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.

1. Neuronal basics of addiction
Werner J. Schmidt
Abt. Neuropharmakologie
Universität Tübingen

2. 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)
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 effect Secondary-
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 The neuronal network
Reinforcement motivation (appetitiv)
approach
brain reward
(consumatory)
Learning operant conditioning
stimulus-response habit
(habit learning)
sensitization

5. 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

6. The brain reward system

7. 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

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

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

11. 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

12. 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

13. Behavioural economics hypothesis
Drugs become 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 The neuronal network
Reinforcement motivation (appetitive phase)
approach
brain reward (consumatory phase)
Learning operant conditioning
stimulus-response habit
(habit learning)
sensitization

15. 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

16. The construct The neuronal 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
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.

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

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

22. 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….“

23. 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

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

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

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

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

29. Glutamate receptor-antagonists block
context-induced craving/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 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

32. Nicotine

33. Nicotine

34. 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?)

35. 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

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. Alcohol

38. Alcohol: anti-craving-therapy
Naltrexon: blocks μ-opiate receptors
Rebound effect after cessation
of treatment

39. Acamprosate
Hypothesis:
Chronic GABAergic inhibition leads 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. Opiates

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: During withdrawal and context-induced craving
is the glutamate-system overactive
NMDA-R Antagonisten: Acamprosate
mGluR5 Antagonisten: MPEP

44. Stimulants

45. Stimulants:
Cocaine, amphetamine: Dopamine enhancer/releaser
Ecstasy (MDMA): Serotonin releaser
Anti craving drug: No
Perspectives:
Glutamate-antagonists: Acamprosate
MPEP
γ-vinyl-GABA
Vaccination

46. Cannabis

47. Cannabis: Hashish and Marihuana
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. Cannabis perspectives
Anti-craving Therapy:
Naltrexon:
Rimonabant (Acomplia®
)

49. Perspectives for treatment of 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 reward system