Neurotransmission, Neuropsychiatry, and Neuropharmacology 2013

NEUROTRANSMISSION, PSYCHIATRY AND
NEUROPHARMACOLOGY 2013
CFIN Course
Donald F. Smith, BSc, MA, PhD, MMSc, DMSc.
Center for Psychiatric Research
Psychiatric Hospital of Aarhus University
8240 Risskov

Basic Monoaminergic Mechanisms
 Who were the founders?
 What did they do?
 What impact has it had?
 How does neurotransmission
translate into behavior?

Names in mixed-up order
Lewis Seiden
Bernard Brodie
Linda Buck
Otto Loewi
John Eccles
John Harvey
Joseph Schildkraut
Seymour Kety
Edith Piaf
Henry Dale
Julius Axelrod
Arvid Carlsson
Mogens Schou

http://www.youtube.com/wa
tch?v=Kya3c4WJZAk

The Nobel Prize in Physiology or
Medicine 1936
shared with Sir Henry Dale
…for chemical transmission of nerve
impulses.
In 1921 Loewi discovered the chemical
transmission of nerve impulses the
research of which was greatly developed
by him and his co-workers in the years
following, culminating ultimately in his
demonstation that the parasympathetic
substance («Vagusstoff») is acetylcholine
and that a substance closely related to
adrenaline played a corresponding role at
the sympathetic nerve endings. It was for
these researches that he received the
Nobel Prize in 1936, jointly with Sir Henry
Dale. This and other discoveries in the
fields of chemistry, physics, and
pharmacology have since then led to a
complete renewal of the concepts of the
sympathetic nervous system.
Otto Loewi

What type of experiment would prove the existence of chemical
transmission?
Think about this question.
Suggest experimental set-ups.
What did Loewi do?

 Autonomic influences on the heart have been recognized for many
centuries. It was not until 1921, however, that a German
physiologist named Otto Loewi stimulated a frog's vagus nerve,
collected the released substance, and applied it to a second,
different frog heart to demonstrate its effects.
 For his discovery of this "vagusstuff" (subsequently shown to be
acetylcholine), Loewi shared the 1936 Nobel Prize in Physiology or
Medicine.
 We now know that acetylcholine released by the vagus nerve is the
predominant parasympathetic influence on the heart while
epinephrine and norepinephrine mediate the principal cardiac
sympathetic effects.
 From Maisel, W.H. J Am Coll Cardiol, 2003; 42:1269-1270

Barger, G. and Dale, H.H., Chemical structure and
sympathomimetic action of amines. J. Physiol. 41: 19-59,
1910
Sir Henry Dale, Transmission of nervous effects by
acetylcholine. Harvey Lectures, 32: 229-245, 1937
Henry Hallett Dale, 1875–1968
Introduced the terminology of cholinergic and
adrenergic nerve supply.

Action Potential Movie
video – type in Google: Hodgkin and Huxley giant squid
experiment
and then select see Bio330
http://www.science.smith.edu/departments/NeuroSci/courses/bi
o330/squid.html

Sir John Carew Eccles
Australian research physiologist who received (with Alan
Hodgkin and Andrew Huxley) the 1963 Nobel Prize for
Physiology or Medicine for his discovery of the chemical
means by which impulses are communicated or
repressed by nerve cells (neurons).

 Figure 1. Dendrites and cell bodies of schematic neurons connected by dendritic-
dendritic gap junctions form a laterally connected input layer (“dendritic web”) within
a neurocomputational architecture. Dendritic web dynamics are temporally coupled to
gamma synchrony EEG, and correspond with integration phases of “integrate and
fire” cycles. Axonal firings provide input to, and output from, integration phases (only
one input, and three output axons are shown). Cell bodies/soma contain nuclei
shown as black circles; microtubule networks pervade the cytoplasm. … gamma EEG-
synchronized integration phases include quantum computations in microtubule
networks which culminate with conscious moments. Insert closeup shows a gap
junction through which microtubule quantum states entangle among different
neurons, enabling macroscopic quantum states in dendritic webs extending
throughout cortex and other brain regions.

