APNC Fall Conference 2012

1. Neurobiology of Addiction and Recovery APNC Fall Conference 2012 Carolina Beach, NC October 17, 2012 John Femino, MD, FASAM, MRO Medical Consultant, Dominion Diagnostics Medical Director, Meadows Edge Recovery Center NE Regional Director, American Society of Addiction Medicine

2. Educational Objectives • Describe reward circuitry and control mechanisms of addiction • Explain set points of self administration • Understand mechanisms of tolerance + physical dependence • Understand pharmacological rationale of MAT • Understand the neurobiological basis of 12 Step sayings • Implement addiction biology into counseling practice • Explain biological rationale for following recovery plan • Bridge the attitudinal gap between abstinence oriented & MAT

3. Jellinek Definition of Dependence Focused on a predictable course of a disease with potential subtypes based on: • The clinical course • Hypothesized causes • Evidence of physiological damage

4. AA Sayings: Description of Illness • I didn’t get into trouble every time I drank, • but every time I got in trouble I was drinking • You can always tell an alcoholic, • but you can’t tell them much • Instant A..hole, just add alcohol • My best friend became my worst enemy • I did my drinking from Park Avenue to park bench

5. AA Sayings: Pathophysiology • I’m a normal person, minus two drinks • One drink is too many and a thousand is not enough • Insanity is defined as doing the same thing over and over again, expecting different results • Alcoholics heal from the outside in, but feel from the inside out • Alcoholism is the only disease that tells you, • you don’t have it • Death, insanity or recovery

6. Substance Dependence (DSM-IV) • Tolerance * • Withdrawal * • Loss of control in limiting intake • Inability to / Persistent desire to cut down or control • Great deal of time spent obtaining, using, or recovering from (compulsion to seek and take drug) • Important activities given up or reduced • Use despite problems caused or exacerbated by use • (* Diagnosis with physiological dependence)

7. NCADD & ASAM Definition Addiction is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations: • The disease is often progressive and fatal • It is characterized by continuous or periodic • Impaired control over substance use • Preoccupation with the drug • Use of substances despite adverse consequences • Distortions of thinking, most notably denial

24. Reinforcement: Neurochemical systems Glutamate Excitatory Input Enkephalin or Dynorphin Inhibitory Neuron k Opioid Receptors Dopamine Receptors Enkephalin Inhibitory Neuron Dopamine Neuron GABA Neuron REWARD m Opioid Receptors GABA-A Receptors GABA Inhibitory Feedback Presynaptic Opioid Receptors (m, d?) GABA Inhibitory Neuron Ventral Tegmental Area (VTA) Nucleus Accumbens (NAc)

25. Neuronal Circuit Changes : Drug Use • Alcohol intoxication causes • Increased dopamine in mesocorticolimbic system • Increased endorphins in mesocorticolimbic system * • Increased GABA in cortical and limbic systems • Increased anandamide (endocannabinoid agonist) • Antagonist medications block acute rewarding effect • Endocannabinoid system (Rimonabant) • Opioid (Naltrexone, Vivitrol) • GABA (flumazinil)

26. Brain Reward Cascade • Unhappy Brain • Happy Brain • From Ken Blum, MD, PhD : Reward Deficiency Solutions System

27. HAPPINESS GENE MAP 5HT2A CLOCK LEPTIN-OB HTR3B MLXIPL OPRK1 DBI OPRM1 PPARG GABRA6 ADIPOQ GABRB3 FTO CHREBP STS MANEA MAO-A MTHFR COMT VDR SLC6A3 TNF alpha DRD4 VEGF VMAT2 ANNKI NOS3 DRD2 PEMT

28. Paths to Craving Behavior:From Chocolate to Morphine Genetic Predisposition Stress Long term addiction • Decreased Chemical Functioning in the Brain • Endorphins • Serotonin • Dopamine • Nor epinephrine • GABA

29. Pseudo-Happiness came in plant form

30. Factors Contributing to Vulnerability to Develop a Specific Addiction use of the drug of abuse essential (100%) Genetic(25-50%) • DNA • SNPs • other polymorphisms Environmental(very high) • prenatal • postnatal • contemporary • cues • comorbidity • mRNA levels • peptides • proteomics • neurochemistry • behaviors Drug-Induced Effects(very high) Kreek et al., 2000

