Biochemistry and

Biological Psychiatry
ass. prof. Zdenk Fiar, CSc.
Department of Psychiatry
1st Faculty of Medicine
Charles University, Prague
Head: prof. MUDr. Ji Raboch, DrSc.

Biochemistry and Biological Psychiatry

cellular neurochemistry (neurons, action

potentials, synapses)
intercellular signalling (neurotransmitters,
receptors, growth factors)
intracellular signalling (G proteins,
effectors, 2nd messengers, proteinkinases,
transcription factors)
psychotropic drugs (antipsychotics,
antidepressants)
biological hypotheses of mental disorders
(schizophrenia, affective disorders)

Biological Psychiatry: Web Pages

1. Educational portal of our faculty:
http://connect.lf1.cuni.cz
http://portal.lf1.cuni.cz/
(section Psychiatry, Psychology, Sexuology)

2. Direct links:
http://www.lf1.cuni.cz/zfisar/psychiatry/
(presentation of lectures from psychiatry)

http://psych.lf1.cuni.cz/bpen/default.htm
(teaching material from biological psychiatry)

Introduction

Biological psychiatry studies disorders

in human mind from the
neurochemical, neuroendocrine and
genetic point of view mainly.
It is postulated that changes in brain
signal transmission (at the level of
chemical synapse) are essential in the
development of mental disorders.

Cellular Neurochemistry

Neurons
Action potentials
Synapses

Neuron

The neurons are the

brain cells that are
responsible for
intracellular and
intercellular signalling.
Action potential is
large and rapidly
reversible fluctuation in
the membrane potential,
that propagate along the
axon.
At the end of axon there
are many nerve
endings (synaptic
terminals, presynaptic
parts, synaptic buttons,
knobs). Nerve ending
form an integral parts of
synapse.
Synapse mediates the
signal transmission from
one neuron to another.

Synapse

Neurons communicate with one

another by
direct electrical coupling
secretion of neurotransmitters

Synapses are specialized structures

for signal transduction from one
neuron to other. Chemical synapses
are studied in the biological
psychiatry.

Morphology of Chemical Synapse

Chemical
Synapse Signal
Transduction

Model of Plasma Membrane

Membrane
Transporters

Intercellular and Intracellular

Signalling

Neurotransmitters
Growth factors
Receptors
G proteins
Effector systems (2nd messengers,
proteinkinases, transcription factors)

Criteria to Identify Neurotransmitters

1.

Presence in presynaptic nerve terminal

2.

Synthesis by presynaptic neuron

3.

4.

5.

Releasing on stimulation (membrane

depolarisation)
Producing rapid-onset and rapidly
reversible responses in the target cell
Existence of specific receptor

There are two main groups of neurotransmitters:

classical neurotransmitters
neuropeptides

Selected Classical Neurotransmitters

System

Transmitter

Cholinergic

acetylcholine

Aminoacidergic

GABA, aspartic acid, glutamic

acid, glycine, homocysteine

Monoaminergic

Catecholamines

Indolamines

Others, related to
aa
Purinergic

dopamine, norepinephrine,
epinephrine
tryptamine, serotonin
histamine, taurine
adenosine, ADP, AMP, ATP
nitric oxide

Catecholamine Biosynthesis

Serotonin Biosynthesis

Reuptake and Metabolism of

Monoamine Neurotransmitters

Reuptake
Monoamine oxidase (MAO)
Catechol-O-methyltransferase (COMT)

Selected Bioactive Peptides

Peptide

Group

substance P, substance K (tachykinins), neurotensin, brain and

cholecystokinin (CCK), gastrin, bombesin
gastrointestinal
peptides
galanin, neuromedin K, neuropeptideY (NPY),
peptide YY (PYY),

neuronal

cortikotropin releasing hormone (CRH)

growth hormone releasing hormone (GHRH),
gonadotropin releasing hormone (GnRH),
somatostatin, thyrotropin releasing hormone (TRH)

hypothalamic
releasing factors

adrenocorticotropic hormone (ACTH)

growth hormone (GH), prolactin (PRL), lutenizing
hormone (LH), thyrotropin (TSH)

pituitary hormones

oxytocin, vasopressin

neurohypophyseal
peptides

atrial natriuretic peptide (ANF), vasoactive intestinal

peptide (VIP)

neuronal and
endocrine

enkephalines (met-, leu-), dynorphin, -endorphin

opiate peptides

Growth Factors in the Nervous System

Neurotrophins

Neurokines

Nerve growth factor (NGF)

