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INTRODUCTION TO BIOLOGICAL PSYCHIATRY
(http://www1.lf1.cuni.cz/~zfisar/bpen/default.htm)
RNDr. Zdenk Fiar, CSc.

Department of Psychiatry
1st Faculty of Medicine, Charles University, Prague
E-mail: zfisar@lf1.cuni.cz
This work was supported by FRV 2448/2002 grant.

Zdenk Fiar: Introduction to Biological Psychiatry
CONTENTS
INTRODUCTION ......................................................................................................................................................... 3
1. NEUROBIOLOGY ........................................................................................................................................... 4
1.1. NEURON...................................................................................................................................................... 4
1.2. GLIA ........................................................................................................................................................... 6
1.3. PLASMA MEMBRANE ................................................................................................................................... 8
1.4. ACTION POTENTIAL................................................................................................................................... 11
1.5. ION CHANNELS .......................................................................................................................................... 13
1.6. SYNAPSE ................................................................................................................................................... 15
1.7. CHEMICAL SYNAPSE ................................................................................................................................. 18
2. NEUROCHEMISTRY .................................................................................................................................... 22
2.1. CRITERIA TO IDENTIFY NEUROTRANSMITTERS .......................................................................................... 22
2.2. CLASSICAL NEUROTRANSMITTERS ............................................................................................................ 23
2.3. NEUROPEPTIDES ....................................................................................................................................... 27
2.4. MEMBRANE TRANSPORTERS ..................................................................................................................... 28
2.5. GROWTH FACTORS .................................................................................................................................... 30
2.6. MEMBRANE RECEPTORS............................................................................................................................ 31
2.7. RECEPTOR CLASSIFICATION ...................................................................................................................... 33
2.8. RECEPTORS COUPLED TO ION CHANNELS .................................................................................................. 33
2.9. RECEPTORS ASSOCIATED WITH G PROTEINS .............................................................................................. 35
2.10. RECEPTORS WITH INTRINSIC GUANYLYL CYCLASE ACTIVITY .................................................................... 35
2.11. RECEPTOR TYPES ...................................................................................................................................... 40
2.12. FEEDBACK AND CROSSCONNECTION ......................................................................................................... 45
3. PSYCHOPHARMACOLOGY....................................................................................................................... 49
3.1. ANTIPSYCHOTICS ...................................................................................................................................... 51
3.2. ANTIDEPRESSANTS ................................................................................................................................... 53
3.3. MECHANISM OF ACTION OF ANTIDEPRESSANTS ......................................................................................... 56
4. SCHIZOPHRENIA ......................................................................................................................................... 59
4.1. ENVIRONMENTAL MODELS ........................................................................................................................ 60
4.2. GENETIC MODELS ..................................................................................................................................... 61
4.3. NEURODEVELOPMENTAL MODELS ............................................................................................................ 62
4.4. DELAYED ONSET OF SYMPTOMS ................................................................................................................ 63
4.5. NEURODEGENERATIVE HYPOTHESIS ......................................................................................................... 63
4.6. BIOCHEMICAL BASIS OF SCHIZOPHRENIA .................................................................................................. 64
5. AFFECTIVE DISORDERS............................................................................................................................ 68
5.1. NEUROENDOCRINE HYPOTHESES............................................................................................................... 68
5.2. NEUROCHEMICAL HYPOTHESES ................................................................................................................ 70
5.3. NEUROTRANSMITTER HYPOTHESES ........................................................................................................... 71
5.4. RECEPTOR HYPOTHESES ............................................................................................................................ 73
5.5. POSTRECEPTOR HYPOTHESES .................................................................................................................... 76
5.6. MOLECULAR AND CELLULAR THEORY OF DEPRESSION.............................................................................. 77
5.7. MOLECULAR MECHANISM OF ACTION OF ANTIDEPRESSANT TREATMENTS ................................................ 77
6. LABORATORY SURVEY IN PSYCHIATRY ............................................................................................ 79
REFERENCES....................................................................................................................................................... 83
2
Introduction
Biological psychiatry occupies itself by mental disorders from biological, chemical and
physical point of view. The base of biological psychiatry is the assumption that human
mind is connected with human body so that mental disorders (processes) are
accompanied with biochemical changes, which can be measured. The second issue of
biological psychiatry is causality of all natural processes, including human mind. This
causality is very complexive and facts described by genetics, neuroendocrinology,
immunology, biochemistry, physics etc. are included.
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 are essential in development of mental disorders.
The purpose of this teaching material is to describe cellular and molecular properties of
neurons, mechanisms of psychotropic drugs action and biological basis of mental
disorders. Familiarity with biochemistry and physiology is supposed.
Apportionable parts of this teaching material are dedicated to essence of neurobiology

