Neurobiology of Addiction - Addiction medicine - Spring Conference Sli… · Neurobiology of Addiction Essentials of Addiction Medicine Program AOAAM Pittsburgh, PA March 2, 2019

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