American Osteopathic Academy of Addiction Medicine Essentials of - - PowerPoint PPT Presentation

American Osteopathic Academy of Addiction Medicine Essentials of Addiction Medicine Neurobiology of Addiction

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, memory

and related circuitry

• Impairment in behavioral control, craving, diminished recognition
• f 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/MesocorticalPathways

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

100 200 300 400 500 600 700 800 900 1000 1100 1 2 3 4 5 hr Time After Amphetamine % of Basal Release

AMPHETAMINE

50 100 150 200 60 120 180

Time (min)

% of Basal Release Empty Box Feeding Di Chiara et al.

FOOD VTA/SN nucleus accumbens frontal cortex

Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction

Drugs and Natural Rewards ACTIVATE Dopamine in Reward Regions

Dopamine

• In short…Dopamine release in Nac mediates “goodness” effects of drugs (reward)

while hijacking the PFC (cognitive control)

• Opioidergic System (“hedonic”): mediates reinforcing effects of alcohol 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 Receptors (Ratio Index)

20 25 30 35 40 45 50 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2`

Bmax/Kd

Normal Controls Cocaine Abusers

Healthy Heart Diseased Heart

Decreased Heart Metabolism in Heart Disease Patient

ADDICTION IS A DISEASE OF THE BRAIN as 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 DA DA

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

• ccurring.

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 DISEASE starts in adolescence and childhood

NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

% in each age group who develop first- time cannabis use disorder

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 70

Age

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

Controls Methamphetamine Abusers

OFC

umol/100gr/min

4

Controls Alcoholics

control addicted

Brain glucose metabolism

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 22 24 26 28 30 32 34 36 38

D2R VS (micromol/100g/min) Metabolism Prefrontal

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

Medications for Opioid Addiction

effect no effect

agonist antagonist

an agonist drug has an active site of similar shape to the endogenous ligand so binds to the receptor and produces the same effect an antagonist drug is close enough 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

Opioid Effect

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 Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence

Normal Control METH Abuser (1 month detox) METH Abuser (14 months detox)

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