Neuronal basis of addiction

2. Neuronal basis of addiction

3. The situation: Obviously it is beyond reality to accomplish a drug free world.... Netherlands public authorities have capitulated in their struggle against drug-runners... (Der Spiegel 5/2004 S. 42) The hard line of the USA in the „war on drugs“ has failed... (Die Zeit 14/2004)

5. Substanztyp Psychische Abhängigkeit: Sucht Körperliche Abhängigkeit Gewöhnung Toleranz Morphin Barbiturat/ Alkohol Cocain Weckamine Nikotin Mescalin/LSD Cannabis +++ ++ +++ ++ ++ ++ ++ +++ ++ (+) - (+) - - ++ + - + - + (+) Definition Tab. Eigenschaften von Suchtmitteln.+++: sehr stark; +: schwach; (+): nur bei einem Teil der Individuen vorhanden; -: nicht vorhanden.

6. Erlernte Toleranz Heroin geringe Dosis (US) Schwache Atemdepression Umgebung (Zimmer) (NS) Assoziation ………...(CS) Umgebung (Zimmer) (CS) Gegenregulation Erhöhung der Dosis(US+) Schwache Atemdepression Umgebung (Zimmer) (CS) Gegenregulation Heroin hohe Dosis (US++) Schwache Atemdepression Neue Umgebung (Bahnhofs WC) keine Gegenregulation Heroin hohe Dosis (US++) tödliche Atemdepression

7. Definitionen für Sucht Früher: Toleranzbildung Entzugserscheinungen nach Absetzen des Suchtmittels Seit ca. 1990 Zwanghaftes Verlangen nach dem Suchtmittel trotz Einsicht in die negativen Konsequenzen.

8. The construct The neuronal network Reinforcement motivation (appetitiv) approach (dopamine?) brain reward (consumatory) (endorphins?) Learning operant conditioning stimulus-response habit (habit learning) sensitization

9. The brain reward system Evaluates every behaviour-outcome loop Ensures the performance of Behaviour, essential for the survival of the individuum. Feeding, specific hungers, drinking, grooming, hiding... Behaviour, essential for the survival of the species Courtship behaviour, Nest building Sexual behaviour Parental behaviour Social behaviour

11. J. Olds 1956 A preliminary mapping of electrical reinforcing effects in the rat brain J. Comp. Physiol.Psychol 49: 507-512 “..the rat is coming back for more stimulation.....“ J. Olds 1958 Self stimulation of the brain Science 127: 315-324

13. The brain reward system

14. The role of dopamine (DA): Up to now:DA in the n. accumbens mediates reward counterarguments : DA release due to aversive stimuli. DA depleted animals experience reward reward related learning in the DA-depleted animal drug-self administration or sucrose-intake is independent from the degree of DA depletion the DA release in the n. accumbens correlates with the effort (lever pressing) not with the amount of reward. New hypothesis:The role of DA is „....to overcome work-related response costs....“ Salamone, J. D. 2003 Dopamine is the energizer to put will into action

16. pf cortex GLU AP-5 GLU n.accumbens • Impaired acquisition of • primary reward • secondary reward • conditioned • approach GABA DA DA VP out VTA

17. pf cortex The role of glutamate GLU GLU DA n.accumbens GABA DA VP GABA out VTA

18. The role of glutamate: Projection cortex-reward system Integral part of the reward system Shapes the activity pattern of striatal and accumbal neurones Major role in addiction-learning and -memory

19. The brain reward system: - is activated by natural rewards in order to compensate for biological needs - is activated by addictive drugs in the absence of biological needs - undergoes changes upon chronic drug intake

20. Behavioural economics hypothesis Drugs become increasingly attractive during the development of addiction because non-drug rewards loose their rewarding value (Gene Heyman) Negative reinforcement hypothesis Drug wanting increases during the development of addiction because drugs elicit a downward shift in rewarding sensitivity, causing pervasive anhedonia (George Koob, Michel Le Moal).

21. The constructThe neuronal network Reinforcement motivation (appetitive phase) approach. Dopamine brain reward (consumatory phase) Opioid system Learning operant conditioning stimulus-response habit (habit learning) sensitization

22. Is addiction learning operant conditioning? Pros: Drug intake as a neutral behaviour leads - to reward.... - to strengthening of behaviour, repetition of this behaviour Cons: Addiction can not be forgotten (incubation effect)) No extinction -by context/cue exposure -by punishment (disulfiram) Therapies based on this learning model have basically failed

23. Gewohnheitslernen Assoziation zwischen einem Reiz und einem Verhalten, die langsam entsteht und durch Wiederholung zur Gewohnheit/ Routine wird. Verhalten Belohnung Umweltreize S-O learning Umweltreize Verhalten Belohnung S-R learning Umweltreize Verhalten

24. Gewohnheits- deklaratives- Lernen unbewusst bewusst

25. The construct The neuronal network Reinforcement motivation (appetitiv) approach brain reward (consumatory) Learning operant conditioning stimulus-response habit (habit learning) sensitization