 Eccles demonstrated that one nerve cell communicates with a neighbouring cell
by releasing chemicals into the synapse (the narrow cleft, or gap, between
the two cells). He showed that the excitement of a nerve cell by an impulse
causes one kind of synapse to release into the neighbouring cell a substance
(probably acetylcholine) that expands the pores in nerve membranes. The
expanded pores then allow free passage of sodium ions into the neighbouring
nerve cell and reverse the polarity of electric charge. This wave of electric
charge, which constitutes the nerve impulse, is conducted from one cell to
another. In the same way, Eccles found, an excited nerve cell induces another
type of synapse to release into the neighbouring cell a substance that
promotes outward passage of positively charged potassium ions across the
membrane, reinforcing the existing polarity and inhibiting the transmission of
an impulse. (See also action potential.)

 Eccles's research, which was based largely on the
findings of Hodgkin and Huxley, settled a long-
standing controversy over whether nerve cells
communicate with each other by chemical or by
electric means. His work had a profound influence on
the medical treatment of nervous diseases and
research on kidney, heart, and brain function.

Julius Axelrod (May 30, 1912 –
December 29 2004) was an
influential American biochemist. He
won a share of the Nobel Prize in
Physiology or Medicine in 1970
along with Bernard Katz and Ulf von
Euler. The Nobel Committee
honored him for his work on the
release and reuptake of
catecholamine neurotransmitters, a
class of chemicals in the brain that
include epinephrine, norepinephrine,
and, as was later discovered,
dopamine. Axelrod also made major
contributions to the understanding of
the pineal gland and how it regulates
the sleep-wake cycle.

 Early studies of possible relationships
between biochemistry and emotions.
 Not possible to examine the living
brain.
 Focus on the autonomic nervous
system.
 Comparisons between adrenaline and
noradrenaline

Adrenaline (Epinephrine) and Noradrenaline (Norepinephrine)
 Adrenaline and noradrenaline are hormones
 Adrenaline is synthesized in the adrenal medulla and is
released into the bloodstream
 Noradrenaline is synthesized in nerves of the sympathetic
branch of the autonomic nervous system (also called the
peripheral sympathetic nervous system) and is released into
the synapse.
 Adrenaline is primarily in the bloodstream
 Noradrenaline is primarily in the brain
 Adrenaline and noradrenaline affect alpha- and beta-
adrenergic receptors
 Alpha- and beta-adrenergic receptors are, for example,
involved in responses of blood vessels and heart.

Physiologic actions of adrenaline
 When in the bloodstream, it rapidly prepares the body for
action in emergency situations. The hormone boosts the
supply of oxygen and glucose to the brain and muscles, while
suppressing other non-emergency bodily processes (digestion
in particular).
 It increases heart rate and stroke volume, dilates the pupils,
and constricts arterioles in the skin and gastrointestinal tract
while dilating arterioles in skeletal muscles. It elevates the
blood sugar level by increasing catabolism of glycogen to
glucose in the liver, and at the same time begins the
breakdown of lipids in fat cells. Like some other stress
hormones, epinephrine has a suppressive effect on the
immune system.[5]

 Norepinephrine is released in the brain by
activation of an area of the brain stem
called the locus ceruleus. This nucleus is the
origin of most norepinephrine pathways in
the brain. Noradrenergic neurons project
bilaterally (send signals to both sides of the
brain) from the locus ceruleus along distinct
pathways to many locations, including the
cerebral cortex, limbic system, and the
spinal cord, forming a neurotransmitter
system.

Noradrenergic Neuropathways
(from Lundbeck Image Website)

Physiologic actions of noradrenaline
 Norepinephrine performs its actions on the
target cell by binding to and activating
adrenergic receptors. Unlike epinephrine,
which activates all adrenergic receptors (α1
α2 β1 β2), norepinephrine activates all but
β2 receptors. The target cell expression of
different types of receptors determines the
ultimate cellular effect, and thus
norepinephrine has different actions on
different cell types.