and neurophysiology (neurons, synapses), neurochemistry (neurotransmitters,
neurotrophins and receptors), psychopharmacology and biological hypothesis of
schizophrenia or affective disorders.
3
1. NEUROBIOLOGY
The brain consists of neurons and glia. There are many different kinds of neurons and
several classes of glial cells. The glia outnumber the neurons ten times or more.
1.1. Neuron
The neurons are the brain cells that are responsible for intracellular and intercellular
signalling. Neurons (Fig. 1.1) share many features in common with other cells, but they
are distinguished by their highly asymmetric shapes and by existence of dendrite
(whose function is reception of signals from the other neurons) and axon (which is
specialized for intracellular transmission of action potential from cell body to synapses).
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 (or
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. The dendritic tree is in continual flux and revises its synaptic connections in
the course of life.
Cytoskeleton is important part of neuron. Cytoskeleton is heterogeneous network of

filamentous structures: major components are microfilaments, neurofilaments and
microtubules. The neuronal cytoskeleton is essential for establishing this cell shape
and for axonal transport (for moving vesicles and other organelles to regions remote
from the neuronal cell body). Protein called molecular motors makes use of the energy
released by hydrolysis of ATP to drive axonal transport.
4
1. NEUROBIOLOGY
Figure 1.1. Neurone
dendritic tree dendritic

spines
neuronal cell
body (soma)
mitochondria
plasma Golgi complex

membrane ribosome
nucleus lysosomes
microtubules
axon hillock
rough endoplasmic
reticulum (Nissl initial segment
substance) myelin sheath
node of Ranvier
axon internodium
synaptic vesicles
telodendrium
synaptic
terminals
5
1.2. Glia
Glial cells (Fig. 1.2) are:
astrocytes
oligodendrocytes (forming the myelin sheath)
microglia
Glia are known to participate in many neuronal functions (Table 1.1). Myelination is
one role of glia that is well understood. The myelin sheath surrounds many, but not all,
axons in nervous system. It is formed by oligodendrocytes on central nervous system
axons and by Schwann cells in the peripheral nervous system. On Figure 1.3 you can
see cross section with an electron microscope - axon is surrounded by concentric
circles of glial membrane. A single Schwann cell may occupy up to about 1 mm of the
length of axon. There are gaps between adjacent Schwann cells of several
micrometers, known as nodes of Ranvier. Region between the nodes of Ranvier is
known as internode.
Table 1.1. Functions of glia

1. act as electrical insulator between neurons
2. participate in the uptake and metabolism of the neurotransmitters
3. act as a scaffolding for neuronal migration and axon outgrowth
4. take up and buffer ions from the extracellular environment
5. act as scavengers to remove debris produced by dying neurons
6. segregate groups of neurons one from another
7. provide structural support for neurons
8. play a role in information handling and memory storage
6
1. NEUROBIOLOGY
Figure 1.2. Glial cells
astrocyte oligodendrocyte microglia
Figure 1.3. Myelin sheath
axon glial cell
node of Ranvier
glia
axon
paranodium nodium paranodium
7
1.3. Plasma membrane

All cells, including neurons and glia, are enclosed by a plasma membrane.
Plasma membrane acts as:
A barrier preventing the content of the cell from mixing with those of the
extracellular space
Effective electrical insulator
Regulator of transport of charged and no charged molecules in and out of the cell
Plasma membranes consist of (Figure 1.4):

