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Neuroanatomy of the reinforcement system of the brain
Christian P. Müller
SGDP-Center, Institute of Psychiatry, King‘s College London
Reinforcement research
...learn about mechanisms of euphoria, reward, and reinforcement.
How to get happy on purpose?
drugs as seemingly „artificial paradises“
... De Quincey, Baudelaire, Freud....
drugs as seemingly „artificial paradises“
Reinforcement research
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Research on mechanisms of addiction was and is closely linked with research on euphoria, hedonia,
reward, and reinforcement
drugs as seemingly „artificial paradises“
Reinforcement research
Reinforcement circuits of the brain
Olds & Milner (1954): Intracranial Self-stimulation
Reinforcement circuits of the brain
Olds & Milner (1954): Intracranial Self-stimulation
James Olds: „pleasure center“ hypothesis
around
lateral hypothalamusassumption:
this brain region mediates the „pleasure“ of sensory stiumuli and drugs
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Roy Wise: Dopamine-hypothesis (1980)
Dopamine-synapse codes for the hedonic/reward value of a stimulus in the
brain
The dopaminergic synapse is the place in the brain where the hedonic value of a stimulus is associated with its sensory
properties.
The dopamine hypothesis
Beyond ncl. accumbens dopamine
Projections
Neurotransmitters
Neurons
Brain areas
Which brain areas are involved in reinforcement?
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Brain areas
inactivation of a brain area• lesion: removal, cooling, use of neurotoxins
• local anaesthetics
animal models of addiction
post mortem measurements• neurtoransmitters
• autoradiography
humans and animals
human addicts or occasional users- acute intoxication
- withdrawal Imageing
e.g. fMRI, PET
Brain areas
Brain areas
ncl. accumbens
prefrontal cortex
amygdala
hippocampus
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental area
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How are these areas interconnected ?
Projections
anterograde tracer• injected in area of origin
• transported along the axons to projection areas
Neuroanatomy
Projections
retrograde tracer • injected in target area
• uptaken by synapses, retrograde transport along the axons to soma
Projections
Berridge & Robinson, TINS (2003)
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ncl. accumbens
prefrontal cortex
amygdala hippocampus
hypothalamus
ventral tegmental area
ventromed. thalamus ventral
pallidum
Projections
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
prefrontal cortex
• receives highly processed information from all sense modalities
• convergence area
• important a.o. for plannig of behavior and impulse control
Projections
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Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
hippocampus
• essential for learning (not for retrieval)
• especially for spacial information
• important for spatial information (spatial cues) regarding to drug use
Projections
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
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amygdala
• important for emotion, especially anxiety
• involved in discrete cue processing related to drug use
• stores also stimulus-reward associations
Projections
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
• hippocampus and amygdala input gate PFC input to Nac
• bring Nac neurons in depolarized „sensitive“ state
O‘Donnell and Grace, J. Neurosci., 1995
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
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hypothalamus
• several nuclei with distinct functions
• processes information about internal milieu of the body (e.g. glucose, wasser, temperatur)
• may be involved in processing of hedonic value of drugs
Projections
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
ventral tegmental
area
• pre-ceeding stimulus is assigned an incentive salience(„wanting“ rather than „liking“)
• neuronal activity increases when after a certain behaviour an unexpected „reward“ (e.g. drug-reward) occurs
• repeated occurrence may lead to incentive sensitization
Projections
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ventral tegmental
area
• increase likelyhood for rewarded behaviour
• incentive salience „energizes“ addiction-related behaviour
When stimulus occurs:
Projections
The nature of the dopaminergic input
The nature of the dopaminergic input
• DA neurons fire upon free unpredicted rewards and during learning of stimulus-reward associations
• no DA activation when association is learned (familiar)
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The nature of the dopaminergic input
• during correct learning trials: DA neurons fire upon reward
• during incorrect learning trials (error): drop in activity of DA neurons at times of expected reward
DA neuronal activity codes not for reward per se but for prediction error
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
ncl. accumbens
limbic-motor interface between structures processing sensory and interoceptive information and motor output structures
translates „motivation to action“
Mogenson et al., Prog Neurobiol. (1983)
Projections
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ncl. accumbens
- processes changes in the predictive importance of sensory stimuli
- projects to motor circuits to influence behavioural planning
Projections
ncl. accumbens
- important in the pre-habitual stage of drug seeking and self-administration
- once these behaviours became habits –less important ( dorsal striatum)
Projections
Projections
prefrontal cortex
hippocampus
amygdala
ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
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ventral pallidum
ventromed. thalamus
premotor. cortex
motor nuclei involved in planing and execution of locomotor behaviour
Projections
How to identify other important neurotransmitters
Transmitter
Transmitter-inactivation • by synthesis blockers
• reducing precursor levels (e.g. tyrosin-free diet)
• transmitter-specific neurotoxines (e.g. 6-OH-DA; 5,7-DHT)
• receptor-antagonists or knock-out
Addiction-related behavioural paradigms
systemic or local
Transmitter
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Transmitter-stimulation • by blocking metabolizing enzymes (e.g.
