the brain system reward addiction
TRANSCRIPT
Neuronal basics of addiction
Werner J. SchmidtAbt. NeuropharmakologieUniversität Tübingen
The situation:
Obviously it is beyond reality to accomplish a drug free world....
Netherlands public authorities have capitulated in theirstruggle 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
Drug Primary effect Secondary-effect
Withdrawal
CocaineAmphetamine
Dopamine-Transporter
Dopamine
Glutamate
NMDA-Receptor
overactivity
Nicotine N-Acetylcholine Receptor
Dopamine
MorphinHeroin
µ-Opiat-Rceptor
Dopamine
AlcoholBenzodiazepineBarbiturate
GABA-AReceptor
NMDA-Rezeptor
PhencyclidineKetamine
Glutamat/NMDA-Rezeptor
Cannabinoids CB1-Rezeptor µ-Opiat-RezeptorDopamine
MDMA/EcstasyLSD
Serotonin-TransporterSerotonin-Receptor (5HT2A)
SerotoninDopamine
The construct The neuronal network
Reinforcement motivation (appetitiv) approach brain reward (consumatory)
Learning operant conditioning
stimulus-response habit (habit learning) sensitization
The brain reward system
Evaluates every behaviour-outcome loop
Ensures the performance ofBehaviour, essential for the survival of the individuum. Feeding, specific hungers, drinking, grooming, hiding...
Behaviour, essential for the survival of the speciesCourtship behaviour, Nest building Sexual behaviourParental behaviourSocial behaviour
The brain reward system
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
pf cortex
n.accumbens
VTA
VP
DA DA
GLU
GLU
out
AP-5
Impaired acquisition of
-primary reward
-secondary reward
-conditioned
approach
GABA
The role of glutamate
DA
pf cortex
n.accumbens
VTA
VP
DA
GLU
GLU
GABAout
GABA
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
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
Behavioural economics hypothesis
Drugs become increasingly attractive duringthe development of addictionbecause non-drug rewards lose their rewarding value(Gene Heyman)
Negative reinforcement hypothesis
Drug wanting increases during the development of addictionbecause drugs elicit a downward shift in rewarding sensitivity,causing pervasive anhedonia (George Koob, Michel Le Moal).
The construct The neuronal network
Reinforcement motivation (appetitive phase) approach brain reward (consumatory phase)
Learning operant conditioning
stimulus-response habit (habit learning) sensitization
Is addiction learning operant conditioning?
Pros:Drug intake as a neutral behaviourleads - 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
The construct The neuronal network
Reinforcement motivation (appetitiv) approach brain reward (consumatory)
Learning operant conditioning
stimulus-response habit (habit learning) sensitization
Parallel learning systems
mental: all brain capacitiescognitive: higher brain
functionslearning
consciousdeclarativeHIPPOCAMPUSTEMPORAL LOBE
unconsciousnon-declarativeBASAL 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
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)
Incentive Sensitization Hypothesis
Repeated intake of a drug- can lead to tolerance
- can lead to sensitization
Sensitization refers to the augmentation of a behaviourupon repeated administration of a drug.
locomotoractivity
Low dose ofamphetamine
amph
etam
ine
0 1 2 3 4 5 n
vehicle
Days N europharmacology Uni-Tuebingen
Drug liking
Controlled intake
Irresistible drug craving
Loss of control
Drug-induced plastic changes
Sensitization
Point of no return
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….“
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
Glutamate and sensitization
Development of sensitization is blocked by GLU/NMDA receptor-antagonists (M. Wolf 1998).
Controversy
Misinterpretation?
Drug liking
Controlled intake
Irresistible drug craving
Loss of control
Drug-induveced plastic changes
Sensitization
Point of no return
Relapse
Underlying networks:
-the priming network
-stress relapse network
-cue / context relapse network
VTA
OrbitofrontalHippocampus
Amygdalapf cortex
n.accumbens
VPDA
DA GABA
GLUGLU
GABAout
Context- induced craving and relapse
Glutamate receptor-antagonists block
context-induced craving/relapse
AcamprosateCaroverinNeramexaneMPEP (mGluR5-R-antagonist)
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
N europharmacology Uni-Tuebingen
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
Nicotine
Nicotine
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?)
Nicotine: Anti-craving drugs under development
Chronic nicotine leads to overactivity of theendocannabinoid 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
Nicotine: Future perspectives
Reboxetin (Edronax®): SNARI
γ-vinyl-GABA=Topiramat (Topomax®): strengthens GABA
Vaccination: Antibodies which bind to nicotine do not cross the BBB
Alcohol
Alcohol: anti-craving-therapy
Naltrexon: blocks μ-opiate receptors
Rebound effect after cessation of treatment
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,
Alkohol: Perspectives
NMDA-receptor-antagonists (Acamprosat, Neramexane) AMPA-receptor-antagonists
mGlu-Rezeptor-antagonists mGluR-5-R-antagonist MPEP acamprosate
Opiates
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
Opiate: Perspektives
Hypothesis: During withdrawal and context-induced craving is the glutamate-system overactive NMDA-R Antagonisten: Acamprosate
mGluR5 Antagonisten: MPEP
Stimulants
Stimulants: Cocaine, amphetamine: Dopamine enhancer/releaser Ecstasy (MDMA): Serotonin releaser
Anti craving drug: No
Perspectives:Glutamate-antagonists: Acamprosate MPEP
γ-vinyl-GABA
Vaccination
Cannabis
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: zentralCB 2 : peripher
Ananda (Sanskrit): Glückseligkeit, beatitude, felicity
Cannabis perspectives
Anti-craving Therapy:
Naltrexon:
Rimonabant (Acomplia®)
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
The brain reward system