Ax and Funkenstein
 Describe some of the experimental set-ups
 Physiologic response of anger & aggression
linked with noradrenaline
 Physiologic response of fear & anxiety linked
with adrenaline
 Higher excretion of noradrenaline in
aggression
 Higher excretion of epinephrine in anxiety

 http://www.youtube.com/watch?v=Ma
8HCM3Z5Ic
 Mouse in maze

 http://www.youtube.com/watch?v=rZ-
zPs_JDhI
 Empathy in rats – short version

 http://www.youtube.com/watch?v=N3
9XHHxwTxU
 Operant behavior

Lewis Seiden
Operant schedules of reinforcement

 Behavior maintained under a differential-reinforcement-of-
low-rate (DRL) 72-s operant schedule, which reinforces
responses with interresponse times greater than 72 s,
exhibits a rather unique sensitivity to antidepressant drugs.
 Antidepressants from a number of pharmacological classes,
including tricyclic antidepressants, selective serotonin or
norepinephrine reuptake inhibitors, monoamine oxidase
inhibitors, as well as a number of atypical antidepressants
and putative antidepressants, reduce response rate and
increase reinforcement rate of rats under this schedule.
 Consistent with clinical data, it appears that activation of
noradrenergic or serotonergic systems provides for parallel
means of producing antidepressant-like effects on DRL
behavior.
 The results of studies using DRL behavior highlight
important roles for central beta-1 adrenergic receptors, as
well as 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors, in
the mediation of antidepressant-like behavioral effects.

 Do class exercise with DRL-schedules
 Pairwise for the students. Each
student decides how long each interval
should be and then reinforces the
other student with candy (M&Ms) each
time the correct response is made.

Joseph Schildkraut was the founding director of the
Neuropsychopharmacology/Psychiatric Chemistry
Laboratory at the Massachusetts Mental Health Center.
Schildkraut received his AB from Harvard College in 1955,
followed by his MD from HMS in 1959. He completed his
residency at MMHC and spent four years at the National
Institute of Mental Health. He rejoined the HMS community
in 1967 and began a career at MMHC that would span
nearly four decades, first as an assistant professor of
psychiatry, becoming full professor in 1974, and retiring as
emeritus in 2004.
Former editor in chief of the Journal of Psychiatric
Research, Schildkraut was the author of more than 200
scientific publications.
His seminal paper, “The Catecholamine Hypothesis of
Affective Disorders,” published in 1965, set the agenda for
biological research on depression for the next 25 years.
This paper was recognized in 1997 as the most cited of all
articles ever published in the American Journal of
Psychiatry and one of the most cited papers in the history
of psychiatry.
Joseph Schildkraut

Seymour Kety
In 1951, Kety became the first scientific director of the
National Institute of Mental Health (NIMH). He
established a broad program of fundamental
research representing all of the disciplines
concerned with the brain and behavior. That
program has nurtured one Nobel Prize-winning
scientist and four recipients of Lasker awards.
Kety not only recruited distinguished scholars to NIMH,
but also conceived and established the research
agenda that put psychiatry and psychology on a
rigorous scientific footing. It has been described as a
"research program of unprecedented breadth," that
included laboratories in each of the pertinent
biological as well as behavioral disciplines.
As a consequence, Kety is credited by the Lasker
Foundation with "shepherding psychiatry into a new
scientific era."

From Lundbeck Image Bank
Note Fusion of a synaptic vesicle with the pre-synaptic membrane
The Central Dogma
1. Synthesis
2. Storage
3. Release
4. Metabolism
5. Reuptake
6. Receptor

As head of the Laboratory for Clinical
Pharmacology at NIH after the war, Dr.
Brodie worked with and trained a group of
scientists who would become the leaders in
the science of neuroscience and drug
metabolism. Their work was accompanied
by increased research into instrumentation
and technology, including the
spectrophotofluorometer. Dr. Brodie won
the Lasker Award, often considered the
American Nobel Prize, in 1967. The award
cited his "extraordinary contributions to
biochemical pharmacology."
Bernard B. Brodie
Imipramine

”Fortunately, we had inbuilt in our programme a serendipity factor,
an ingredient that I recommend with some reservations to the
streamlined pharmaceutical laboratories of today – an animal
caretaker who on occasion mixes the animals up a bit. One day he
sent us rats that unbeknown to us had been receiving daily doses of
imipramine for quite another kind of experiment. As a matter of
fact, they were not even our rats – they belonged to Dr. Gillette and
I can sympathize with his annoyance when he discovered that his
animals had disappeared. Since we had no idea that the rats had
been treated with imipramine, you may imagine our surprise when
on administration of reserpine the animals almost literally climbed
the walls”
Bernard B. Brodie, Some ideas on the mode of action of imipramine-
type antidepressants, 1965

Bernard B. Brodie; Alfred Pletscher; Parkhurst A. Shore, Science, New Series, Vol. 122, No. 3177. (Nov. 18, 1955), p. 968.