Brain-derived neurotrophic factor (BDNF)
Neurotrophin 3 (NT3)
Neurotrophin 4/5 (NT4/5)
Ciliary neurotrophic factor (CNTF)
Leukemia inhibitory factor (LIF)
Interleukin 6 (IL-6)
Cardiotrophin 1 (CT-1)

Fibroblast growth
factors

FGF-1
FGF-2

Transforming growth
factor
superfamily

Transforming growth factors (TGF)

Bone morphogenetic factors (BMPs)
Glial-derived neurotrophic factor (GDNF)
Neurturin

Epidermal growth
factor
superfamily

Epidermal growth factor (EGF)

Transforming growth factor (TGF)
Neuregilins

Other growth factors

Platelet-derived growth factor (PDGF)

Insulin-like growth factor I (IGF-I)

Membrane Receptors

Receptor is macromolecule
specialized on transmission of
information.
Receptor complex includes:
1.
2.

Specific binding site

Internal ion channel or transduction
element
3. Effector system (ion channels or
system of 2nd messengers)

Regulation of receptors
1. Density of receptors (down-regulation,
up-regulation)
2. Properties of receptors
(desensitisation, hypersensitivity)

Receptor Classification
1.

2.
3.

4.

Receptor coupled directly to the ion

channel
Receptor associated with G proteins
Receptor with intrinsic guanylyl
cyclase activity
Receptor with intrinsic tyrosine
kinase activity

1. Receptors with Internal Ion Channel

1. Receptors with
Internal Ion Channel
acetylcholine

Nicotinic acetylcholine
receptor is made of 5
subunits, 2 of which
(shown in orange) bind
acetylcholine (red).

membrane

receptor

acetylcholine

1. Receptors with internal ion channel

GABAA receptor, nicotonic acetylcholine
receptors, ionotropic glutamate receptors, etc.

2. Receptors
Associated with
G Proteins

1. adenylyl cyclase system

2. phosphoinositide system
3. arachidonic acid system

Receptors Associated with G Proteins

SYSTEM

Adenylyl
cyclase system

Phosphoinositide Arachidonic acid

system
system

NEURONE, 5-HT, DA,

TRANSMITTER Ach

NE, 5-HT, DA, Ach

Histamine

TRANSDUCER Gs, Gi

Gp

Unknown Gprotein

PRIMARY
EFFECTOR

Adenylyl cyclase

Phospholipase C

Phospholipase A

SECONDARY
MESSENGER

cAMP

IP3, DAG, Ca++

Arachidonic acid

Calcium and
calmoduline
dependent protein
kinases
Protein kinase C

SECONDARY
EFFECTOR

Protein kinase A

5-Lipoxygenase
12-Lipoxygenase
Cycloxygenase

Types of Receptors
System
Type
acetylcholinergic

acetylcholine nicotinic receptors

acetylcholine muscarinic receptors

monoaminergic 1-adrenoceptors
2-adrenoceptors
-adrenoceptors
dopamine receptors
serotonin receptor
aminoacidergic

GABA receptors
glutamate ionotropic receptors
glutamate metabotropic receptors
glycine receptors
histamine receptors

peptidergic

opioid receptors
other peptide receptors

purinergic

adenosine receptors (P1 purinoceptors)

Subtypes of Norepinephrine
Receptors
RECEPTORS
1-adrenoceptors

2-adrenoceptors

-adrenoceptors

Subtype

Transducer

Structure
(aa/TM)

1A

Gq/11

IP3/DAG

466/7

1B

Gq/11

IP3/DAG

519/7

1D

Gq/11

IP3/DAG

572/7

2A

Gi/o

cAMP

450/7

2B

Gi/o

cAMP

450/7

2C

Gi/o

cAMP

461/7

2D

Gi/o

cAMP

450/7

Gs

cAMP

477/7

Gs

cAMP

413/7

Subtypes of Dopamine Receptors

RECEPTORS
dopamine

Subtype

Transducer

Structure
(aa/TM)

D1

Gs

cAMP

446/7

D2

Gi
Gq/11

cAMP
IP3/DAG, K+,
Ca2+

443/7

D3

Gi

cAMP

400/7

D4

Gi

cAMP, K+

386/7

D5

Gs

cAMP

477/7

Subtypes of Serotonin Receptors

RECEPTORS
5-HT
(5-hydroxytryptamine)

