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The brain system reward addiction
The brain reward system is activated by natural rewards to meet biological needs, but is also activated by addictive drugs even when no needs are present. Chronic drug use causes plastic changes in the brain that contribute to addiction. Glutamate signaling plays a key role in addiction learning and craving. Future anti-craving therapies aim to target drug-induced changes in neuronal networks specific to each addiction, moving toward individualized treatment approaches.
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The brain system reward addiction
- 1. Neuronal basics ofaddiction Werner J. Schmidt Abt. Neuropharmakologie Universität Tübingen
- 2. The situation: Obviously itis 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) We need to learn how to: - deal with drugs of addiction in a responsible way… -to develop therapies The precondition for that is to learn how drugs work in the brain
- 3. Drug Primary effectSecondary- effect Withdrawal Cocaine Amphetamine Dopamine- Transporter Dopamine Glutamate NMDA-Receptor overactivity Nicotine N-Acetylcholine Receptor Dopamine Morphin Heroin µ-Opiat- Rceptor Dopamine Alcohol Benzodiazepine Barbiturate GABA-A Receptor NMDA-Rezeptor Phencyclidine Ketamine Glutamat/ NMDA-Rezeptor Cannabinoids CB1-Rezeptor µ-Opiat-Rezeptor Dopamine MDMA/Ecstasy LSD Serotonin- Transporter Serotonin-Receptor (5HT2A) Serotonin Dopamine
- 4. The construct Theneuronal network Reinforcement motivation (appetitiv) approach brain reward (consumatory) Learning operant conditioning stimulus-response habit (habit learning) sensitization
- 5. The brain rewardsystem 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
- 6. The brain rewardsystem
- 7. The role ofdopamine (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
- 9. pf cortex n.accumbens VTA VP DA DA GLU GLU out AP-5 Impairedacquisition of -primary reward -secondary reward -conditioned approach GABA
- 10. The role ofglutamate DA pf cortex n.accumbens VTA VP DA GLU GLU GABA out GABA
- 11. The role ofglutamate: 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
- 12. The brain rewardsystem: - 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
- 13. Behavioural economics hypothesis Drugsbecome increasingly attractive during the development of addiction because non-drug rewards lose 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).
- 14. The construct Theneuronal network Reinforcement motivation (appetitive phase) approach brain reward (consumatory phase) Learning operant conditioning stimulus-response habit (habit learning) sensitization
- 15. Is addiction learningoperant 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
- 16. The construct Theneuronal network Reinforcement motivation (appetitiv) approach brain reward (consumatory) Learning operant conditioning stimulus-response habit (habit learning) sensitization
- 17. Parallel learning systems mental:all brain capacities cognitive: higher brain functions learning conscious declarative HIPPOCAMPUS TEMPORAL LOBE unconscious non-declarative BASAL GANGLIA mutual inhibitory knowledges extinguishable not-extinguishable skills, motor and cognitive adaptive behaviour rule like behaviour = habits Time course: conscious incrementally acquired habit control associations
- 18. 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)
- 19. Incentive Sensitization Hypothesis Repeatedintake 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.
- 20. locomotor activity Low dose of amphetamine amphetamine 01 2 3 4 5 n vehicle Days Neuropharmacology Uni-Tuebingen
- 21. Drug liking Controlled intake Irresistibledrug craving Loss of control Drug-induced plastic changes Sensitization Point of no return
- 22. Compulsivity of addictivebehaviour 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….“
- 23. Is there aconnection 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
- 24. Glutamate and sensitization Developmentof sensitization is blocked by GLU/NMDA receptor-antagonists (M. Wolf 1998). Controversy Misinterpretation?
- 26. Drug liking Controlled intake Irresistibledrug craving Loss of control Drug-induveced plastic changes Sensitization Point of no return
- 27. Relapse Underlying networks: -the primingnetwork -stress relapse network -cue / context relapse network
- 28.
