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Neurobiology of Addiction
Essentials of Addiction Medicine ProgramAOAAM
Pittsburgh, PAMarch 2, 2019
Stephen A. Wyatt, DO
Medical Director, Addiction Medicine
Behavioral Health Service
Atrium Heath/Carolinas HealthCare System
No Disclosures
What is addiction?
• Compulsion to seek and take the drug
• Loss of control in limiting intake
• Emergence of negative emotional state when access to drug is prevented (dependence)
• Relapsing disorder with roots in impulsivity and compulsivity and neurobiological mechanisms that change as an individual moves from one domain to another
Addiction
Prefrontal cortex debates whether to relieve craving or not
bigger reward
drug ingested
substantial reward
VTA triggers DA in NA to get drug
Amygdala tells DA neuron in VTA something good is about to happen
Cue
The definition of addiction (ASAM)
• A primary chronic disease of brain reward, motivation, memoryand related circuitry
• Impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response
• Dysfunction in these neural circuits leads to characteristic biological, psychological, social and spiritual manifestations
What causes addiction?
• ½ Genetic
• ½ Environmental:
• Impaired resiliency through parenting or life experiences
• Culture of how addiction is actualized
Reflective Reward System (“Top Down”)
• Prefrontal cortex → NA
• Regulates impulses, emotions, analyzing situations
• Controls what reactive reward system is triggering
Neural Mechanisms
Feature Neural substrate
Reward Mesocorticolimbic dopamine pathway
Inhibition of behavior
Prefrontal cortex (PFC)- lateral
Associative learning Amygdala (medial temporal lobe)
Mesolimbic/Mesocortical Pathways
Mesolimbic Pathway
• Naturally triggered by events that cause dopamine release
• Inputs from brain’s own morphine (endorphins), anadamide(marijuana), nicotine (Ach), cocaine & amphetamine (dopamine) → DA release
• Drugs of abuse (DOA) bypass brain’s NTs to directly stimulate receptors
Stimulation of the Reward Circuit
Neurochemical substrate for acute rewarding effects
Drug of abuse Neurotransmitter Site
Cocaine and amphetamines Dopamine Nucleus accumbens
-Aminobutyric acid Amygdala
Opioids Opioid peptides Nucleus accumbens
Dopamine Ventral tegmental area
Endocannabinoids
Nicotine Dopamine Nucleus accumbens
-Aminobutyric acid Ventral tegmental area
Opioid peptides Amygdala
9-Tetrahydrocannabinol Endocannabinoids Nucleus accumbens
Opioid peptides Ventral tegmental area
Dopamine
Alcohol Dopamine Nucleus accumbens
Opioid peptides Ventral tegmental area
-Aminobutyric acid Amygdala
Glutamate
Endocannabinoids
What role does will power play?
Reactive Reward System (“Bottom Up”)
• Motivation/drive to achieve pleasure or avoid pain• VTA is site of DA cell bodies• NA is where DA neurons project• Amygdala is connected to VTA and NA• Rewarding input → phasic DA firing in NA → “fun” →
conditioned reward• NA → amygdala → reward learning• Amygdala → VTA = relevance detection to previous
pleasure• Amygdala → NA = emotional response, impulsivity,
automatic
0
100
200
300
400
500
600
700
800
900
1000
1100
0 1 2 3 4 5 hrTime After Amphetamine
% o
f B
asa
l R
ele
ase
AMPHETAMINE
0
50
100
150
200
0 60 120 180
Time (min)
% o
f B
asa
l R
ele
ase
Empty
Box Feeding
Di Chiara et al.
FOODVTA/SN
nucleus accumbens
frontalcortex
Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptionsthat result in addiction
Drugs and Natural Rewards ACTIVATE Dopamine in Reward Regions
• In short…Dopamine release in Nac mediates “goodness” effects of drugs (reward) while hijacking the PFC (cognitive control) and the OFC (motivation).
• Opioidergic System (“hedonic”): mediates reinforcing effects of EtOH by indirectly modulating DA release.
Dopamine D2 Receptors are Lower in Addiction
Cocaine
Alcohol
Heroin
Meth
control addicted Volkow et al., Neuro Learn Mem 2002.
1.5
2
2.5
3
3.5
4
4.5
15 20 25 30 35 40 45 50
DA
D2 R
ecep
tors
(Rat
io I
ndex
)
20 25 30 35 40 45 50
1.6
1.8
2
2.2
2.4
2.6
2.8
3
3.2`
Bm
ax/K
d
Normal ControlsCocaine Abusers
Healthy Heart Diseased Heart
Decreased Heart Metabolism in Heart Disease Patient
ADDICTION IS A DISEASE OF THE BRAINas other diseases it affects the tissue function
Control Cocaine Abuser
Decreased Brain Metabolism in Drug Abuse Patient
Sources: From the laboratories of Drs. N. Volkow and H. Schelbert
High
Low
Repeated Drug Use Changes the Brain Weakens the Brain Dopamine System
TYROSINE
DA
DOPA
DA
DA
DA
DA
DA
DA
REPEATED USE OF COCAINE OR OTHER DRUGS REDUCES LEVELS OF DOPAMINE D2 RECEPTORS
TYROSINE
DA
DOPA
DA
DA
DA
DA DA DA
DA
DADA
DA
COCAINE
TYROSINE
DA
DOPA
DA
DA
DA
DA
DA
DA
Control Cocaine Abuser
PLEASURE
Mechanism of Action -GABAA Receptor
• The GABAA receptor
• An ionotropic receptor and ligand-gated ion channel.