MAO blocker; AChE-blocker)
• releaser or reuptake blocker
• precursor (tyrosin-rich diet; L-DOPA)
• receptor-agonists or overexpression
Addiction-related behavioural paradigms
systemic or local
Transmitter
Transmitter
Important transmitters:
GABA
-
Glutamat
+
serotonin
+/-
prefrontal cortex
hippocampus
amygdala
Ncl. accumbens
ventral pallidum
ventromed. thalamus
hypothalamus
ventral tegmental
area
premotor. cortex
Glu +
Glu +
Glu +
DA +/-
GABA - GABA -
Glu +
Transmitter
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Ncl. accumbens
DA +/-Glu +
Glu +
GABA -
Transmitter
McBride et al. Behav Brain Res. (1999)
Transmitter
Ncl. accumbens
Transmitter
Furtyher modulating transmitters:
• Noradrenaline
• Acetylcholine
• Histamine
• CRF
• other neuropeptides
• ???
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The refined model: Ikemoto & Panksepp (1999)
Distinction between mechanisms of approximation and consumption
The refined model: Ikemoto & Panksepp (1999)
Required for approximation:
declarative perception
incentive attribution
• memory
• stimulus-respons associations
• to stimulus
• nigrostriatal DA-system
The refined model: Ikemoto & Panksepp (1999)
Two different systems for approximation:
2.) Habit system
• for well trained behavioral responses (stimulus dependent)
1.) Flexible system
• During learning of new incentives (outcome dependent)
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The refined model: Ikemoto & Panksepp (1999)
• Incentive detected
(at low stimulus reward association )
• Ncl. accumbens DA activated
• DA „energices“ flexible approximation response
• ... and enhances incentive properties of stimulus representation
1.) Flexible approximation
The refined model: Ikemoto & Panksepp (1999)
2.) Habituated approximation
• well established stimulus-response association
• Independent from Nac and Nac DA
• requires nigrostriatal DA system
The refined model: Ikemoto & Panksepp (1999)
Consumption
• by brain stem mechanisms
• Nac DA only role in learning/ incentive assignment for declarative memories
• if consumed stimulus (UCS) pleasant and unexpected: incentive assignment to antecedent CS
• until stimulus-response association formed
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Anatomical evidence
• Combination of anterograde and retrograde tracing in Macaque monkeys
Importance for addiction
• trained Rhesus monkeys to self-administer cocaine
• measured glucose utilization after acute (5d) and chronic exposure (100d) after last session with 14C-DG
• reported initial decrease in ncl. accumbens
• with increased administration: spreading to dorsal striatum
Importance for addiction
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Importance for addiction
• disconnection study
• interuption of striato-nigral-striato circuitry
• Cocaine self-administration: second order schedule
lesion of Nac core
DA antagonist
Belin and Everitt, Neuron, 2008
Importance for addiction
• decreased drug seeking behaviour in trained rats in second order schedule of reinforcement
Belin and Everitt, Neuron, 2008
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Kalivas PW, Volkow ND (2005) The neural basis of addiction: A pathology of motivation and choice. American Journal of Psychiatry 162:1403-1413.
Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467-476.
Koob GF, Le MM (2008) Addiction and the brain antireward system. Annu Rev Psychol 59:29-53.
McBride WJ, Murphy JM, Ikemoto S (1999) Localization of brain reinforcement mechanisms: intracranial self-administration and intracranial place-conditioning studies. Behav Brain Res 101:129-152.
Robinson TE, Berridge KC (2003) Addiction. Annu Rev Psychol 54:25-53.
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