Neurobiology of Addiction Essentials of Addiction Medicine Program - PowerPoint PPT Presentation

Neurobiology of Addiction Essentials of Addiction Medicine Program AOAAM Pittsburgh, PA March 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 Cue Amygdala tells DA neuron in VTA something good is about to happen VTA triggers DA in NA to get drug substantial reward drug ingested bigger reward Prefrontal cortex debates whether to relieve craving or not

The definition of addiction (ASAM) • A primary chronic disease of brain reward, motivation, memory and 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 Mesolimbic/MesocorticalPathways Feature Neural substrate Reward Mesocorticolimbic dopamine pathway Inhibition of Prefrontal cortex behavior (PFC)- lateral Associative learning Amygdala (medial temporal lobe)

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

Drugs and Natural Rewards ACTIVATE Dopamine in Reward Regions 1100 1000 AMPHETAMINE 900 % of Basal Release 800 frontal 700 600 cortex 500 400 300 200 100 0 nucleus 0 1 2 3 4 5 hr Time After Amphetamine accumbens VTA/SN FOOD 200 % of Basal Release 150 100 Empty Drugs of abuse increase DA in the 50 Feeding Box Nucleus Accumbens, which is believed 0 0 60 120 180 to trigger the neuroadaptions Time (min) Di Chiara et al. that result in addiction

• 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 Normal Controls 4.5 Cocaine Abusers 4 DA D2 Receptors Cocaine (Ratio Index) 3.5 3 2.5 2 Meth 1.5 15 20 25 30 35 40 45 50 3.2` 3 2.8 Alcohol Bmax/Kd 2.6 2.4 2.2 2 1.8 1.6 20 25 30 35 40 45 50 Heroin control addicted Volkow et al., Neuro Learn Mem 2002.

ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Decreased Brain Metabolism in Drug Abuse Patient High Control Cocaine Abuser Decreased Heart Metabolism in Heart Disease Patient Low Diseased Heart Healthy Heart Sources: From the laboratories of Drs. N. Volkow and H. Schelbert

Repeated Drug Use Changes the Brain Weakens the Brain Dopamine System Cocaine Abuser Control TYROSINE TYROSINE TYROSINE DOPA DOPA DOPA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA COCAINE DA DA DA DA DA DA DA DA DA DA PLEASURE REPEATED USE OF COCAINE OR OTHER DRUGS REDUCES LEVELS OF DOPAMINE D2 RECEPTORS

Mechanism of Action - GABA A Receptor • The GABA A 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.

Mechanism of Action – GABA A Receptor • GABA A 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, benzodiazepines, ethanol non-benzodiazepines, neuroactive steroids, barbiturates, inhaled anaesthetics 22

ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.6% Prefrontal % in each age group who develop first- Cortex 1.4% 1.2% time cannabis use disorder 1.0% 0.8% Amygdala 0.6% Brain areas where volumes are smaller in 0.4% adolescents than young adults 0.2% Sowell, E.R. et al., Nature Neuroscience, 2, 859-861, 1999 0.0% 5 10 15 18 25 30 35 40 45 50 55 60 65 70 Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

Low Levels of Striatal D2 Receptors Are Associated with Impaired Activity in Frontal Regions DA D2 receptors 65 60 55 Brain glucose metabolism 50 control addicted 45 40 Control Cocaine Abuser 35 umol/100gr/min 30 1.8 2 2. 2.4 2. 2.8 3 3.2 3. 90 2 6 4 OFC 80 70 60 50 Methamphetamine 40 Controls Abusers 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 4 38 Metabolism Prefrontal (micromol/100g/min) 36 34 32 0 30 28 26 Controls Alcoholics 24 22 1.5 2 2.5 3 3.5 D2 Receptors (BP ND ) D2R VS Volkow et al., PNAS 2011 108(37): 15037-42

Addicted Brain Non-Addicted Brain Control Control CG STOP Saliency Saliency Drive Drive Drive GO Saliency OFC NAc Memory Memory Memory Amygdala Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

Medications for Opioid Addiction antagonist agonist Full Agonist (Methadone) Opioid Effect no effect Partial Agonist (Buprenorphine) effect an antagonist drug is close enough in shape to bind to the receptor but not close enough to produce an effect. It also an agonist drug has an takes up receptor space and so active site of similar shape Antagonist prevents the endogenous to the endogenous ligand (Naloxone) ligand from binding so binds to the receptor and produces the same effect 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

ADDICTION CAN BE TREATED Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 0 ml/gm METH Abuser Normal Control METH Abuser (1 month detox) (14 months detox) Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

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