Lipid bilayer (phospholipids, glycolipids, sphingomyelin, cholesterol)
Integral and peripheral proteins (ion channels, receptors, enzymes, transporters)
Main properties of lipid bilayer are included in model of fluid mosaic:

1. Heterogeneity in the plane horizontal and vertical
2. Fluid state of most lipids at physiological conditions
3. Translation and rotation movement of membrane molecules
Dynamic properties of biological membranes enable movement and mutual interactions
of membrane proteins (Figure 1.5), so membrane lipids can participate on signal
transduction.
8
1. NEUROBIOLOGY
Figure 1.4. Model of plasma membrane
peripheral glycoproteins glycolipids

proteins
cholesterol integral proteins ion -helix

phospholipids channels
9
Figure 1.5. Lipid bilayer and function of membrane proteins
lipid bilayer
in fluid state
movement movement
perpendicular in the plane
to membrane of membrane
lipid bilayer
in gel state
(See: Shinitzky M.: Membrane fluidity and receptor function. In: Membrane Fluidity, M. Kates, L.A.
Manson, eds., Plenum Publ. Corp. 1984, pp. 585-601.)
10
1. NEUROBIOLOGY
1.4. Action potential

All living cell, including neurons, exhibit a voltage difference across plasma membrane
known as membrane potential. In neurons the resting potential is usually in the range
-40 to -90 mV. Information is carried from one part of the neuron to another in the form
of active response of membrane termed as action potential. Action potential is a large
and rapidly reversible fluctuation in the membrane potential, that propagate along the
axon. Generation and propagation of action potentials are enabled by membrane ion
channels.
Specific properties of axonal membranes allowing signal transmission in the form of

action potentials:
1. There is a threshold for generation of action potential; i.e. small random
fluctuations in the membrane potential are not interpreted as useful information.
2. The all-or-none law ensures full size of action potential.
3. There is frequency coding of the strength and latency of the initial stimulus.
4. Properties of the axonal membrane allow passive spread of the action potential
depolarization along the axon, which is essential in propagation of active
response. Saltatory conduction, i.e. jumping of action potentials along
myelinated axons, is enabled by passive spread of depolarizing stimulus and by
accumulation of ion channels in the nodes of Ranvier.
When the depolarization exceeds threshold the active response of the membrane
occurs and a large change in membrane potential is observed several milliseconds in
duration (Figure 1.6). The amplitude of the action potential is independent on stimulus
intensity. The membrane potential depolarises very rapidly, and then there is a slightly
less rapid return to the resting level. It is impossible to evoke another action potential
immediately after firing of an action potential; this absolute refractory period is followed
by relative refractory period, during which initial depolarization must be larger to evoke
action potential.
Amplitude of action potential carries little information about stimulus that triggered them;
in fact information about stimulus strength and latency can be coded in the frequency of
action potential firing (Figure 1.7).
11
Figure 1.6. Action potential
equilibrium
potential for Na+
40
(mV) 20
- 20
- 40
threshold
- 60
resting potential
- 80 following following
equilibrium latency depolarization hyperpolarization
potential for K+
1 2 4 8 16 32
depolarizing time (ms)
stimulus
Figure 1.7. Frequency coding

depolarizing stimulus
depolarization
small short longer long large+long
stimulus (mV)
+20
0
response
(mV) +30
threshold
resting potential
time (ms)
(See: Levitan I.B. a Kaczmarek L.K.: The Neuron. Oxford Univ. Press, New York, Oxford, 1997; Ganong
W.F.: Pehled lkask fyziologie. Nakl. a vyd. H&H, 1995.)
12
1. NEUROBIOLOGY
1.5. Ion channels