Subtype

Transducer

Structure

5-HT1A

Gi/o

cAMP

421/7

5-HT1B

Gi/o

cAMP

390/7

5-HT1D

Gi/o

cAMP

377/7

5-ht1E

Gi/o

cAMP

365/7

5-ht1F

Gi/o

cAMP

366/7

5-HT2A

Gq/11

IP3/DAG

471/7

5-HT2B

Gq/11

IP3/DAG

481/7

5-HT2C

Gq/11

IP3/DAG

458/7

5-HT3

internal cationic channel 478

5-HT4

Gs

5-ht5A

5-ht6

Gs

cAMP

387/7
357/7

cAMP

440/7

Feedback to Transmitter-Releasing

Crossconnection of Transducing
Systems on Postreceptor Level

AR adrenoceptor
G G protein
PI-PLC phosphoinositide
specific phospholipase C
IP3 inositoltriphosphate
DG diacylglycerol
CaM calmodulin
AC adenylyl cyclase
PKC protein kinase C

Psychotropic Drugs
Biochemical hypotheses of mental disorders
are based on the study of mechanisms of
action of psychotropic drugs at the level of:
chemical synapse
intracellular processes connected with
signal transduction

Classification of Psychotropics
parameter

effect

group

watchfulness
(vigility)

positive

psychostimulant drugs

negative

hypnotic drugs

affectivity

positive

antidepressants
anxiolytics

psychic
integrations
memory

negative

dysphoric drugs

positive

neuroleptics, atypical
antipsychotics

negative

hallucinogenic agents

positive

nootropics

negative

amnestic drugs

Main Psychotropic Drugs

Antipsychotics
Antidepressants
Anxiolytics
Hypnotics
Cognitives
Psychostimulants
Hallucinogens

Potential Action of Psychotropics

1. Synthesis and storage of
neurotransmitters
2. Releasing of neurotransmitters
3. Receptor-neurotransmitter
interactions (agonists, antagonists)
4. Catabolism of neurotransmitters
5. Reuptake of neurotransmitters
6. Transduction element (G protein)
7. Effector's system
8. Transcription factor activity and gene

Classification of Antipsychotics
Group

Conventional
antipsychotics
(classical neuroleptics)

Atypical antipsychotics
(antipsychotics of 2nd
generation)

Examples
chlorpromazine, chlorprotixene,
clopenthixole, levopromazine,
periciazine, thioridazine
droperidole, flupentixol,
fluphenazine, fluspirilene,
haloperidol, melperone,
oxyprothepine, penfluridol,
perphenazine, pimozide,
prochlorperazine, trifluoperazine
amisulpiride, clozapine,
olanzapine, quetiapine,
risperidone, sertindole, sulpiride,
aripiprazole

Mechanisms of Action of
Antipsychotics
Conventional
antipsychotics

Atypical
antipsychotics

D2 receptor blockade of postsynaptic in

the mesolimbic pathway

D2 receptor blockade of postsynaptic in the

mesolimbic pathway to reduce positive
symptoms;
enhanced dopamine release and 5-HT2A
receptor blockade in the mesocortical
pathway to reduce negative symptoms;
other receptor-binding properties may
contribute to efficacy in treating cognitive
symptoms, aggressive symptoms and
depression in schizophrenia

Receptor Systems Affected by Atypical Antipsychotics

risperidone D2, 5-HT2A, 5-HT7, 1, 2
sertindole

D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1

ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI
loxapine

D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, M1,

H1, NRI

zotepine

D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3,

D4, 1, H1, NRI

clozapine

D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6,

5-HT7, D1, D3, D4, 1, 2, M1, H1

olanzapine

D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3,

D4, D5, 1, M1-5, H1

Classification of Antidepressants
(based on acute pharmacological actions)

Inhibitors of
neurotransmitter
catabolism

monoamine oxidase inhibitors (IMAO)

serotonin reuptake inhibitors (SRI)

norepinephrine reuptake inhibitors (NRI)
selective SRI (SSRI)
selective NRI (SNRI)
serotonin/norepinephrine inhibitors (SNRI)
norepinephrine and dopamine reuptake
inhibitors (NDRI)
5-HT2A antagonist/reuptake inhibitors (SARI)

Reuptake
inhibitors

Agonists of
receptors
Antagonists of
receptors

5-HT1A
2-AR
5-HT2

Inhibitors or stimulators of other components of signal transduction

Action of
SSRI

Biological Hypotheses of Mental

Disorders

Schizophrenia
Affective disorders

Schizophrenia
Biological models of schizophrenia
can be divided into four related
classes:
Environmental models
Genetic models
Neurodevelopmental models
Dopamine hypothesis

Schizophrenia - Genetic Models

Multifactorial-polygenic threshold
model:
Schizophrenia is the result of a combined
effect of multiple genes interacting with
variety of environmental factors.
The liability to schizophrenia is linked to
one end of the distribution of a continuous
trait, and there may be a threshold for the
clinical expression of the disease.

