Drugs and Addiction

1. Drugs and Addiction Neuropsychiatry Lecture 11.21.12 Jeannine Foley

2. Which of the following treatments for opioid dependence is both an opioid receptor agonist and antagonist? • A Clonidine • B Methadone • C Lofexidine • D. Naltrexone • E. Buprenorphine

3. Which of the following treatments for opioid dependence is both an opioid receptor agonist and antagonist? • A Clonidine • B Methadone • C Lofexidine • D. Naltrexone • E. Buprenorphine

4. The CAGE Questionnaire surveys an individual's relationship between alcohol and • A. concentration. • B gambling. • C. anxiety. • Deating • E. guilt.

5. The CAGE Questionnaire surveys an individual's relationship between alcohol and • A. concentration. • B gambling. • C. anxiety. • Deating • E. guilt.

6. Chronic abuse of which of the following drugs can cause intracerebralvasculitis / or hemorrhage, or subarachnoid hemorrhage? • A Heroin • B. Marijuana • C. d-Amphetamine • D. Phencyclidine • E. Lysergic acid diethylamide

7. Chronic abuse of which of the following drugs can cause intracerebralvasculitis / or hemorrhage, or subarachnoid hemorrhage? • A Heroin • B. Marijuana • C. d-Amphetamine • D. Phencyclidine • E. Lysergic acid diethylamide

8. Dopamine has been shown to inhibit the release of: • A follicle-stimulating hormone. • B. antidiuretic hormone • C. testosterone. • D. prolactin • E. thyroxin

9. Dopamine has been shown to inhibit the release of: • A follicle-stimulating hormone. • B. antidiuretic hormone • C. testosterone. • D. prolactin • E. thyroxin

10. Abrupt drug withdrawal is most likely to be life-threatening for a person addicted to. • A. heroin. • B. cocaine. • C. naloxone. • D. amobarbital. • E. phencyclidine (PCP).

11. Abrupt drug withdrawal is most likely to be life-threatening for a person addicted to. • A. heroin. • B. cocaine. • C. naloxone. • D. amobarbital. • E. phencyclidine (PCP).

12. Severe opiate overdose is appropriately treated with: • A. naloxone. • B. naltrexone. • C. pentazocine. • D. buprenorphine. • E. levo-alpha-acetylmethadol.

13. Severe opiate overdose is appropriately treated with: • A. naloxone. • B. naltrexone. • C. pentazocine. • D. buprenorphine. • E. levo-alpha-acetylmethadol.

14. Elevation of which of the following laboratory tests is most useful in detecting chronic alcohol abuse? • A. Alkaline phosphatase • B. White blood cell count • C Creatinine phosphokinase • D. Gamma-glutamyltransferase

15. Elevation of which of the following laboratory tests is most useful in detecting chronic alcohol abuse? • A. Alkaline phosphatase • B. White blood cell count • C Creatinine phosphokinase • D. Gamma-glutamyltransferase

16. Select a function for the gamma-aminobutyric acid-A (GABA-A) receptor • A. Depolarizes cells by opening channels that principally allow calcium to enter the cell • B. Gates channels that allow sodium, but not calcium, to cross the cell membrane • C. Gates chloride channels • D. Activates G proteins and modulates calcium and potassium channels • E. Activates adenylyl cyclase and raises cyclic adenosine monophosphate (cAMP)

17. Select a function for the gamma-aminobutyric acid-A (GABA-A) receptor • A. Depolarizes cells by opening channels that principally allow calcium to enter the cell • B. Gates channels that allow sodium, but not calcium, to cross the cell membrane • C. Gates chloride channels • D. Activates G proteins and modulates calcium and potassium channels • E. Activates adenylyl cyclase and raises cyclic adenosine monophosphate (cAMP)

18. Select a function for the Dopamine (Dl) receptor • A. Depolarizes cells by opening channels that principally allow calcium to enter the cell • B. Gates channels that allow sodium, but not calcium, to cross the cell membrane • C. Gates chloride channels • D. Activates G proteins and modulates calcium and potassium channels • E. Activates adenylyl cyclase and raises cyclic adenosine monophosphate (cAMP)