Ion channels underlie electrical signalling in neurons. It is the sum of the various
currents flowing at any point that determines the neuron's membrane potential (Figure
1.8). The activities of the sodium and potassium channels responsible for axonal action
potentials are dependent on voltage.
Sequence of events during the nerve impulse in a large unmyelinated axon (Figure 1.9):
1. Membrane at rest
2. Initial stimulus sodium channel opens Na+ enters axon membrane
depolarisation
3. At peak of impulse sodium channel inactivates, potassium channel opens
K+ leaves axon refractory period
4. After refractory period sodium channel inactivation removed both channels
closed
It is now evident that there is a considerable diversity of ion currents in axons, cell
bodies and dendrites. Voltage clamp and patch clamp techniques make possible
revealing of heterogeneity of voltage dependent sodium, calcium, and potassium
channels.
13
Figure 1.8. Membrane permeability for Na+ and K+ during action potential
30 action potential
20
Ion permeability (mS/cm2)
permeability for Na+

0
(mV)
20
permeability for K+ - 20
10 - 40
- 60
0
1 2 3 time (ms)
(see Voet D., Voetov J.G.: Biochemie. Victoria Publ., Praha, 1995.)
Figure 1.9. Ion flow during action potential
Na+ channel K+ channel

beginning of depolarizing
resting state stimulus
rapid opening of Na+

depolarization channels; slow opening of
K+ channels
K+ channels open;
repolarization Na+ channels inactivated
(refractory period)
slow closing of K+
hyperpolarization channels;
removal of inactivation and
closed Na+ channels
(See: Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C. Decker Inc., Toronto, Philadelphia,
1989.)
14
1. NEUROBIOLOGY
1.6. Synapse
Neurons communicate with one another by direct electrical coupling or by the secretion
of neurotransmitters (Table 1.2).
Table 1.2. Intercellular communication

1. direct transfer of molecules and ions from the cytoplasm of one cell into that of
another (gap junction; electrical synapse)
2. the release of a chemical that diffuses to, and acts on, another cell (secretion;
chemical synapse)
3. direct physical contact of cell surfaces
Electrical coupling is mediated by connexins, i.e. proteins that form pores linking the
cytoplasm of adjacent cells, so ions and small molecules can diffuse through pores from
one cell to another.
Neurosecretion is a more complex process. Stimulation of cells is followed by an

elevation of intracellular calcium, which is important intracellular messenger. Increased
presynaptic Ca2+ levels allow the vesicles to fuse with the plasma membrane and to
release their contents in the synaptic cleft.
Synapses are specialized structures for signal transduction from one neuron to other.
Chemical synapses are studied in the biological psychiatry. Morphology of chemical
synapse is shown on Figure 1.10. Different kinds of synapses are shown on Figure
1.11.
15
Figure 1.10. Morphology of chemical synapse
glia presynaptic cell
axon
microtubules
mitochondria
synaptic vesicles
presynaptic
membrane
synaptic
cleft
postsynaptic
membrane
postsynaptic cell
(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972)
16
1. NEUROBIOLOGY
Figure 1.11. Synapses
axo-dendritic synapse
axo-somatic synapse
reverse collaterale
axo-axonic synapse
button from node of

Ranvier
reverse collaterale
presynaptic elements
en passant axo-axonic synapse
synaptic knob
(terminal button)
(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972; modified.)
17
1.7. Chemical synapse

The main interest of biological psychiatry is knowledge of changes in signal transduction
through chemical synapse (Figure 1.12) in the mental disorder and during its treatment.
It is known that many psychotropic drugs act on the level of chemical synapse; it is on
the level of changes of availability of neurotransmitters, regulation of receptors and
adaptation of post receptor events. Therefore this teaching material is dedicated to
molecular mechanisms of nerve signal transduction.
Table 1.3. Basic steps in signal transduction

1. Depolarisation of presynaptic membrane leads to opening of voltage gated
calcium channels.
2. Ca2+ enters to presynaptic part and activates many enzymes.
3. Neurotransmitters are released from synaptic vesicles by exocytosis to synaptic
cleft. They diffuse to postsynaptic and presynaptic membrane receptors and
specifically bind to them.
4. Receptors are activated and either ion channels are opened or closed, or
activities of intracellular enzymes are changed. These changes lead to
physiological effect of signal transduction.
Release of neurotransmitters is closely linked to the entry of calcium. With repetitive

stimulation, phenomenon as facilitation, potentiation and depression of neurotransmitter
release may occur.
Following neurotransmitter release postsynaptic or presynaptic membrane receptors are

activated. In inhibition synapse efflux of potassium ions causes hyperpolarization of
postsynaptic membrane; in excitation synapse influx of sodium ions causes
depolarization of postsynaptic membrane (Figure 1.13).
Temporal and/or spatial summation of synaptic potentials is necessary to the evocation

of desirable physiological effect since the amount of neurotransmitters released from
one vesicle is generally insufficient (Figure 1.14).
18
1. NEUROBIOLOGY
Figure 1.12. Chemical synapse - signal transduction
PRESYNAPTIC PART action potential
e
Ca2+
c
d
c - Ca entry through voltage-gated channel

