See:

1
See Chapter 13. Modulation of synaptic
transmission Second messengers. Principles of
Neuroscience Kandel ER et al 4th edition, 2000,
McGraw-Hill Page 229
2
Fast GABA, glutamate, acetylcholine Slow
biogenic amines Dopamine Serotonin/5-HT NE Ace
tylcholine Peptides
3
OUT
Cl-
Na
Glu
GABA
Cl-
Na
GABAA receptor
Glutamate/AMPA receptor
Inhibition
Excitation
IN
4
Simple circuits
5
Feed-forward inhibition
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7
Negative feedback Feedback inhibition
8
Neocortex
Interneuron - uses GABA
Pyramidal neuron - uses glutamate
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10

• Arousal
• Processing signals relate to plain pleasure.
  Regulating
• body homeostasis
• Emotion and feeling
• Attention
• Wakefulness sleep
• 5. learning
• The construction of consciousness.

11
Fast synaptic transmission -ligand-operated ion
channels the hardware of the brain Slow
synaptic transmission the software that
controls fast transmission
12
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13
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14
7 transmembrane domain receptor
Out
NH2
In
2nd messengers
G
COOH
15
Ionotropic
Metabotropic
16
The monoamines Dopamine Epinephrine
(adrenergic) Norepinephrine (noradrenergic) Se
rotonin
17
Neurotransmitter receptors
Neurotransmitter receptors
Ion pumps
Second messengers
Protein kinases
Transcription Factors Cell nucleus
Ion channels
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19
7-transmembrane-domain receptors
20
Excitatory input
Glutamate
Neuromodulatory inputs
Neuromodulatory inputs
ACh
GluR
NE
M1
b1
Ca2
5-HT
DA
IP3 DG
D1
Ca2-dependent Kinases/phosphatases
cAMP
PKC
5-HT2C
Hist
Hist
PKA
Down-stream substrates
H2
H1
Gene expression
Short-term synaptic modification
Long-term synaptic modification
21
Particular modulator transmitters should not be
regarded as purely excitatory or
inhibitory. Their exact action depends on
context. On the same cell, they can be either
excitatory or inhibitory depending on the state
of the cell.
22
The Nobel prize in 2000 went to three
neuroscientists for working out the role of
biogenic amines/monoamines in the nervous
system Arvid Carlsson Paul Greengard Eric
Kandel
23
The Nobel Prize in 2000 went to three
neuroscientists for working out the role of
biogenic amines/monoamines in the nervous
system Arvid Carlsson (dopamine/l-dopa
therapy) Paul Greengard (role of
phosphorylation) Eric Kandel (serotonin in
learning memory)
24
Carlsson, A (2001). A paradigm shift in brain
research. Science, vol. 294, p1021-1024 Green
gard, P (2001). The neurobiology of slow synaptic
transmission. Science, vol. 294,
p1024-1030 Kandel, ER (2001). The molecular
biology of memory storage a dialogue between
genes and synapses. Science, vol. 294, p1030-1038
25
Catecholamines Norephinephrine
26
A synapse that uses norepinephrine (NE)
27
MAO Inhibitors
Monoamine oxidase, located on outer membrane of
mitochondria deaminates catecholamines free
in nerve terminal that are not protected by
vesicles
Antidepressant
Selective inhibitor, reboxetine
Stimulant
Cocaine blocks the NET
Reuptake of NE
28
NE potentiation of responses to GABA Purkinje
cells
29
Out
GABA
GABA
PO4
In
30
GABA response
time
Noradrenergic potentiation of cerebellar Purkinje
cell responses to GABA cAMP as intracellular
intermediary.
31
NE
GABAA receptor
b-adrenergic receptor
b1
AC
PO4
Gs
cAMP
ATP
32
Out
GABA
GABA
PO4
In
POSTSYNAPTIC MODULATION
33
Why does a small amount of stress help you learn
better?
34
b-adrenergics and memory
35
After several hours.
36
Unless b-adrenergic activation of postsynaptic
cell takes place
Active during memory formation
NE
Glu
Stabilization of LTP
cAMP
PKA
Inhibition of protein phosphatase I
37