19. Select a function for the Dopamine (Dl) receptor • A. Depolarizes cells by opening channels that principally allow calcium to enter the cell • B. Gates channels that allow sodium, but not calcium, to cross the cell membrane • C. Gates chloride channels • D. Activates G proteins and modulates calcium and potassium channels • E. Activates adenylyl cyclase and raises cyclic adenosine monophosphate (cAMP)

20. Which of the following substances contributes most to premature death anddisability in the United States? • A Heroin • B. Cocaine • C. Alcohol • D Nicotine • E Amphetamine

21. Which of the following substances contributes most to premature death anddisability in the United States? • A Heroin • B. Cocaine • C. Alcohol • D Nicotine • E Amphetamine

22. The cycle of addiction

23. Human vs Mouse Brain Anatomy

24. Addiction Circuitry Dopamine Glutamate GABA Orexin Kauer and Malenka, 2007

25. Modeling Addictive behavior Drug/Alc • To model relapse behavior, train animals in apparatus with contingent or non-contingent cocaine exposure and withdraw them for a period of time. • Induce relapse via stress, drug administration, or cue Image from NIAAA

26. Psychomotor Sensitization

27. Addictive drugs enhance DA neurotransmission • Increased extracellular DA in the striatum • Increased SA when DA Rs are partially antagonized, with cessation at more complete blockade • Inhibition of SA when DA synthesis is blocked • Cessation of SA when DA neurons have axons ablated

28. The most addictive drugs tend to be the most harmful Nutt D, King LA, Saulsbury W, Blakemore C (March 2007)

29. Ethanol • ½ Americans over 12 consume alcohol • ¼ Americans binge drink • 3 drinks increases DA by 138% in men and 69% in women • 5-20mM induces reinforcing DA concentration • Causes GABA disinhibition • Directly activates VTA DA neurons

30. Ethanol increases DA to a different extent in different species of rats Bustamante et al., 2009

31. Nicotine • 1/3 of the population over 13 uses it • Most common cause of drug-induced premature death and disability • Enhances excitatory output to DA neurons • Acts on presynaptic Rs on DA terminals • 240nM/cigarette max brain concentration • Decreases to 25nM overnight

32. Chronic stress blocks the nicotine induced increase in striatal dopamine

33. Opioids -Increase burst firing of VTA DA neurons -Disinhibition by inactivation of GABA neurons Dopamine GABA

34. Morphine increases DA in the NAc Ogawa et al., 2007 PNAS

35. Cocaine and Amphetamines

36. Cocaine injections cause rapid dopamine release in the NAc and VTA Bradberry and Roth, 1989 Neurosci Letters

37. Cocaine-Induced Glutamate Signaling in the NAc Glutamate in NAc Cornish and Kalivas, 2000 McFarland et al., 2003

38. Increasing GABA Concentrations Attenuate Cocaine Seeking Behavior McFarland and Kalivas, 2001

39. Plasticity is attenuated in the NAc After Extinction Moussawi et al., 2009

41. Modulation of synaptic function and plasticity in the VTA

42. Synaptic strength measured by the AMPAR/NMDAR ratio

43. Orexin enhances NMDAR EPSCs in VTA neurons

44. Modulation of synaptic function and plasticity in the NAc

45. Mesolimbic system on drugs

46. Glia surround synapses and release glutamate

47. Glutamate homeostasis hypothesis of addiction

48. Effects of Cocaine on Spine Morphology

49. Addiction: pathological synaptic plasticity • Reward behavior circuits become habitually active and have decreased response to environmental stimuli and top down processing • Behavior starts as drug seeking and is easily influenced by external stimuli. Changes in D2R levels in NAc alter behavioral circuits which become habitual then compulsive • People with abnormal D2R concentrations may be more vulnerable to addiction • Differential effects of drugs

50. PFC activity is reduced in subjects which abuse cocaine