2+
d - Ca -catalysed reaction exocytosis

2+
e - Inactivation of intracellular Ca
2+
f - Diffusion of neurotransmitter
g - Reaction with receptors of postsynaptic cell and changes in membrane
permeability
19
Figure 1.13. Excitation and inhibition postsynaptic potentials
excitation synapse inhibition synapse
synaptic vesicles
synaptic cleft
(released transmitters)
postsynaptic
membrane
Na+ K+ Cl- K+
time (ms)
resulted ion current 0 4 8 12 16
-70
(mV)
-65
excitation
postsynaptic inhibition
potential postsynaptic
-65 potential

-70 (mV)
0 4 8 12 16 resulted ion current
time (ms)
(See: Netter F.H.: Physiology and Functional Neuroanatomy. Nervous System I. CIBA-GEIGY Ltd.,
Basle, 1989.)
20
1. NEUROBIOLOGY
Figure 1.14. Summation of excitation and inhibition
A) Insufficient excitation
excitation
inhibition
B) Temporal summation of excitation
excitation
inhibition
C) Spatial summation of excitation
excitation
inhibition
D) Excitation + inhibition
inhibition
excitation presynaptic inhibition
inhibition postsynaptic inhibition
21
2. NEUROCHEMISTRY
2.1. Criteria to identify neurotransmitters

A multitude of chemicals called neurotransmitters mediate intercellular communication
in the nervous system. Although they exhibit great diversity in many of their properties,
all are stored in vesicles in nerve terminals and are released to the extracellular space
via process requiring calcium ions. Their action is terminated by reuptake into
presynaptic terminal or glial cells by specific transporter proteins or by catabolism in
synaptic cleft or in presynaptic terminal. Criteria to identify neurotransmitters are shown
in the Table 2.1.
Table 2.1. Criteria to identify neurotransmitter

1. presence in presynaptic nerve terminal
2. synthesis by presynaptic neuron
3. releasing on stimulation (membrane depolarisation)
4. producing rapid-onset and rapidly reversible responses in the target cell
5. existence of specific receptor
From the chemical point of view are neurotransmitters monoamines, amino acids and
peptides. There are two main groups of neurotransmitters:
1. classical neurotransmitters
2. neuropeptides
22
2. NEUROCHEMISTRY
2.2. Classical neurotransmitters

All classical neurotransmitters (Table 2.2) are synthesized in nerve terminals.
The first molecule to be implicated as neurotransmitter was acetylcholine (Ach). It was

demonstrated that acetylcholine is the transmitter at neuromuscular synapses, as well
as at a variety of neuron-neuron synapses. Ach is synthesized from choline and
acetyl-coenzyme A in the nerve endings; reaction is catalyzed by the enzyme choline
acetyltransferase (Figure 2.1). ACh is rapidly degraded in synaptic cleft by the enzyme
acetylcholinesterase to choline and acetate.
Catecholamines (dopamine, norepinephrine and epinephrine) are synthesized from

