Download Acetylcholine and Dopamine Interactions

D-ITET/IBT
Neuromodulatory System Interactions
Acetylcholine and Dopamine
Neuropharmacology
(Computational Psychiatry Seminar: Spring 2014)
09.05.2014
D-ITET / IBT / TNU
1
Introduction
dopamine
acetylcholine
Interactions
Neurotransmitter systems
Acetylcholine
Dopamine
.
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Introduction
dopamine
acetylcholine
Interactions
Receptors
Dopamine
G protein coupled R
G protein coupled R
activates
inhibits
adenylyl cyclase
adenylyl cyclase
D1,D5: Gs 
09.05.2014
D2-D4: Gi
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Introduction
dopamine
acetylcholine
Interactions
Receptors
Dopamine
G protein coupled R
G protein coupled R
activates
inhibits
adenylyl cyclase
adenylyl cyclase
dopamine
D1 receptor
D1,D5: Gs 
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D2-D4: Gi
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Introduction
dopamine
acetylcholine
Interactions
09.05.2014
Receptors
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Introduction
dopamine
acetylcholine
Interactions
Receptors
Acetylcholine
Nicotinic
M uscarinic
ionotropic
metabotropic
 1-7 and
9-10
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M 1,M 3,
 2-4
M 5: Gq/11
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M 2,M 4: Gi/o
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Introduction
dopamine
acetylcholine
Interactions
Receptors
Acetylcholine
Nicotinic
M uscarinic
ionotropic
metabotropic
M 1,M 3,
M 5: Gq/11
09.05.2014
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M 2,M 4: Gi/o
7
Introduction
dopamine
acetylcholine
Interactions
Receptors
Acetylcholine
Nicotinic
M uscarinic
ionotropic
metabotropic
M 1,M 3,
M 5: Gq/11
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M 2,M 4: Gi/o
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Introduction
dopamine
acetylcholine
Interactions
09.05.2014
Receptors
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Introduction
dopamine
acetylcholine
Interactions
Dopamine & reward learning
Dopamine neurons code TD error
Schultz, W., 1998, Journal of Neurophysiology
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Introduction
dopamine
acetylcholine
Interactions
Sensory Associative Learning (fM RI study)
Hierarchical Gaussian Filter (HGF)
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Introduction
dopamine
acetylcholine
Interactions
Hierarchical Gaussian Filter (HGF)
𝜋𝑖−1
∆𝜇𝑖 ∝
𝑃𝐸𝑖−1
𝜋𝑖
𝜗
(𝑘−1)
𝑥3
(𝑘)
𝑥3
p(x3(k)) ~ N(x3(k-1),ϑ)
𝜀3 ∝
𝜅, 𝜔
(𝑘−1)
𝑥2
(𝑘)
𝑥2
(𝑘) (𝑘)
𝜎3 𝛿2
p(x2(k)) ~ N(x2(k-1), exp(κx3+ω))
𝜀2 = 𝜎2
(𝑘−1)
𝑥1
𝑘
𝑘
𝛿1
(𝑘)
𝑥1
p(x1=1) = s(x2)
M athys et al. 2011, Front Hum Neurosci.
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Introduction
dopamine
acetylcholine
Interactions
Sensory Associative Learning
Precision-weighted prediction errors about the
visual outcome, 𝜺𝟐
𝜀2 : second fM RI study
𝜀2 : first fM RI study
𝜀2 : conjunction z = -18
Red: p<0.05 FWE w hole-brain corrected
p<0.05 SVC FWE corrected
𝜀2 = 𝜎2
𝑘
𝑘
𝛿1
Iglesias et al. 2013, Neuron.
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Introduction
dopamine
acetylcholine
Interactions
Sensory Associative Learning
Precision-weighted prediction errors about
probability, 𝜺𝟑
𝜀3 : conjunction across studies
𝜀3 : first fM RI study
Red: p<0.05 SVC FWE corrected
p<0.001, uncorrected
𝜀3 ∝
(𝑘) (𝑘)
𝜎3 𝛿2
𝜀3 : second fM RI study
Iglesias et al. 2013, Neuron.
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Introduction
dopamine
acetylcholine
Interactions
Acetylcholine: precision signaling
Prediction:
Deep
pyramidal cells
PE: superficial
pyramidal cells
Precision:
synaptic gain
M oran et al. 2013, The Journal of Neuroscience.