Arvid Carlsson shared the Nobel
Prize in Physiology or Medicine of
2000 with Richard Kandel and Paul
Greenberg for their discoveries
concerning signal transduction in the
nervous system. Arvid Carlsson

Molecular Structures
Nortriptyline Imipramine
Pharmacological Profiles of NETs and SERTs
SERTs and NETs are the pharmacological targets for a variety of therapeutic
antidepressants and abused substances. Tricyclic antidepressant sensitivity
is shared by NETs and SERTs, but not by DA transporters. Tertiary amine
tricyclics (imipramine, amitriptyline) are more potent at SERTs as
compared to the NET-preferring secondary amine tricyclics
desipramine and nortriptyline. The steric interactions by which the
addition of a single methyl group increases potency of the tertiary amines for
SERT are not known; however, mutagenesis of the SERT protein should
prove useful in identifying residues important in this effect and allow
predictions concerning binding of ligands to the transporter.

Tricyclic Actions

 Show Forced-Swim Test
http://www.youtube.com/watch?v=Wq2
dyNILb5U&NR=1&feature=endscreen

Serotonin and Avoidance Behavior
Prof. John Harvey

Serotonin and Behavior
 http://www.youtube.com/watch?v=kX
xKBiidbeo
 Altering Serotonin Levels Changes
Monkey Behavior and Status

That’s probably enough for today

Noradrenaline & Serotonin
Neurotransmission
Sleep
Disturbance
Sexual
Disturbance
Memory
Disturbance
Thought
Disorders
Suicidal
Tendency
Low Self-
Esteem
Eating
Disorders
Psychomotor
Disturbance
Psychosomatic
Disorders

Mechanism of action of
noradrenaline re-uptake
transporters
The action of noradrenaline at the
synapse is terminated by its re-uptake
across the pre-synaptic membrane. This
is an energy dependent process.
Sodium/potassium ATPases use energy
from ATP hydrolysis to create a
concentration gradient of ions across
the pre-synaptic membrane that drives
the opening of the transporter and co-
transport of sodium and chloride ions
and noradrenaline from the synaptic
cleft. Potassium ions binding to the
transporter enable it to return to the
outward position. Release of the
potassium ions into the synaptic cleft
equilibrates the ionic gradient across the
pre-synaptic membrane. The
noradrenaline re-uptake transporter is
then available to bind another
noradrenaline molecule for re-uptake.

Mechanism of action of 5-HT re-uptake
transporters
The action of 5-HT at the synapse is
terminated by its re-uptake across the pre-
synaptic membrane. This is an energy
dependent process. Sodium/potassium
ATPases use energy from ATP hydrolysis to
create a concentration gradient of ions across
the pre-synaptic membrane that drives the
opening of the transporter and co-transport of
sodium and chloride ions and 5-HT from the
synaptic cleft. Potassium ions binding to the
transporter enable it to return to the outward
position. Release of the potassium ions into
the synaptic cleft equilibrates the ionic
gradient across the pre-synaptic membrane.
The 5-HT re-uptake transporter is then
available to bind another 5-HT molecule for
re-uptake.

 Mention that molecular ”tools” can be
purchased for testing hypotheses
about the role of each receptor in
neurotransmission and behavioral
tasks.

Key compounds for The Catecholamine
(and Serotonin) Hypothesis of
Affective Disorders
 Reserpine
 Tetrabenazine
 Amphetamine
 Monoamine oxidase inhibitors
 Imipramine
 Dehydroxyphenylalanine (DOPA)

From website of Journal of Affective Disorders, March, 2009

Depressive Disorders
Sleep
Disturbance
Sexual
Disturbance
Memory
Disturbance
Thought
Disorders
Suicidal
Tendency
Low Self-
Esteem
Eating
Disorders
Psychomotor
Disturbance
Psychosomatic
Disorders

Antidepressants (clinical and preclinical) that have
been tested as PET radioligands
 Paroxetine
 Citalopram
 Fluoxetine
 Venlafaxine
 Clomipramine
 Nefopam
 Mianserin
 NS2381 & NS2456
 McN5652

An infant monkey clinging to its terry cloth “mother.”
Harry F. Harlow, “Love in Infant Monkeys,” 1959

I don’t understand this information!
Can someone explain it to me?