Schizophrenia Neurodevelopmental Models

A substantial group of patients, who
receive diagnosis of schizophrenia in
adult life, have experienced a
disturbance of the orderly development
of the brain decades before the
symptomatic phase of the illness.

Basis of Classical Dopamine

Hypothesis of Schizophrenia
1.

2.

3.

Dopamine-releasing drugs (amphetamine,

mescaline, LSD) can induce state closely
resembling paranoid schizophrenia.
Antipsychotics, that are effective in the
treatment of schizophrenia, have in
common the ability to inhibit the
dopaminergic system by blocking action of
dopamine in the brain.
Antipsychotics raise dopamine turnover.

Classical Dopamine Hypothesis of

Schizophrenia
Psychotic symptoms are related to
dopaminergic hyperactivity in the
brain. Hyperactivity of dopaminergic
systems during schizophrenia is result
of increased sensitivity and density of
dopamine D2 receptors. This increased
activity can be localized in specific
brain regions.

Biological Psychiatry and

Affective Disorders
BIOLOGY

genetics

vulnerability to mental
disorders

stress

increased sensitivity

chronobiology

desynchronisation of
biological rhythms

NEUROCHEMISTRY neurotransmitters availability, metabolism

IMMUNONEUROENDOCRINOLOGY

receptors

number, affinity, sensitivity

postreceptor
processes

G proteins, 2nd messengers,

phosphorylation,
transcription

HPA

increased activity during

depression

(hypothalamicpituitaryadrenocortical)

system
immune function

different changes during

depression

Data for Neurotransmitter

Hypothesis
1.

2.

3.

Tricyclic antidepressants through

blockade of neurotransmitter reuptake
increase neurotransmission at
noradrenergic and serotonergic synapses
MAOIs increase availability of monoamine
neurotransmitters in synaptic cleft
Depressive symptoms are observed after
treatment by reserpine, which depletes
biogenic amines in synapse

Monoamine Hypothesis
Depression was due to a deficiency of
monoamine neurotransmitters,
norepinephrine and serotonin.
Advanced monoamine theory: serotonin or
norepinephrine levels in the brain are
regulated by MAO-A activity mainly. However,
specific symptoms of depression or mania are
related to changes in the activity of
monoamine transporters in specific brain
regions. So, both MAO-A activity and density
of transporters are included in the
pathophysiology of affective disorders.

Permissive Biogenic Amine

Hypothesis
A deficit in central serotonergic transmission
permits affective disorder, but is insufficient
for its cause; changes in central
catecholaminergic transmission, when they
occur in the context of a deficit in
serotonergic transmission, act as a
proximate cause for affective disorders and
determine their quality (catecholaminergic
transmission being elevated in mania and
diminished in depression).

Receptor Hypotheses
The common final result of chronic
treatment by majority of
antidepressants is the downregulation or up-regulation of
postsynaptic or presynaptic receptors.
The delay of clinical response
corresponds with these receptor
alterations.

Receptor Hypotheses
Receptor catecholamine hypothesis:
Supersensitivity of catecholamine receptors
in the presence of low levels of serotonin is
the biochemical basis of depression.
Classical norepinephrine receptor
hypothesis:
There is increased density of postsynaptic
-AR in depression. Long-term
antidepressant treatment causes down
regulation of 1-AR. Transient increase of
neurotransmitter availability can cause fault
to mania.

Neurotransmitter Regulation of
Mood and Behavior
Dopamine
Motivation
Alertness
Pleasure Attention
Energy
Interest
Reward

Norepinephrine

Mood
Anxiety

Obsession
Compulsion
Serotonin

Nutt 2008

Postreceptor Hypotheses
Neurotrophic hypothesis (molecular and
cellular theory) of depression:
Transcription factor, cAMP response elementbinding protein (CREB), is one intracellular target
of long-term antidepressant treatment and brainderived neurotrophic factor (BDNF) is one
target gene of CREB. Chronic stress leads to
decrease in expression of BDNF in hippocampus.
Long-term increase in levels of glucocorticoids,
ischemia, neurotoxins, hypoglycaemia etc.
decreases neuron survival. Long-term
antidepressant treatment leads to increase in
expression of BDNF and his receptor trkB through
elevated function of serotonin and norepinephrine
systems.
Duman et al. 1997

Neurotrophic Effects of Antidepressants

Nestler et al. 2002

Antidepressant Treatments

Thank you for your attention

Web pages:
http://connect.lf1.cuni.cz
http://portal.lf1.cuni.cz