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Introduction
dopamine
acetylcholine
Interactions
Pharmacological study: EEG, healthy volunteers
Galantamine: AChEI (Acetylcholinesterase inhibitor) &
nicotinic allosteric modulator
Farlow , M .R., Clinical pharmacokinetics of galantamine. Clin Pharmacokinet, 2003. 42(15): p. 1383-92.
Soreq, H. and S. Seidman, Acetylcholinesterase [mdash] new roles for an old actor. Nat Rev Neurosci, 2001. 2(4): p. 294-302.
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Introduction
dopamine
acetylcholine
Interactions
Pharmacological study: EEG, healthy volunteers
M oran et al. 2013, The Journal of Neuroscience.
09.05.2014
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Introduction
dopamine
acetylcholine
Interactions
Pharmacological study: EEG, healthy volunteers
Placebo:
Galantamine:
one-shot learning
d1: enhances
precision
d2: attenuates
repetition suppression
Biological mechanisms
producing RS?
Network analysis:
M oran et al. 2013, The Journal of Neuroscience.
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Introduction
dopamine
acetylcholine
Interactions
Pharmacological study: EEG, healthy volunteers
All levels of auditory netw ork processing tones
Galantamine effects on:
- Forw ard connections from superficial
pyramidal cells (report PE)
- Postsynaptic gain at superficial pyramidal cells
(encoding the precision of PE)
- Backw ard connections from deep pyramidal
cells (report predictions)
M oran et al. 2013, The Journal of Neuroscience.
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Introduction
dopamine
acetylcholine
Interactions
Pharmacological study: EEG, healthy volunteers
Effect of galantamine:
- Change in the gain of superficial pyramidal
cells in primary auditory cortex
- This gain corresponds to the precision of
PE
- Augmentation of ACh reduces adaptation to
suprising stimuli
M oran et al. 2013, The Journal of Neuroscience.
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Introduction
dopamine
acetylcholine
interaction
Diseases/ Psychiatric disorders
Dopamine
Schizophrenia
09.05.2014
M ood
disorders
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Addiction
Parkinson’s
disease
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Introduction
dopamine
acetylcholine
interaction
Diseases/ Psychiatric disorders
Acetylcholine
Schizophrenia
09.05.2014
M ood
disorders
D-ITET / IBT / TNU
Addiction
Parkinson’s
disease
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Introduction
dopamine
acetylcholine
interaction
Diseases/ Psychiatric disorders
Dopamine
Schizophrenia
09.05.2014
M ood
disorders
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Alzheimer
disease
Parkinson’s
disease
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Introduction
dopamine
acetylcholine
interaction
Diseases/ Psychiatric disorders
Acetylcholine
Schizophrenia
09.05.2014
M ood
disorders
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Alzheimer
disease
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Introduction
dopamine
acetylcholine
interaction
Nicotine dependence
Nicotinic receptor on
postsynaptic DA neurons
- Undergo desensitization
w ithin seconds
- Additional mechanism
contributes to prolonged
effects of nicotine
http://www.phasa.org.za/wp-content/uploads/2014/02/picture-news-item-nicotine-dependence.jpg
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Introduction
dopamine
acetylcholine
interaction
LTP of excitatory inputs by nicotine
The evoked EPSC by glutamate could
be blocked by application of DNQX –
a glutamate receptor antagonist.
Mansvelder, H.D., et al. 2000, Neuron
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Introduction
dopamine
acetylcholine
interaction
LTP of excitatory inputs by nicotine
2) a) Hiperpolarization-activated current -DA neuron
Glu neurons
DA neurons
Nicotine enhances evoked
excitatory synaptic transmission to
VTA DA neurons
Mansvelder, H.D., et al. 2000, Neuron
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Introduction
dopamine
acetylcholine
interaction
LTP of excitatory inputs by nicotine
M LA: M ethyllycaconitine
antagonist of nAChRs of the alpha 7
subtype
 prevents the increase of EPSC
frequency
M EC: M ecamylamine
a non-alpha-7 antagonist
 did not inhibit the effect of
nicotine on EPSC frequency
Mansvelder, H.D., et al. 2000, Neuron
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Introduction
dopamine
acetylcholine
interaction
LTP of excitatory inputs by nicotine
Detail of nicotinic action:
http://www.frontiersin.org/files/Articles/27779/fnmol-05-00083-r2/
image_m/fnmol-05-00083-g001.jpg
09.05.2014
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Stahl S.M. & Muntner N. 2013, Cambridge
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Dorsal
striatum
Ventral
striatum
cortex
glutamate
thalamus
~ medium spiny neurons (M SN, w ith lots of dendrites)
containing GABA
~ large, aspiny cholinergic interneurons (TAN: tonically
active cholinergic neurons)
~ fast spiking interneuron (FS) &
~ low -threshold spiking interneuron (LTS)
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
interaction betw een
- excitatory input from the
cortex or thalamus
- DA input from the midbrain
- cholinergic innervation
through TANs
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Glu
GABA
GABA
Striatopallidal pathway:
Striatonigral pathway:
inhibitory, indirect pathw ay
excitatory, direct pathw ay
GABA
Glu
Glu
GABA
Perreault, M.L. et al. 2011, Front. Neuroanat.