From Science, 301: 16033-16038, 2003

 ”Although the impact of neurogenetics
on social sciences has long been
anticipated and represents an
inevitable – albeit welcome –
development, the transition from
complicated correlations to useful
predictions will be a challenge.”
 Klaus-Peter Lesch, Embo reports, 2007

Families of Serotonergic Receptors

Serotonergic Neuropathways
(from Lundbeck Image Website)

 5-HT receptor subtypes
 The actions of 5-HT are mediated by a range of different 5-HT receptors. The 5-HT
receptors are classified into seven main receptor subtypes, 5-HT1–7. Six of the seven
subtypes are G-protein-coupled receptors; 5-HT3 is a ligand-gated cation channel.
 5-HT1 receptors occur primarily in the brain and cerebral blood vessels (5-HT1D
only), where they mediate neural inhibition and vasoconstriction. They function
mainly as inhibitory presynaptic receptors, linked to inhibition of adenylate cyclase.
Specific agonists at 5-HT1 receptors include sumatriptan (used in migraine therapy)
and buspirone (used in the treatment of anxiety). Spiperone and methiothepin are
specific antagonists of 5-HT1 receptors.
 5-HT2 receptors are found in the CNS and in many peripheral sites. They act through
phospholisae C to produce excitatory neuronal and smooth muscle effects. Specific
ligands at 5-HT sites include LSD – acting as an agonist in the CNS and as an
antagonist in the periphery – and ketanserin and methysergide (both antagonists).

 5-HT3 receptors occur mainly in the peripheral nervous system, particularly
on nociceptive afferent neurones and on autonomic and enteric neurones. The
effects of these receptors are excitatory, mediated by receptor-coupled ion
channels. 5-HT3 antagonists (eg ondansetron, tropisetron) are used
predominantly as anti-emetic drugs.
 5-HT4 receptors are found in the brain, as well as peripheral organs like the
heart, bladder and gastrointestinal (GI) tract. Within the GI tract they
produce neuronal excitation and mediate the effect of 5-HT in stimulating
peristalsis. A specific 5-HT4 agonist is metoclopramide used for treating
gastrointestinal disorders.
 Little is known about the function and pharmacology of 5-HT5, 5-HT6 and 5-
HT7 receptors.

5-HT receptors – 7-transmembrane spanning, G-protein coupled receptors
There are four broad ‘superfamilies’ of receptor: (1) the channel-linked (ionotropic)
receptors; (2) the G-protein coupled (metabotropic) receptors; (3) the kinase-linked
receptors; and (4) receptors that regulate gene transcription. The 5-HT1, 2, 4, 5, 6 and
7 receptors belong to the G-protein coupled superfamily. They are membrane
receptors that have 7 transmembrane spanning a-helices. 5-HT binding to the ‘binding
groove’ on the extracellular portion of the receptor activates the G-proteins, which
initiate secondary messenger signalling pathways. The downstream effect is either
inhibitory or stimulatory, depending on the type of G-protein linked to the receptor – 5-
HT1 receptors are linked to inhibitory G-proteins, whereas 5-HT2, 4, 6 and 7 are linked
to stimulatory G-proteins.

Distribution of 5-HT1A receptors in the normal brain
There are seven sub-types of 5-HT receptor and the 1A subtype is
widely expressed throughout the brain. The highest levels of this sub-
type are found in the hippocampus and medial temporal cortex, with
slightly lower levels in the pre-frontal cortex. Low levels of 5-HT1A are
found in the basal ganglia.

Distribution of 5-HT1A receptors in depression
In depression the density of 5-HT1A receptors is altered compared
with the normal brain. The 5-HT1A receptor density is increased in
the hippocampus and medial temporal cortex, while the density of
these receptors is reduced compared with normal in the cerebellum,
basal ganglia and prefrontal cortex.

Distribution of 5-HT2 receptors in the normal brain
There are seven main types of serotonin receptors in the brain. The 5-
HT2 receptors (A, B and C subtypes) are widely distributed throughout
the brain. Briefly, these receptors can be found in the cerebral cortex,
amygdala, hypothalamus, hippocampus, substantia nigra, choroid
plexus, substantia innominata and some components of the basal
ganglia.