• b-adrenergic receptor activation helps memories
• better memories when you are paying attention
• because of higher emotional stimulation

38
SEROTONIN 5-HT
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41
PRESYNAPTIC MODULATION
42
See Chapter 63. Cellular mechanisms of
learning. Page 1247. Principles of
Neuroscience Kandel ER et al 4th edition, 2000,
McGraw-Hill See also, Chapter 13, Figure 13-12
in Kandel et al Or Chpater 50. Learning and
memory basic mechanisms. Page 1275 Fundamental
Neuroscience, second edition, Squire LR et al,
2003, Academic Press
43
Humans
Serotonin - a chemical manifestation of
personality High level of serotonin
compulsives obsessive-compulsive disorders e.g.
compulsive hand-washing Low levels of serotonin
depression, suicide. Listening to Prozac, P.D.
Kramer, 1993
44
The 5-HT neurons in the brain
45
A synapse that uses serotonin/5-HT
46
Treatment of depression. anxiety disorders,
obsessive-compulsive disorders
Re-uptake of 5-HT/serotonin
47
Genetic variation in the gene promoter region of
the serotonin transporter. risk factor for
anxiety, alcoholism, mood disorders slight
differences in level of expression
48
Catecholamines Dopamine
49
Dopamine pathways in the brain
50
Dopamine pathways do many things Control flow of
blood through the brain Motor control
(nigrostriatal) system Behavioural
control Dopamine is the brains motivational
chemical. It works on glutamate synapses to
modulate their excitability. A shortage of
brain dopamine causes an indecisive personality,
unable to initiate even the bodys own movement.
Parkinsons disease. Time stops. L-DOPA
therapy. Awakenings film. (Oliver
Sachs) Excess dopamine, more arousal. Attention
defecit disorder. May cause schizophrenia. Dop
amines action is essential for drug addiction.

51
L-DOPA rescues Parkinsonian rabbits
Rabbits treated with reserpine
The same rabbits 15 minutes after treatment
with L-DOPA

• Carlsson, 1960
• See Science, vol 294, p1002, 2 November 2001

52
DARP-32 Dopamine and cAMP-regulated
phosphoprotein Molecular weight, 32 kDa DARP-32
is a molecular integrator
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54
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55
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56
Neocortex neurons
Neural ensembles
57
neocortex
Substantia nigra
Dop
58
1
2
3
4
Dop
59
1
3
4
2
Dop
60
neocortex
Substantia nigra
61
neocortex
Substantia nigra
Parkinsons disease. No dopamine No neural
ensembles can be selected
62
Schizophrenia? Active neural ensembles too
extended?
neocortex
Substantia nigra
63
Other neuromodulators (NE, serotonin)
probably work in a similar way to dopamine They
assist with the selection/maintenance of
different neural ensembles.
64
Molecular actions of dopamine
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66
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67
Polymorphisms of genes involved in aminergic
(dopamine/serotonin) neurotransmission Effects
on personality? Dopamine D4 receptor - novelty
seeking Promoter of serotonin transporter gene -
harm avoidance/anxiety
68
D4 dopamine receptor
16 amino acid repeat sequence present in two to
11 copies - minisatellite phrase
69
D4 dopamine receptor
The larger the number of repeats, the more
ineffective is the dopamine D4 receptor in
signalling
70
The larger the number of loop 3 repeats, the more
ineffective the dopamine D4 receptor in
signalling Long D4DR genes imply low
responsiveness to dopamine short D4DR gene
imply high responsiveness The idea People with
long D4DR genes have low responsiveness to
dopamine, so they need to take a more
adventurous approach to life to get the same
dopamine buzz that short-gened people get from
simple things. Obviously, this is just one
possible factor of many. Dont oversimplify!
71
Neuromodulators
Slow synaptic transmission
William.Wisden_at_urz.uni-heidelberg.de Alan_at_uni-hd.
de Alan Summerfield