- 29. Glutamate receptor-antagonists block context-inducedcraving/relapse Acamprosate Caroverin Neramexane MPEP (mGluR5-R-antagonist)
- 30. DRUG TARGET WITHDRAWAL Cocaine Amphetamine Dopamine- Transporter↓ Nicotine N-Acetylcholin Receptor ↑ Morphine Heroin µ-Opiat- Receptor ↑ Alcohol Benzodiazepine Barbiturate GABA-A Receptor ↑ Phencyclidine Ketamine Glutamate/ NMDA-Receptor ↓ Cannabis CB1-Receptor ↑ MDMA/Ecstasy LSD Serotonin-Transporter ↓ Serotonin-Receptor (5HT2A) glutamatergic hyperactivity Neuropharmacology Uni-Tuebingen
- 31. How to developof anti-craving drugs? Identification of the network damaged by a drug Selective intervention into the respective network = Drug-specific and Individual-specific therapy
- 32.
- 33.
- 34. Nicotine Is self-administered byanimals Mecamylamine blocks self-administration Anti-craving-therapy Nicotine -patch, spray, chewing-gum (substitution) Bupropion (Zyban® ): enhances dopamine, serotonine, noradrenaline release (substitution/compensation?)
- 35. Nicotine: Anti-craving drugsunder 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
- 36. Nicotine: Future perspectives Reboxetin(Edronax® ): SNARI γ-vinyl-GABA=Topiramat (Topomax® ): strengthens GABA Vaccination: Antibodies which bind to nicotine do not cross the BBB
- 37.
- 38. Alcohol: anti-craving-therapy Naltrexon: blocksμ-opiate receptors Rebound effect after cessation of treatment
- 39. Acamprosate Hypothesis: Chronic GABAergic inhibitionleads to glutamatergic overactivty (like a homeostatic response) Acamprosat (Campral® ): GLU-receptor-antagonist Effective against context-induced craving No rebound effects,
- 40. Alkohol: Perspectives NMDA-receptor-antagonists (Acamprosat,Neramexane) AMPA-receptor-antagonists mGlu-Rezeptor-antagonists mGluR-5-R-antagonist MPEP acamprosate
- 41.
- 42. Opiates Substitution therapy Levomethadon (L-Polamidon® ):Opiate-R-agonist Buprenorphin (Subutex® ) (Temgesic® ) Partial μ-R-agonist, κ-R-antagonist LAAM (levo-α-acetylmethadol-HCl) Heroin
- 43. Opiate: Perspektives Hypothesis: Duringwithdrawal and context-induced craving is the glutamate-system overactive NMDA-R Antagonisten: Acamprosate mGluR5 Antagonisten: MPEP
- 44.
- 45. Stimulants: Cocaine, amphetamine: Dopamineenhancer/releaser Ecstasy (MDMA): Serotonin releaser Anti craving drug: No Perspectives: Glutamate-antagonists: Acamprosate MPEP γ-vinyl-GABA Vaccination
- 46.
- 47. Cannabis: Hashish andMarihuana Endocannabinoids: Anandamid Arachidonylethanolamid Synaptic release: not vesicular not activity-dependent Retrograde transmitter Inhibitory on transmitter release in the target neuron CB1 Rezeptor: zentral CB 2 : peripher Ananda (Sanskrit): Glückseligkeit, beatitude, felicity
- 48.
- 49. Perspectives for treatmentof addiction Combination of different anti-craving-drugs Goal of a rational development: Identification of the drug-induced changes in the respective neuronal network. Specific intervention = Addiction-specific and individual-specific therapy
- 50. The brain rewardsystem
Editor's Notes
- #3 Offensichtlich ist es realitätsfremd anzunehmen, eine suchtmittelfreie Welt schaffen zu können. Vielleicht ist es besser den Umgang mit Suchtmittel zu lernen, einen Rahmen dafür zu schaffen der auf der Kenntnis der Suchtrelevanten Hirnmechanismen beruht Und wissenschaftlich fundierte Therapiemöglichkeiten zu etablieren.