Distribution of 5-HT2 receptors in the brain of those affected
by depression
In depression the distribution of 5-HT2 receptors is altered
compared with the normal brain. The 5-HT2 receptor density is
decreased in the frontal, temporal, parietal and occipital cortical
regions compared with normal. 5-HT2 expression in the
hippocampus, basal ganglia, substantia nigra, hypothalamus,
choroid plexus and substantia innominata remains unaffected by
depression. From Lundbeck Image Bank

Distribution of 5-HT3 receptors in the brain
The 5-HT3 receptor subtype is a ligand-gated ion channel that controls
dopamine release. It is a common target of antiemetic therapy, as well as
other psychoactive drugs. A high density of 5-HT3 receptors has been
identified in the human brainstem, particularly in the area postrema (the
putative vomiting center of the brain) and the nucleus tractus solitarius.
Lower levels of expression of the 5-HT3 receptor have been shown in the
limbic system, hippocampus and the cerebral cortex.

The 5-HT3 receptor
The 5-HT3 receptor is distinct from the other 5-HT receptor
subtypes, in that it is a ligand-gated ion channel that is permeable to
sodium and potassium. The 5-HT3 receptor is structurally similar to
the nicotinic acetylcholine receptor and is composed of 5 subunits.
Two subunits have been cloned, 5-HT3A and 5-HT3B, and
homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the
receptor have both been characterised

Mechanism of action of a 5-HT3 antagonist
Binding of an agonist at the 5-HT binding site causes a
conformational change and activation of the 5-HT3 receptor. As a
ligand gated ion channel this permits the movement of positively
charged ions from the synaptic cleft into the cytoplasm. Binding
of an antagonist at the 5-HT binding site prevents this activation
and cell depolarisation is inhibited.

Distribution of 5-HT4 receptors in the brain
The 5-HT4 receptor subtype is coupled to a G-protein that
stimulates the intracellular messenger adenylate cyclase that, in
turn, regulates neurotransmission. In the human brain, a high
density of 5-HT4 receptors has been identified in the striato-nigral
system, notably in the caudate nucleus, lenticular nucleus (putamen
and globus pallidus) and the substantia nigra. Lower levels of
expression of the 5-HT4 receptor have been shown in the
hippocampus and the frontal cortex.

Distribution of 5-HT6 and 5-HT7 receptors in the brain
The 5-HT6 and 5-HT7 subtypes of serotonin receptor are coupled to a G-protein
that stimulates the intracellular messenger adenylate cyclase that, in turn,
regulates neurotransmission. In the human brain, a high density of 5-HT6
receptors has been identified in the olfactory tubercle, corpus striatum, nucleus
accumbens, dentate gyrus and hippocampus. Lower levels of expression of the
5-HT6 receptor have been shown in the cerebellum and amygdala. Studies in
the rat suggest the 5-HT7 receptor is widely distributed in the brain; examination
of human brain tissue has shown expression in the thalamus.

The Problem that needs Solving!
Noone knows the neurobiological basis of
depression. The long-term aim is to invent
procedures for early diagnosis of
treatment-resistant depression and for
guiding its evidence-based treatment.

Autoradiographic studies using
[3H]citalopram and [3H]imipramine
identify the amygdala, thalamus,
hypothalamus, CA3 region of the
hippocampus, substantia nigra, locus
coeruleus, and the raphe nuclei of the
midbrain as the brain regions with the
highest level of 5HT uptake sites.
Location of Serotonin Transporter

Brief Account of Background
• The neurotransmitter serotonin is allegedly involved in
therapeutic actions of most antidepressant drugs.
• Clomipramine is an ”old-style” antidepressant drug. It
acts primarily on serotonergic mechanisms, particularly
when it is given intravenously.
• Citalopram is a ”new-style” antidepressant drug. It shows
remarkable selectively on serotonergic mechanisms

Some evidence for a role of the mediodorsal nucleus of the
thalamus (MDT) in depressive disorders.
 PET radioligands of antidepressant drugs
accumulate in the MDT
 There is a relatively high density of serotonin
uptake sites in the MDT
 Neuronal damage of the MDT is associated with
symptoms of depressive disorder
 Limbic regions are reciprocally innervated by the
MDT
 Clomipramine, an antidepressant drug, alters the
relative rate of blood flow in the MDT

Aim: to determine whether an intravenous
infusion of clomipramine or citalopram
affects the relative rate of blood flow in the
mediodorsal nucleus of the thalamus of
healthy humans.

