Neurobiology of Addiction

1. Neurobiology of Addiction Mark Publicker, MD FASAM Medical Director Mercy Recovery Center

3. Addiction • A chronic but treatable brain disease characterized by • loss of control • compulsive use • use despite known harm • relapse

4. Comorbid substance abuse • Common problem in psychiatric patients • Contributes to treatment refractoriness, non-compliance and increased health services utilization and cost

5. Rand Survey of Care, 2001 • 3% US population has co-occuring disorders • Of these: • 72% received no treatment in previous 12 months • Only 8% received both mental and substance abuse treatment • Only 23% of those in treatment received “appropriate treatment”

6. Depression Anxiety disorders Bipolar disorder Schizophrenia ADHD PTSD ASP Axis II disorders Co-morbid psychiatric disorders

7. Epidemiology • 50% lifetime prevalence of substance abuse disorders for psychiatric patients • Schizophrenia: prevalence rates of 70% in some surverys • Onset of symptoms earlier in drug-abusing schizophrenics

8. Epidemiology • Schizophrenia: substance abuse associated with higher rates of homelessness, non-compliance, medical illness and violence • Bipolar disorder: rates estimated to be 50-70% • Associated with worse prognosis

9. Epidemiology • Unipolar depression: 30-50% • Associated with treatment resistance and greater severity • Worsens alcohol dependence treatment outcomes

10. Epidemiology • ADHD: NIDA estimates up to 50% of substance abuse patients • Increased risk of SUD up to 9 times • Effective childhood treatment reduces risk

11. Epidemiology • PTSD: increased risk of SUD • Hypothalamic and noradrenergic mechanisms • PTSD precedes SUD • Substance abuse modifies neurobiologic substrate, intensifying PTSD symptoms which in turn intensify SUD

12. PTSD • In course of use, drug abusers place selves in dangerous situations • Withdrawal symptoms overlap with arousal symptoms • Increased CRH sensitizes LC, increasing noradrenergic tone which increases CRH release • Increased CRH by both substance abuse and PTSD potentiate fear responses in amygdala

13. Epidemiology - Nicotine • Nicotine-dependent patients with comorbid disorders: 7.1% US population consume 34.2% of all cigarettes smoked

14. Havassy et al. AJP 1/2004 • Comparison study of comorbid patients recruited in two treatment settings • Residential (non-hospital) psychiatric for seriously mentally ill patients • Equivalent Substance abuse residential program

15. Havassy et al. • Of 420 eligible patients, 54% (N=226) met comorbid criteria • More MI patients met comorbid criteria than did SA (60%-49%)

16. Cloninger’s personality typology • Reward dependence • Harm avoidance • Novelty seeking

17. Covariation of risk behaviors • % Sex TobAlcMJ • Sex: 100 83 88 74 • Tobacco: 45 100 92 67 • Marijuana: 56 94 95100

18. Family risk factors • Tarter 1999: developmental window: father stops use: • Before age 6 - child=control in sud and asp • After age 6 - no decrease in later sud

19. Culture • Role of factors promoting or inhibiting use • Age • Gender • Ethnicity • Protective cultural boundaries

20. Women and injection drug abuse • Sexual and/or physical abuse significant risk factor for initiation and maintenance • NYC study: • 39% sexually abused before 16 • 27% before 13

21. Women and injection drug abuse • Women much more likely to have psychiatric diagnoses • NYC study: 65% women in methadone maintenance therapy have been abused as adults • Differences in needle-sharing behavior

22. Nerve cells

23. Synapse and neurotransmission

24. Dopamine neurotransmission

25. Dopamine and c-AMP

26. Dopamine receptors and reuptake pumps

27. Cocaine binding to uptake pumps

28. PET scan: brain on cocaine

29. Opiates binding to opiate receptors in the NA

30. Increased cAMP activity

31. THC binding sites

32. THC binding increases dopamine release in NA

33. Havassy et al • No significant differences in overall rates of mental disorders • Higher prevalence of schizophrenic spectrum disorders in MI setting (43%-31%) • No signficant difference in bipolar prevalence

34. Havassy et al • SA setting: decreased likelihood of suicide and psychiatric hospitalization history • No significant differences in rates of substance abuse • Severity of SA higher in SA setting

35. Havassy et al • SA prevalence • Less opiate and cocaine use in schizophrenic patients • No difference in days of use More similarities than differences in two settings

36. Self-medication hypothesis • Evidence nicotine attenuates stress reactivity • Schizophrenia: use nicotine to deal with negative symptoms: sleep, dysphoria, antipsychotic adverse effects and to improve cognitive function

37. Neurobiology • Drugs of abuse interact and alter neural substrates related to the pathobiology of psychiatric disorders • More neuropsychologic impairment

38. Substance augmentation • Koob: ‘feed-forward system’ increases stress reactivity • Withdrawal states • Problem-solution interaction

39. Neurotransmitters • Dopamine • Opioids • Glutamate • GABA • Cannabinoids • Norepinephrine

40. Dopamine • Neurotransmitter - a chemical messenger • Levels increase in the reward center when animals do those behaviors which ensure survival • D2 receptor: knockout mice

41. Dopamine and Anticipation • Dopamine levels increase in response to cue • If reward not presented, dopamine levels decrease • Decreased dopamine causes dysphoria • Example: drug cue but no drug leads to dysphoria and increased drive to obtain the drug

42. Dopamine and Withdrawal • Decreased D2 receptors in withdrawal persisting for months • Plays mediating role in drug craving and drug seeking, dysphoria and relapse

43. Opioids • Three major receptor subtypes: mu, kappa, delta • Mu key to opiate addiction Knockout mice: no morphine dependence or withdrawal • Neuroimaging: increased mu receptors in abstinence • Craving results

44. Opioids • Kappa stimulation decreases dopamine function in the NA resulting in dysphoria • Dynorphin is a kappa agonist • Buprenorphine is a kappa antagonist

45. Glutamate • Prinicpal excitatory neurotransmitter • Pathways from the prefrontal cortex and amygdala project to NA • Plays role in reinstatement of drug-seeking behavior

46. Glutamate • NMDA receptor implicated in multiple addictions: • Alcohol • Nicotine • Cannabinoids • Cocaine • Amphetamine • Opioids

47. Glutamate • NMDA receptors upregulated in addiction as well as in chronic pain states • NMDA receptor antagonists decrease sensitization and craving

48. GABA • Principle inhibitory neurotransmitter • GABA-benzodiazepine receptor • Benzodiazepines only class of drugs of abuse that don’t increase dopamine • GHB activates GABA complex • GABA tone decreased with alcohol and opioid dependence

49. Cannabinoids • Two receptors: CB1 (Brain) and CB2 (immune) • Activation: inhibits GABA leading to increase in dopamine in NA • Share properties with opioids • anti-nociception • sedation

50. Definition • “Addiction is a cycle of spiraling dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and a loss of control over drug taking” George Koob