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