• Activation, selectively conducts Cl-
through its pore, resulting in hyperpolarization (stabilization), of the neuron.
• Resulting in an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.
22
• GABAA receptor is the binding site for GABA
• Different allosteric binding sites modulate the activity
• Direct agonists
• Enhanced GABA binding
• The allosteric sites are the targets of various drugs,
Mechanism of Action –GABAA Receptor
benzodiazepines,non-benzodiazepines,barbiturates,
ethanol neuroactive steroids,
inhaled anaesthetics
ADDICTION IS A DEVELOPMENTAL DISEASEstarts in adolescence and childhood
NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003
% in
eac
h a
ge g
rou
p w
ho
dev
elo
p f
irst
-ti
me
can
nab
is u
se d
iso
rder
0.0%
0.2%
0.4%
0.6%
0.8%
1.0%
1.2%
1.4%
1.6%
5 10 15 18 25 30 35 40 45 50 55 60 65 70Age
Age at cannabis use disorder as per DSM IV
Brain areas where volumes are smaller in adolescents than young adults
Sowell, E.R. et al., Nature Neuroscience, 2, 859-861, 1999
Prefrontal Cortex
Amygdala
ControlsMethamphetamine
Abusers
OF
Cu
mo
l/1
00
gr/
min
4
0
Controls Alcoholics
con
tro
l
ad
dic
ted
Bra
in g
luco
se m
etab
oli
sm
30
40
50
60
70
80
90
2.9 3 3.1 3.2 3.3 3.4 3.5 3.6
D2 Receptors (BPND)1.5 2 2.5 3 3.5 4
25
30
35
40
45
50
D2R VS
(Bmax/Kd)
Meta
bolis
m CG
(micr
omol
/100g
/min
)
1.5 2 2.5 3 3.5 422
24
26
28
30
32
34
36
38
D2R VS
(Bmax/Kd)
Meta
bolis
m OF
C
(micr
omol
/100g
/min
)
1.5 2 2.5 3 3.5 430
35
40
45
50
D2R VS
(Bmax/Kd)
Meta
bolis
m Pr
efron
tal
(micr
omol
/100g
/min
)
30
35
40
45
50
55
60
65
1.8 2 2.
2
2.4 2.
6
2.8 3 3.2 3.
4
Control Cocaine Abuser
DA D2 receptors
Volkow et al., PNAS 2011 108(37): 15037-42
Low Levels of Striatal D2 Receptors Are Associated with Impaired Activity in Frontal Regions
Drive
OFCSaliency
NAc
MemoryAmygdala
Control
CG
Non-Addicted BrainAddicted Brain
STOP
GODrive
Memory
Saliency
Control
Drive
Memory
Saliency
Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.
Medications for Opioid Addiction
effect
no effect
agonist antagonist
an agonist drug has anactive site of similar shapeto the endogenous ligandso binds to the receptor
and produces the same effect
an antagonist drug is closeenough in shape to bind to the receptor but not close enough to produce an effect. It also
takes up receptor space and so prevents the endogenous
ligand from binding
Op
ioid
Eff
ect
Full Agonist(Methadone)
Partial Agonist(Buprenorphine)
Antagonist(Naloxone)
Log Dose
Source: SAMHSA, 2012 National Survey on Drug Use and Health, 2013.
Other secondary factors
• Underlying biologic deficit of enhanced reward function
• Neuroadaptation in motivational circuitry secondary to repeated use
• Cognitive and affective disorders
• Disruption of healthy supports and relationships
• Exposure to trauma (coping abilities overwhelmed)
• Distortion in meaning, purpose, and values that guide behavior
• Distortion in a person’s connection with self, others, and the transcendent
Partial Recovery of Brain Dopamine Transportersin Methamphetamine (METH)Abuser After Protracted Abstinence
Normal Control METH Abuser(1 month detox)
METH Abuser(14 months detox)
0
3
ml/gm
Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.
ADDICTION CAN BE TREATED
Some Resources
▪ www.pcssnow.org
▪ Provider clinical support system for medication assisted treatments
▪ www.aoaam.org
▪ Amer. Osteo. Acad. of Addiction Medicine
▪ www.asam.org
▪ Amer. Soc. Of Addiction Medicine
▪ www.drugabuse.gov/ NIDA
▪ www.NIAAA.nih.gov/ NIAAA
▪ www.scopeofpain.com/ Scope of Pain