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Glu
GABA
GABA
D2 receptor signaling
inhibits the inhibition of
the striatopallidal neurons
D1 receptor signaling
increases the
responsiveness of
striatonigral neurons
GABA
Glu
PPT
Glu
GABA
Perreault, M.L. et al. 2011, Front. Neuroanat.
09.05.2014
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
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Introduction
dopamine
acetylcholine
interaction
striatal DA release  activity of DA neurons
Threlfell, S. & Cragg, S.J. 2011,
Frontiers in systems Neuroscience
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Control: ACh binding to
nAChR on DA axons
- Increases initial DA
release probability
- Contributes to
subsequent short-term
depression
DHβE: blockade of β2nAChRs on DA axons
- Reduces initial DA release
probability
- Relieves short-term
DHβE:β2* :
depression
nAChR antagonist
Threlfell, S. & Cragg, S.J. 2011, Frontiers in systems Neuroscience
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Oxo-M : mAChR agonist
Threlfell, S. & Cragg, S.J. 2011, Frontiers in systems Neuroscience
09.05.2014
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Introduction
dopamine
acetylcholine
interaction
ACh-DA interactions: striatum
Threlfell, S. & Cragg, S.J. 2011, Frontiers in systems Neuroscience
09.05.2014
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Introduction
dopamine
acetylcholine
interaction
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09.05.2014
Reading List
Iglesias, Sandra, Christoph Daniel M athys, Kay Henning Brodersen, Lars Kasper, Hanneke E.M . den
Ouden, and Klaas E. Stephan. 2013. “ Hierarchical Prediction Errors in M idbrain and Basal Forebrain
during Sensory Learning.” Neuron 80(2):519-30.
M oran, Rosalyn J., Pablo Campo, M kael Symmonds, Klaas E. Stephan, Raymond J. Dolan, and Karl
J. Friston. 2013. “ Free Energy, Precision and Learning: The Role of Cholinergic Neuromodulation.”
The Journal of Neuroscience 33 (19): 8227–36.
Yu, Angela J., and Peter Dayan. 2005. “ Uncertainty, Neuromodulation, and Attention.” Neuron 46
(4): 681–92.
Lester, Deranda B, Tiffany D. Rogers, and Charles D. Blaha. 2010. “ Acetylcholine–Dopamine
Interactions in the Pathophysiology and Treatment of CNS Disorders.” CNS Neuroscience &
Therapeutics 16 (3): 137–62.
M ansvelder, Huibert D, and Daniel S M cGehee. 2000. “ Long-Term Potentiation of Excitatory Inputs
to Brain Rew ard Areas by Nicotine.” Neuron 27 (2): 349–57.
M ao, Danyan, Keith Gallagher, and Daniel S. M cGehee. 2011. “ Nicotine Potentiation of Excitatory
Inputs to Ventral Tegmental Area Dopamine Neurons.” The Journal of Neuroscience 31 (18): 6710–
20.
Scarr, E., Gibbons, A.S., Neo, J., Udaw ela, M ., and Dean, B. (2013). Cholinergic connectivity: it’s
implications for psychiatric disorders. Frontiers in Cellular Neuroscience 7.
Threlfell, S., and Cragg, S.J. (2011). Dopamine signaling in dorsal versus ventral striatum: the
dynamic role of cholinergic interneurons. Frontiers in systems neuroscience 5.
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Introduction
dopamine
acetylcholine
interaction
Thank you
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