050
00
100100
200200
300300
400400
500500
600600
700700
800800
900900
10001000
11001100
00 11 22 33 44 5 hr5 hr
Time After AmphetamineTime After Amphetamine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
DADA
DOPACDOPAC
HVAHVA
AccumbensAccumbensAMPHETAMINEAMPHETAMINE
100
Marijuana
101
Marijuana
102
THC Binds in Nucleus Accumbens
103
THC• Binding in nucleus accumbens
increases dopamine release
• THC binds to receptors specific for a natural brain chemical (anandamide)
104
105
Drug Effects On Neurotransmission: Ecstasy
• Binds to reuptake pumps
• REVERSES the pumps
• Also inhibits dopamine transporters
106
• 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
107
Sex 200, Nicotine 235
00
100100
150150
200200
250250
00 11 22 3 hr3 hr
Time After NicotineTime After Nicotine
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
AccumbensAccumbens
CaudateCaudate
NICOTINENICOTINE
108
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
109
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
110
Sex 200, Alcohol 200
100100
150150
200200
250250
00 11 22 33 4hr4hr
Time After EthanolTime After Ethanol
% o
f B
as
al
Re
lea
se
% o
f B
as
al
Re
lea
se
0.250.25
0.50.5
11
2.52.5
AccumbensAccumbens
00
Dose (g/kg ip)Dose (g/kg ip)
ETHANOLETHANOLETHANOLETHANOL
111
Short Term Effects: Endogenous Opioids
Brain pathways involved in:
• Pain
• Pleasure
• Appetite
• Sexual function
• Natural drive states
112
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
113
Binding Sites in the Brain
114
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
115
Opiates Binding to Receptors
116
Opioids
• Alcohol opioid effect is blocked by drug naltrexone (antagonist)
• Naltrexone pretreatment extinguishes alcohol self-administration in monkeys
• Basis for Revia® and Vivitrol®
117
Other Drug Effects
• Substances may bind to multiple brain sites
• Different effects at different sites– Methamphetamine
• Reward pathway: high• Other dopamine areas: hallucinations
118
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
119
Addiction Cycle
120
Long Term (Chronic) Effects of Drug Use
• Adaptations/ alterations within the brain
• Longer term aspects of addiction– Craving– Relapse– Cellular level
121
Effects of Chronic Drug Use
• Long lasting
• Involve multiple brain circuits– Reward– Motivation– Learning– Inhibitory control– Executive functioning
122
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.
123
Addiction Cycle
124
Addiction Cycle
• Becomes more uncontrollable as brain becomes more addicted– Frequency of drug use– Route of drug use– Chronicity of drug use
125
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
126
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
127
Implications for Recalibration*
128
How/ Why do cells change like this?
• Changes in how the cell works INSIDE
• Changes in cell size, shape and receptors
129
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
130
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
131
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
132
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)
133
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
134
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
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001
135
• 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
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001
Basis for Plasticity: Summary
136
Other Chronic Drug Effects
• Cell Death (“Neurotoxicity”)– Neurons don’t grow back– Alcohol, ecstasy, methamphetamine
• Effect memory, mood, learning (Part 2 topics)
137
138
Chronic Effects (Ecstasy)
139
Chronic Effects (Cocaine) • Over time, brain
activity as measured by PET trends towards normal
• Neuropsychological function may never normalize
140
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
141
Day 1 Neuroscience
– Review brain– Reward circuit– Changes from drug use– Who gets addicted?
142
What makes a drug addictive
• Onset of action
• Subjective effect
• Half life
143
Drug Ingestion
144
Rapid Onset Increases Risk of Addiction
145
Half Life
• Rapid discontinuation of effects leads to “negative reinforcement”– Repeated use to avoid withdrawal/rebound
effects
146
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
147
Who Gets Addicted?
• Animal models
• Genetics
• Developmental
• Environment
• Mental illness
148
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
149
Animal Models of Relapse
• “Drug Seeking Behavior”
• Stimulated by:– Exposure to the drug– Cues associated with prior drug exposure– Stress
150
Animal Strains
• Different readiness to self-administer drugs
• Different cellular and molecular responses to chronic drug exposure
151
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
152
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
153
Who Gets Addicted?
• Animal models
• Genetics
• Developmental
• Environment
154
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
155
Genetics *
• 40-60% of addiction attributable to genetic factors
• What are some other genetically influenced diseases?
156
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
157
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.
158
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
159
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
160
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
161
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
162
GeneticsGeneticsGeneticsGenetics
EnvironmentEnvironmentEnvironmentEnvironment
Gene/Gene/EnvironmentEnvironmentInteractionInteraction
Gene/Gene/EnvironmentEnvironmentInteractionInteraction
163
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
surge
164
Relative sensitivity of different mouse strains to opioids
(Pasternak, 2004)
165
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
166
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
167
• Genetics/ D2 receptor density may help explain variability in liking drug effect
168
2.5
0
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.
169
Genetically Altered Animals
170
Who Gets Addicted?
• Animal models
• Genetics
• Developmental
• Environment
171
Independence + Irresponsibility=Adolescence
172
Developmental: Adolescence
• Normal behaviors increase probability of drug experimentation– Risk-taking– Novelty-seeking– Peer pressure– Rebelling against authority
173
Developmental: Adolescence
• Brain development incomplete
• Myelination of frontal lobe regions not complete– Frontal lobe: judgment, impulse control,
174
Maturation of brain age 5-21
175
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
176
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?
177
Developmental: Adolescence
• Neuroadaptations to drugs different than adult brains– Nicotine, alcohol, cannabinoids
• Greater vulnerability to addiction as adults?
178
Alcohol on Developing Brain
179
Most people start drug experimentation ages 8-16
• What are the implications?*
180
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
181
What would an effective prevention program look like?*
182
Who Gets Addicted?
• Animal models
• Genetics
• Developmental
• Environment
183
Environmental Aspects of Addiction
• How available is the drug?– Recent drug abuse patterns in the U.S.– What contributes to an “epidemic”?
184
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
185
Environment: Viet Nam and Heroin
• 20% soldiers in Viet Nam addicted to heroin
• 1% continued addiction in U.S.
• What are the environmental factors?
186
HALT
187
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
188
Environmental Aspects of Addiction
Overlap with genetics/ stressors• Low SES
• Low parental support
What are the alternative rewards/ reinforcers?
189
Macaque Monkeys
190
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
191
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
192
Environment and Stress/ Rewards
Social status affects brain Dopamine D2 receptors
– Low social status • Less expression of D2 receptors• Increased cocaine self administration
193
More likelyMore likelyto self-to self-administeradministerCocaineCocaine
More likelyMore likelyto self-to self-administeradministerCocaineCocaine
PET Images: Dopamine Receptor Density
194
Effect of Social Dominance on CocaineEffect of Social Dominance on CocaineSelf -AdministrationSelf -Administration
*
*
.003 .01 .03 .1
0.0
0.5
1.0
1.5
2.0 TOTAL INTAKE
(mg/kg/session)
Cocaine (mg/kg/injection)
Subordinate
DominantMea
n i
nta
ke/s
essi
on
(m
g/k
g)
195
Implications of Monkey Experiments for Addiction
Treatment?*
196
Addiction Cycle
197
Summary
• Brain
• Neurotransmitters
• Pathways
• Vulnerabilities
198
Genetics: Exercise in Chocolate*
199
Part 2
• Part 2 Applied Neuroscience– Understanding craving– Correlates of compulsion– Cognitive aspects of drug use– Emerging pharmacology for treatment of
addiction