tyrosine (Figure 2.2). Indolamines (serotonin and tryptamine) are synthesized from
tryptophan (Figure 2.3.). Action of catecholamines and indolamines on target cells is
terminated much more slowly than those of acetylcholine; they are removed from
synaptic cleft by reuptake. The major enzymes involved in the catabolism of
catecholamines are monoamine oxidase (MAO) or catechol-O-methyltransferase
(COMT). Serotonin is metabolized by MAO.
There are evidence that dysfunction in brain catecholamine or indolamine pathways
contribute to affective disorders and schizophrenia. Some antidepressant prolongs
monoamine neurotransmitters action by inhibiting their high affinity reuptake system.
Catecholamine theory of psychotic illness focuses on dysfunction at dopaminergic
synapses.
There are three major amino acid neurotransmitters in the nervous system: -amino
butyric acid (GABA), glycine and glutamic acid. GABA and glycine are inhibitory
neurotransmitters; glutamate and aspartate are excitatory neurotransmitters.
Specific properties have nitric oxide, which does not interact with membrane receptors
but diffuse to target intracellular receptor.
23
Table 2.2. Selected classical neurotransmitters

System Transmitter Precursor
cholinergic acetylcholine choline+acetylcoenzym A
aminoacidergic GABA glucose glutamate
aspartic acid glucose+glutamine; glutamate
glutamic acid glucose+glutamine; aspartate
glycine serine
homocysteine cysteinecystine
monoaminergic
catecholamines dopamine tyrosineDOPAdopamine
norepinephrine norepinephrineepinephrine
epinephrine
indolamines tryptamine
serotonin tryptophan5-hydroxytryptophan
others, related to aa histamine histidine
taurine cysteinecysteamine
purinergic adenosine
ADP
AMP
ATP
24
2. NEUROCHEMISTRY
Figure 2.1. Synthesis and release of acetylcholine
AXON axoplasmic transport

of choline acetyltransferase
(synthesized in soma)
NERVE TERMINAL glucose uptake

choline uptake
glucose metabolism
mitochondrial enzymes
acetyl-CoA + choline
choline acetyltransferase
acetylcholine + CoA
vesicles free acetylcholine (cytoplasmic)
SYNAPTIC released acetylcholine

CLEFT
hydrolysis by acetylcholinesterase
choline + acetate
25
Figure 2.2. Catecholamine biosynthesis
L-tyrosine
tyrosine hydroxylase
L-DOPA (3,4-dihydroxyphenylalanine)
DOPA decarboxylase
dopamine (DA)
dopamine--hydroxylase
norepinephrine (NE; also called noradrenaline or NA)
phenylethanolamine N-methyltransferase
epinephrine (adrenaline)
Figure 2.3. Serotonin biosynthesis
tryptophan
tryptophan hydroxylase
5-hydroxytryptophan
decarboxylase
5-hydroxytryptamine (5-HT, serotonin)
26
2. NEUROCHEMISTRY
2.3. Neuropeptides
It was identified a great number of neuropeptides (Table 2.3) and new neuropeptides
are discovered continually. -endorphin is important in psychiatry, since it has a role in
pain and in stress. All neuropeptides are synthesized in the cell body in following steps:
1. transcription of pre-propeptide gene and creation of pre-propeptide RNA; 2.
translation into pre-propeptide, which enters the endoplasmic reticulum; 3. forming of
the propeptide, which is direct precursor of neuropeptide; 4. propeptide enters vesicles,
where it is converted into the neuropeptide. The action of neuropeptides in the synaptic
cleft is terminated by peptidases; there is no reuptake for neuropeptides. Neuropeptides
are co-transmitters usually and their transduction mechanism is coupled with G
proteins.
Table 2.3. Selected bioactive peptides

Peptide Group
substance P, substance K (tachykinins)
neurotensin
brain and gastrointestinal
cholecystokinin (CCK)
peptides
gastrin
bombesin
galanin
neuromedin K
neuronal
neuropeptideY (NPY)
peptide YY (PYY)
cortikotropin releasing hormone (CRH)
growth hormone releasing hormone (GHRH)
hypothalamic releasing
gonadotropin releasing hormone (GnRH)
factors
somatostatin
thyrotropin releasing hormone (TRH)
adrenocorticotropic hormone (ACTH)
growth hormone (GH)
prolactin (PRL) pituitary hormones
lutenizing hormone (LH)
thyrotropin (TSH)
oxytocin
neurohypophyseal peptides
vasopressin
atrial natriuretic peptide (ANF)
neuronal and endocrine
vasoactive intestinal peptide (VIP)
enkephalines (met-, leu-)
dynorphin opiate peptides
-endorphin
27
2.4. Membrane transporters

