1. Drug addiction – learning gone wild? Dr Stuart McLaren MRCPsych. Phase 1 Psychopharmacology module 15.02.13

2. Structure of session Introduction Dopamine and the mesolimbic reward systems in the brain Systems modulating the mesolimbic system –GABA –Opioids –Glutamate Tolerance and withdrawal Substitution or maintenance treatments

3. Substance dependence (3+ in last year) Strong desire or sense of compulsion to take alcohol Difficulties controlling alcohol-taking behaviour Physiological withdrawal state when alcohol is stopped or reduced Evidence of tolerance Neglect of alternative pleasures or interests (so- called ‘salience’) Persisting with alcohol use despite harmful consequences

4. Phases of treatment 1 Substitution therapy Opiates – methadone, buprenorphine, heroin Stimulants – controversial Alcohol – not generally used Benzodiazepines - controversial

5. Phases of treatment 2 Detoxification Opiates –  dose methadone or buprenorphine, lofexidine Stimulants – none, symptomatic Alcohol – benzodiazepines, anticonvulsants, ? acamprosate Benzodiazepines -  dose

6. Phases of treatment 3 Relapse prevention Opiates – naltrexone Stimulants – none Alcohol – acamprosate, naltrexone, disulfiram, baclofen Benzodiazepines - none

7. Molecular targets of drugs of misuse Cocaine and amphetamines Primary targetDopamine transporter (DAT) Main acute effects  Dopamine Adaptions  DA-ergic activity,  glutamatergic activity Other actionsLocal anaesthetic, includes 5-HT, ?NA release

8. Molecular targets of drugs of misuse Opiates Primary targetMu (  ) opiate receptors Main effects?  Dopamine Adaptions  sensitivity of MOR, upregulation of NA activity Other actionsKappa (  ) and delta (  ) opiate receptors

9. Molecular targets of drugs of misuse Alcohol Primary targetGABA/glutamate Main effects  GABA /  glutamate Adaptions  GABA sensitivity, upregulated NMDA glutamate Other actionsMany other systems reward, opioid, GABA- B, dopamine

10. A simplified model of addiction

11. Model proposing a network of four circuits involved with addiction

12. Reward (or reinforcements) – objects or events that make us come back for more

13. Intracranial self-administration of morphine in a rat

14. Activation of the reward pathway by electrical stimulation

15. Activation of human striatum by various rewards

16. Brain images at different times after drug administration

17. The role of dopamine in reward circuits

18. Dopamine (D1-like) receptor structure

19. Dopamine circuits in the brain

20. Mechanism of drug-related increase in dopamine activity Block of dopamine transporter (DAT) in NAcc e.g. Cocaine Reuptake blockade plus direct DA release from terminals e.g. Amphetamine Increased DA neuronal firing via disinhibition in the VTA e.g. Alcohol, opiates, nicotine

21. Dopamine binding to receptors and uptake pumps in the nucleus accumbens: the action of cocaine

22. Key structures and connections involved in addiction Lingford-Hughes A et al. Br Med Bull 2010;96:93-110 © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

23. fMRI during cocaine intoxication vs. saline infusion

24. Low level of dopamine D2 receptors in methamphetamine abusers

25. Where substances of abuse interact with the dopaminergic mesolimbic system and its key modulators.67. Lingford-Hughes A et al. Br Med Bull 2010;96:93-110 © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

26. PET study of the effect of chronic drug exposure

27. PET scan of raclopride binding in the striatum of cocaine and methamphetamine abusers

28. Axial sections with PET showing DA D2 receptors in non human primates

29. The action of bupropion Atypical antidepressant Used in treatment of nicotine dependence, detoxification and relapse prevention DA and NA reuptake inhibitor, antagonist at nicotinic acetylcholinergic receptor Meta-analysis of 49 trials > effective than placebo Action independent of antidepressant effect

30. Bupropion blocks the DAT

31. Conventional mechanism of action of disulfiram in relapse prevention

32. Other action of disulfiram,  DA levels

33. Other neurotransmitter systems that modulate the mesolimbic system GABA

34. GABA-A receptor structure

35. Alcohol’s effect on neurotransmitter systems involved in the brain’s reward pathways

36. Action of the brain’s GABA system in the presence of alcohol

37. Action of the brain’s GABA system after chronic alcohol exposure

38. The action of baclofen GABA – B agonist Licensed for muscle spasm Increases tonic inhibition of mesolimbic DA neurons Reduces DA release in the ventral striatum Reduces drug seeking and consumption of alcohol, cocaine and nicotine Reduces relapse in alcohol dependence, not yet mainstream

39. Other neurotransmitter systems that modulate the mesolimbic system Opioids

40. The neuroactive peptide beta- endorphin

41. Structure of diamorphine

42. Opioid receptor structure

43. Opioid receptor function Mu (MOR)analgesia, respiratory depression, pupillary constriction Kappa (KOR)dysphoria, depersonalization, sedation MOR + DOR activation of reward KOR attenuates reward

44. MOR receptors are present in the VTA on the GABA inhibitory neurons

45. Opiates binding to opiate receptors in the nucleus accubens: increased dopamine release

46. The action of naltrexone Non-selective opiate antagonist Increases activity in the OfCx (?  control) Blocks reward associated with MOR in the VTA via preventing increased DA activity Used both in opiate and alcohol dependence relapse prevention May be useful in some impulse-control disorders such as pathological gambling

47. Other neurotransmitter systems that modulate the mesolimbic system glutamate

48. Receptors modified by alcohol

49. Glutamate receptor structure

50. Alcohol’s effect on neurotransmitter systems involved in the brain’s reward pathways

51. Alcohol’s effect on endogenous opioids and the mesolimbic DA system

52. Activation of the brain’s glutamate system

53. Activation of the brain’s glutamate system with alcohol

54. The action of acamprosate Used in alcohol relapse prevention Said to be ‘anticraving’ in action  glutamatergic activity  GABA–ergic activity Partial agonist at the NMDA receptor in Nacc May be neuroprotective during alcohol withdrawal

55. Tolerance and withdrawal Two sides of the same coin

56. Neurotransmitters implicated in substance withdrawal ↓dopamine‘dysphoria’ ↓serotonin‘dysphoria’  GABA -Aanxiety, panic ↓neuropeptide Yanti-stress ↑dynorphin‘dysphoria’ ↑CRFstress ↑noradrenalinestress  glutamatehyperexcitability

57. Actions of the brain’s GABA system in chronic alcohol exposure and withdrawal

58. Action of the brain’s glutamate system after chronic exposure to alcohol and during withdrawal

59. Alcohol withdrawal Benzodiazepines  GABA-ergic function Anticonvulsants e.g. Lamotrigine (glutamate release inhibitor) Acamprosate  NMDA hyperactivity, and may have neuroprotective effects (i.e. reduced cell death)

60. Opiate withdrawal Lofexidine and clonidine Alpha-2 receptor agonist Reduces noradrenergic overactivity associated with opiate withdrawal (MOR are inhibitory and NA activity upregulated in ascending brain pathways) Main site of action the locus coeruleus May cause hypotension, clonidine>lofexidine

61. Substitute or maintenance treatment A very good evidence base but still controversial with some

62. Opioid maintenance therapy Methadone Full MOR agonist Receptor occupancy ~ 32% Long acting (half life ~ 24 hours) Buprenorphine Partial MOR agonist, KOR antagonist High affinity Long acting (half life > 24 hours)

63. Novel mechanisms Stress/antistress systems Glial cells

64. The effect of alcohol on reward and stress circuits in the brain

65. Astrocyte function