31. The Human Genome(as currently understood) • In the human genome, there are ~3 billion bases (nucleotides) • In humans, there are estimated to be ~30,000 genes (many but not all identified and annotated) • Each gene is a sequence of bases or nucleotides Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004

32. Single Nucleotide Polymorphisms (SNPs) in Genes: Definitions • SNP — a single nucleotide polymorphism, that is, one nucleotide or base of any base pair • Allelic Frequency: <1% low or rare 1–5% intermediate >5% high, frequent Kreek (Rockefeller University) & Hassin (Columbia P&S), 2004

33. Control Mechanisms: Genetic Issues • Biological mechanisms for loss of control • Endogenous dopamine deficiency / imbalance • Alcoholism metabolism genes – fast and high dose • Alcoholism protective gene – ALDH • Early Onset Addiction • High Risk behavior – dopamine deficiency • Impulse control and Frontal Lobe Dysfunction • Conduct disorder and legal problems • High dose and polysubstance pattern

34. The Dopamine D2 Receptor Gene

35. The Reward Gene

36. PREDICTIVE VALUE USING BAYES THEOREM OF CARRYING THE DRD2 Taq A1 ALLELE Total Impulsive-compulsive –Addictive Predictive value 74.4% The assumptions supporting the data are explained in Blum et al. Journal Royal Society of Medicine 1996;89:396-400

38. Normal Reward Circuitry Healthy Number of Receptor Sites Reduced Receptor Sites Brain Reward Chemistry Differences between those with the DRD2 A2 allele and those with the A1 allele DRD2 Taq A1 allele DRD2 Taq A2 allele

39. A2 Gene = Normal D2 Receptors

40. A1 Gene = 1/3 Lower D2 Receptors Equates to 100,000,000 people living in the USA

42. Reward Deficiency Syndrome

43. Tolerance and Neuroadaptation

44. Tolerance: Definitions • Tolerance: The phenomenon of decreased effect with prolonged exposure to a drug • Acute tolerance: during the time-course of a single exposure to drug • Chronic tolerance: over repeated use of drug

45. Tolerance: Cellular Mechanisms • Early recovery and abstinence • Reward threshold increases • Set point of Ah increases • Endogenous reward system is downregulated and less responsive to internal rewarding stimuli • Neuronal activity • Decreases in dopaminergic and serotonergic transmission in nucleus accumbens during alcohol withdrawal (measured by in vivo microdialysis) • Decreases in GABAergic transmission during alcohol withdrawal

46. Tolerance: Change Number of Receptors

47. Molecular Mechanisms of Neuroadaptation GABA NMDA Opiods/DA/CB1 K+ Adenyl cyclase Cl- Na+/Ca+ Ca+ cAMP second messengers Protein kinase signal tranduction pathways (PKA/ PKC, CaMK, MAPK etc. ) Fos, CREB, ELK-1, Jun (Transcription Factors) Changes in Gene Expression (Nestler, Neuron, 1996) (Koob, Neuron, 1998)

48. Addiction is a Brain Disease Repeated Drug Exposure... • Changes “Reward” Set-Point • Prolonged Dysregulation leads to vulnerability to drug use behavior, long after acute withdrawal. (Koob, Neuron, 1998)

49. Hedonic Homeostatic Dysregulation Hedonic Set Point is Altered with Chronic Drug Use “Feel good” Normal Affective Response to Drugs/Alcohol Initially use to get high… Now use to get normal. Hedonic Scale “Cravings” “Feel bad” Altered Dysregulated Set-Point following chronic drug use (Koob, Science, 1997)

50. Set Points in Self-Administration • On Signal • Description of thoughts, feelings and behaviors that result in “thought of using” or “craving” • Ah Signal - Euphoria • “the high” - The feeling of enjoyment and satisfaction (satiation) “I’ve had enough” is when enough is enough • Off Signal - Dysphoria • Description of thoughts, feelings and behaviors that send a signal of “I’ve had too much”