Time Line of PET scanning for Project 90
i.v. infusion
(30 min)
Volunteer
arrives
Install
Venflon
Place in
Scanner
H2
15O H2
15O
H2
15O
H2
15O
H2
15O H2
15O
Debriefing
Double-blind
Placebo,
Clomipramine
or Citalopram

 18 healthy volunteers based on interview,
MMSI, depression rating, blood data, EKG,
and MR.
 3 scans with [15O]H2O (preinfusion
condition)
 30 min intravenous infusion of isotonic
saline (placebo), clomipramine or
citalopram (randomized, double-blind)
 3 scans with [15O]H2O (postinfusion
condition)
 Data analysis by random effects model
using SPM99

Dorsomedial Thalamus
Pallidum
GABA
Striatum
GABA
Amygdala
Dorsal
Raphé
ACh
ACh
5-HT
NA
Hippocampus
Neocortex
Locus
Ceruleus
Substantia
Nigra
GABA
DA
GABA
Glutamate
Hypothalamus
ACh
Glutamate
Glutamate
Parabrachial
Nucleus
ACh

Blier, P. European Neuropsychopharmacology, 13: 57-66, 2003.

= NA neuron
= 5-HT neuron
= α2-autoreceptor
= α2-heteroceptor
NA
NA
NA
NA
NA
NA
NA
NA
5-HT
5-HT
Noradrenaline (NA) exerts a tonic, inhibitory action on serotonin (5-HT) release
via α2-heteroceptors, so antagonism of α2-heteroceptors enhances 5-HT release.
NA binding at α2-autoreceptors reduces NA release, so antagonism of
α2-autoreceptors enhances NA release.

Noradrenaline a2 adrenergic
receptor
There are two different types of
adrenoreceptor – the α and β
receptors. The α receptors are
further classified into α1 and α2
subtypes and the β receptors are
further classified into β1, β2 and β3
subtypes. The α2 adrenoreceptors
are widely distributed throughout the
body and are found in adrenergic
neurones, blood vessels, the
pancreas and in smooth muscle.
Coupled to inhibitory G-proteins,α2
adrenoreceptors have an inhibitory
effect on neurotransmission when
bound by an agonist.

Mechanism of action of an a2 adrenergic receptor antagonist
An α2 adrenergic receptor antagonist prevents the activation of the
α2 adrenergic receptor. The α2 receptor is coupled to inhibitory G-
proteins, which dissociate from the receptor following agonist
binding, and inhibit both secondary messenger signaling
mechanisms and cell depolarisation. Antagonist binding to the α2
adrenergic receptor prevents secondary messenger inhibition and
allows cell depolarisation to occur.

0
2
4
6
8
10
12
0 10 20 30 40 50 60
Time (min)
Radioactivity
(kBq/cc)
Cerebellum
Amygdala
Frontal cortex
Thalamus
Striatum
Hippocampus
Time-course of radioactivity derived from
[N-methyl-11C]mirtazapine in selected regions
of human brain.

Parametric map of the binding potential
of [11C]mirtazapine in 17 healthy human
volunteers.
1.5
0.5
1.0

Sense of Danger
Corticostriato- thalamic Pathway
Symptoms of Depression
5-HT
Sleep Disorders Cognitive
Disorders
Eating Disorders
ACh NA
GABA
Unconditioned
Responses
Conditioned
Responses
Emotional Memory
Amygdalothalamo-
cortical Pathway
Visceral
Limbic Pathway
5-HT
ACh
Corticothalamic
Pathway
Cortico-
cortico Pathway
Cortical
Limbic
Pathway

Who’s Who in Psychopharmacology
 1) Otto Loewi
 2) Henry Dale
 3) Julius Axelrod
 4) Joseph Schildkraut
 5) Seymour Kety
 6) Bernard Brodie
 7) Arvid Carlsson
 8) Mogens Schou
 9) Edith Piaf
 10) John Harvey
 11) Lewis Seiden
 12) Linda Buck
 13) John Eccles

