See:

Chapter 13. Modulation of synaptic transmission:

Second messengers.

“Principles of Neuroscience” Kandel ER et al

4th edition, 2000, McGraw-Hill

Page 229
Fast: GABA, glutamate, acetylcholine

Slow: biogenic amines

Dopamine
Serotonin/5-HT
NE
Acetylcholine
Peptides
OUT

G Cl- G Na+
A l
B u
A

Cl- Na+
GABAA receptor Glutamate/AMPA
receptor
Inhibition Excitation
IN
Simple circuits
Feed-forward inhibition
Negative feedback

Feedback inhibition
 Neocortex

Interneuron - uses GABA

Pyramidal neuron
- uses glutamate
 Cerebral cortex

Sensory input Information integration Motor output

cognition, thought,
mood, emotion

acetylcholine norepinephrine dopamine histamine

serotonin
Arousal:

1. Processing signals relate to plain & pleasure. Regulating

body homeostasis
4. Emotion and feeling
5. Attention
6. Wakefulness & sleep
5. learning

The construction of consciousness.

Fast synaptic transmission -ligand-operated ion channels
the hardware of the brain

Slow synaptic transmission: the software that controls

fast transmission
 Ionotropic and metabotropic receptors

Fast Slow

Ion flow in/out Second messenger cascades

milliseconds seconds
1/1000 of a second !
Out 7 transmembrane
NH2 domain receptor

In

2nd messengers

COOH G
 Ionotropic

Metabotropic
The monoamines

Dopamine

Epinephrine (adrenergic)

Norepinephrine (noradrenergic)

Serotonin
 Neurotransmitter
receptors

Ion pumps Neurotransmitter

receptors

Second messengers

Protein kinases

Transcription Factors
Ion channels Cell nucleus
7-transmembrane-domain receptors
 Excitatory input Glutamate
Neuromodulatory Neuromodulatory
inputs inputs
GluR ACh
NE
1 M1
Ca2+
DA 5-HT
IP3 + DG
D1 Ca2+-dependent
cAMP Kinases/phosphatases

PKC 5-HT2C
Hist Hist
PKA Down-stream substrates

H2 Gene expression H1

Short-term synaptic modification Long-term synaptic modification

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.
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
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)

Carlsson, A (2001). A paradigm shift in brain research.
Science, vol. 294, p1021-1024

**Greengard, 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
Catecholamines

Norephinephrine
A synapse that uses norepinephrine (NE)
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
Cocaine blocks the NET Stimulant

Reuptake of NE
NE potentiation of responses to GABA

Purkinje cells
Out

Cl- Cl-
GABA GABA

PO4

Cl- Cl- Cl- Cl- Cl- Cl-

In
 GABA + cAMP

GABA + NE
GABA
response

GABA

time

Noradrenergic potentiation of cerebellar Purkinje cell responses

to GABA: cAMP as intracellular intermediary.
 NE
-adrenergic GABAA receptor
receptor
1

AC PO4
Gs
cAMP

PKA reg
ATP
PKA cat
Out

Cl- Cl-
GABA GABA

PO4

Cl- Cl- Cl- Cl- Cl- Cl-

In POSTSYNAPTIC MODULATION
Why does a small amount of stress help you learn better?
 -adrenergics and memory

Presynaptic Postsynaptic
Before LTP

After LTP

More glutamate receptors

= bigger response
 After LTP

More glutamate receptors

= bigger response

After several hours…….

Presynaptic Postsynaptic
LTP decays
Unless -adrenergic activation of postsynaptic cell takes place…

Active during memory

formation
NE

Glu

Stabilization of LTP
cAMP
PKA
Inhibition of
protein phosphatase I
-adrenergic receptor activation helps memories

-better memories when you are paying attention

because of higher emotional stimulation
SEROTONIN
5-HT
PRESYNAPTIC
MODULATION
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
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

The 5-HT neurons in the brain
A synapse that uses serotonin/5-HT
 Fluoxetine/Prozac blocks the SERT
Treatment of depression.
Re-uptake of 5-HT/serotonin anxiety disorders,
obsessive-compulsive disorders
Genetic variation in the gene promoter region of the
serotonin transporter.
risk factor for anxiety, alcoholism, mood disorders

slight differences in level of expression

Catecholamines

Dopamine
Dopamine pathways in the brain
Dopamine pathways do many things:
Control flow of blood through the brain

Motor control (nigrostriatal) system

Behavioural control
Dopamine is the brain’s 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 body’s own
movement. Parkinson’s disease. Time stops.
L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs)

Excess dopamine, more arousal. Attention defecit

disorder. May cause schizophrenia.
Dopamine’s action is essential for drug addiction.
 L-DOPA rescues Parkinsonian rabbits

Rabbits treated with

reserpine

The same rabbits

15 minutes after
treatment with
L-DOPA

A. Carlsson, 1960
See Science, vol 294, p1002, 2 November 2001
DARP-32

Dopamine and cAMP-regulated phosphoprotein

Molecular weight, 32 kDa

DARP-32 is a molecular integrator

 Overlapping cell

Neocortex
neurons

Neural ensembles
neocortex

Substantia
nigra
Dop
1 2

Dop
1 3

Dop
neocortex

Substantia
nigra
Dop
neocortex

Substantia
nigra
Parkinson’s disease. No dopamine
No neural ensembles can be selected
 Schizophrenia?
Active neural ensembles too extended?

neocortex

Substantia
nigra
DA
Other neuromodulators (NE, serotonin) probably
work in a similar way to dopamine

They assist with the selection/maintenance of different

neural ensembles.
Molecular actions of dopamine
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
 D4 dopamine receptor

16 amino acid repeat sequence present in two

to 11 copies - minisatellite phrase
 D4 dopamine receptor

The larger the number of repeats, the more

ineffective is the dopamine D4 receptor
in signalling
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.

Don’t oversimplify!
Neuromodulators
Slow synaptic transmission
William.Wisden@urz.uni-heidelberg.de

Alan@uni-hd.de

Alan Summerfield