26. Parallel learning systems conscious declarative HIPPOCAMPUS TEMPORAL LOBE unconscious non-declarative BASAL GANGLIA mutual inhibitory knowledges skills, motor and cognitive adaptive behaviour rule like behaviour = habits extinguishable not-extinguishable Time course: conscious incrementally acquired habit control associations

27. Is addiction habit-learning? • Pros: • - Addiction learning is implicit learning • - learnt addiction is very stable • addictive behaviour is maintained even in the absence of • reward • - the nigro-striatal system is involved • Automatic processing hypothesis: • During the development of addiction drug-taking becomes habitual and craving occurs when habitual behaviours are prevented (Steve Tiffany) • Cons: • Habits are usually not compulsive (Terry Robinson)

28. „….viele Suchtmittel induzieren nach einer gewissen Zeit der Einnahme keine Euphorie mehr. Was also veranlasst den Süchtigen weiterhin Suchtmittel zu konsumieren?....“ L. Helmuth 2001, Science 294 (5544): 983- Mögliche Erklärung: Suchtmittelkonsum ist zur Gewohnheit geworden

29. Incentive Sensitization Hypothesis Repeated intake of a drug- can lead to tolerance - can lead to sensitization Sensitization refers to the augmentation of a behaviour upon repeated administration of a drug.

30. locomotor activity amphetamine Low dose of amphetamine vehicle 0 1 2 3 4 5 n Days Neuropharmacology Uni-Tuebingen

31. Drug liking Irresistible drug craving Controlled intake Loss of control Drug-induced plastic changes Sensitization Point of no return

32. Compulsivity of addictive behaviour is due to sensitization. (Berridge and Robinson 1993, 2003) Incentive sensitization hypopthesis „……by way of sensitization, incentive salience is attributed to events associated with drug intake. Incentive salience… transforms the perception of stimuli, imbuing them with salience, making them attractive, wanted incentive stimuli….“

33. Is there a connection between • Sensitization and addiction? • Sensitization builds up an addiction memory • A memory for the addictive drug. • A memory for contexts and stimuli associated with the drug effects. • Sensitization facilitates self-administration of other addicitve drugs • (cross sensitization) • -The degree/strength of sensitization determines the propensity for relapse • -Individuals show very different propensities for sensitization. • After sensitization, the behavioural reaction is stronger, • occurs in a shorter latency • occurs under lower doses

34. Glutamate and sensitization Development of sensitization is blocked by GLU/NMDA receptor-antagonists (M. Wolf 1998). Controversy Misinterpretation?

36. Drug liking Irresistible drug craving Controlled intake Loss of control Drug-induveced plastic changes Sensitization Point of no return

37. Relapse • Underlying networks: • -the priming network • stress relapse network • cue / context relapse network

38. Context-induced craving and relapse Orbitofrontal Hippocampus Amygdala pf cortex GLU GLU n.accumbens GABA DA DA VP GABA out VTA

39. Glutamate receptor-antagonists block context-induced craving/relapse Acamprosate Caroverin Neramexane MPEP (mGluR5-R-antagonist)

40. Substanztyp Psychical dependence Physical/ somatic dependence Tolerance Morphin Barbiturat/ Alkohol Cocain Amphetamines Nikotin Mescalin/LSD Cannabis +++ ++ +++ ++ ++ ++ ++ +++ ++ (+) - (+) - - ++ + - + - + (+) Properties of addictive drugs.+++: very strong; +: poor; (+): only in some individuals; -: absent.

41. Learned tolerance Heroin small dose (US) weak breathing depression Context (room) (NS) Association ………...(CS) Context (room) (CS) compensatory regulation Increase in dosage(US+) weak breathing depression Context (room) (CS) compensatory regulation Heroin high dosage (US++) weak breathing depression New context (WC…) no breathing depression Heroin hohe Dosis (US++) lethal breathing depression

42. Neuropharmacology Uni-Tuebingen

43. How to develop of anti-craving drugs? Identification of the network damaged by a drug Selective intervention into the respective network = Drug-specific and Individual-specific therapy

44. Pharmacologic: substitution compensation

45. Nicotine

46. Nicotine

47. Nicotine Is self-administered by animals Mecamylamine blocks self-administration Anti-craving-therapy Nicotine -patch, spray, chewing-gum (substitution) Bupropion (Zyban®): enhances dopamine, serotonine, noradrenaline release (substitution/compensation?)

48. Nicotine: Anti-craving drugs under development Chronic nicotine leads to overactivity of the endocannabinoid system. Rimonabant (Acomplia®): antagonist at CB 1 receptors Phase III doubles the number of abstinents. no weight gain Market-introduction as anti-obesity drug in 2006

49. Nicotine: Future perspectives Reboxetin (Edronax®): SNARI γ-vinyl-GABA=Topiramat (Topomax®): strengthens GABA Vaccination: Antibodies which bind to nicotine do not cross the BBB

50. Alcohol