Drugs affecting NETs and
SERTs
 Other potent NET antagonists include nomifensine, mazindol, and
nisoxetine. Highly selective antagonists for SERTs such as paroxetine
and fluoxetine have been developed whose chemical structures differ
from the tricyclic nucleus, but which are effective antidepressants
supporting alterations in serotonin neurons as targets in affective
disorders (22). Cocaine is a nonselective, competitive antagonist of
NE, 5HT, and DA transport. The addictive potential of cocaine is
though to be a consequence of actions on CNS DATs, whereas the
life-threatening cardiovascular effects of cocaine may involve
blockade of NETs at sympathetic and CNS autonomic synapses.
Some other drugs of abuse including p-chloroamphetamine,
fenfluramine, and (3,4-methylenedioxy) methamphetamine (MDMA,
"ecstasy") also are inhibitors of 5HT uptake. Interestingly, MDMA and
the other amphetamines are neurotoxic substrates for SERTs and
additionally cause efflux of 5HT by a transported-mediated exchange
process (59).

 Studies demonstrate (a) a high density of [3H]nisoxetine
binding sites in rat brain regions containing a high density of
noradrenergic soma or terminals, including the locus
coeruleus and hypothalamic nuclei, and (b) a low density in
regions receiving sparse noradrenergic innervation, such as
the striatum (61). A marked loss of [3H]nisoxetine labeled
sites occurs following chemical brain lesions with the
neurotoxins 6-hydroxydopamine (6-OHDA) and DSP-4,
indicating that forebrain labeling is most likely associated with
noradrenergic terminals rather than targets or surrounding
glia, although a small perisynaptic contribution which
disappears with loss of innervation cannot be excluded.
Distinction between NATs and DATs

Before 2002 most PET and SPECT studies involving
radiolabelled SSRI’s were performed with:
N
I
CO2Me
Me
ß-CIT N
S
CH3
H
(+)-McN 5652

Today the most promising candidates are based
on substituted phenylthiobenzylamine
derivatives:
S
N
CH3
NH2
I
CH3
S
NH2
NC
N
CH3
CH3
S
NH2
H3C
N
CH3
CH3
ADAM DASB MADAM

The Nobel Prize in Physiology
or Medicine 2004
shared for discoveries of
odorant receptors and the
organization of the olfactory
system
Prof. Linda B. Buck

Mogens Schou
Mogens Schou received the Lasker Prize
of Clinical Medical Research in 1987 for
his contribution to lithium therapy for
affective disorders.

 J Physiol (Paris). 1981;77(2-3):455-61. Links
– Enhancement of the 5-HT neurotransmission by antidepressant treatments.
– De Montigny C.
– The hypothesis of an etiopathogenic role of 5-HT and that of a mediation by the 5-HT
system in the effect of antidepressant treatments have often been confused. Little
unequivocal evidence exists for a 5-HT deficit in depression. However, several recent
animal and clinical data suggest that the 5-HT system might contribute to the therapeutic
effect of various antidepressant treatments. Long-term administration of tricyclic
antidepressant (TCA) drugs induces a sensitization of rat forebrain neurons to
iontophoretically-applied 5-HT. Repeated electroconvulsive shocks result also in an
increased sensitivity of forebrain 5-HT receptors. However, chronic administration of a new
antidepressant drug, zimelidine, a potent and long-lasting 5-HT uptake blocker, fails to
modify 5-HT receptor sensitivity. These results suggest that enhancement of 5-HT
neurotransmission obtained via either pre- or postsynaptic mechanisms might determine
the antidepressant effect of these treatments. In a recent clinical study, we observed that
lithium administration to TCA-resistant depressive patients induced a rapid relief of
depression. It is possible that the presynaptic enhancing effect of lithium on the 5-HT
system might unveil the TCA-induced sensitization of the postsynaptic 5-HT receptors.
Most depressed patients exhibit marked diurnal variations of mood. Preliminary
experiments in rats revealed that the responsiveness of hippocampal neurons to
iontophoretically-applied 5-HT is enhanced in the evening. Similar diurnal variations of 5-
HT receptor sensitivity might occur in human brain and be related to diurnal variation of
mood in depression. Since normal individuals do not show these fluctuations of mood, it is
proposed that the "mood regulating system" might become 5-HT dependent in depressed
patients.

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