Neurotransmitters are removed from synaptic cleft by enzymatic degradation or by
active transport to presynaptic button or to surrounding glia cells. The main way of
acetylcholine removing from synaptic cleft is metabolism by acetylcholinesterase. But
for majority of neurotransmitters speculated in biochemical hypothesis of mental
disorders there are specific membrane transporters (Figure 2.4).
The main classes of membrane transporters:

1. Na+/Cl- dependent transporters are embedded in the presynaptic membrane
mainly; they transport serotonin, norepinephrine or dopamine
2. Vesicular transporters carries neurotransmitters into synaptic vesicles (it is
important to prevent neurotransmitter degradation)
3. Na+ dependent transporters are localized in the membrane of glia cells; they
transport GABA, glutamate or aspartate
28
2. NEUROCHEMISTRY
Figure 2.4. Membrane transporters
GLIA PRESYNAPTIC
ion pump
ADP ion
channel
ATP
synaptic
vesicle
d
e c autoreceptor
transporter
transmitter
ion channel receptor

POSTSYNAPTIC
c - Na /Cl dependent transporter

+ -
d - vesicular transporter
e - Na dependent transporter
+
29
2.5. Growth factors

Growth factors are proteins that stimulate cellular proliferation and promote cellular
survival. They are essential for nervous system development and function. Different
cells including neurons and glia produce growth factors. They are released from cell and
after interaction with membrane receptors changes in activity of intracellular enzymes
occur. So, mechanism of their action is similar to action of neurotransmitters, but they
are not released in response to membrane depolarization and changes intracellular
calcium levels.
There are 6 major classes of growth factors, which act within nervous system (Table
2.4.). From the psychiatry point of view neurotrophins are most important.
Neurotrophins support the survival and phenotypic specificity of subsets of neurons.
Brain-derived neurotrophic factor (BDNF) has a role in response on stress and in
action of antidepressants.
Table 2.4. Growth factors in the nervous system

Neurotrophins Nerve growth factor (NGF)
Brain-derived neurotrophic factor (BDNF)
Neurotrophin 3 (NT3)
Neurotrophin 4/5 (NT4/5)
Neurokines 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)
30
2. NEUROCHEMISTRY
2.6. Membrane receptors

Receptor is macromolecule specialized on transmission of information. It is defined as
binding site with functional relationships. A binding site is not necessarily a physiological
receptor, since neurotransmitters must bind to uptake systems and metabolic enzymes
also. To determine whether a binding site is real receptor pharmacology of binding site
and biological response must coincide.
Receptor complex includes:
1. Specific binding site
2. Transduction element
3. Effector system (2nd messengers)
Effector system includes enzymes adenylyl cyclase or phospholipase, which generate
2nd messengers, such as cyclic adenosine monophosphate (cAMP), cyclic guanosine
monophosphate (cGMP), inositoltriphosphate (IP3), diacylglycerol (DG), calcium (Ca2+);
second messengers activate protein kinases A, G, C or CaM-II.
Receptors are able to adapt their properties to increased or decreased activation (Table
2.5, Figure 2.5). Changes in the number of receptors are known mechanism of their
adaptation. But response to receptor activation can be altered at unchanged density of
receptors too. Regulation of properties of receptors consists of decreased or increased
activity of post receptor events, which results in decreased or increased final
physiological response to receptor stimulation (Table 2.6).
Table 2.5. Regulation of receptors

Number of receptors (down-regulation, up-regulation)
Properties of receptors (desensitisation, hypersensitivity)
Table 2.6. Mechanisms of receptor desensitisation

Interactions of subunits of active molecules (by phosphorylation, ribosylation, changes
in membrane lipid composition, etc.)
Production of messengers - inhibitors of receptors
Production of receptor clusters (by cytoskeleton)
Internalisation of receptors (by endocytosis)
31
Figure 2.5. Adaptation of receptors
secondary hyperfunction reactive hyperfunction

(upregulation)
balance
RECEPTOR
NEUROTRANSMITTER
adaptive hypofunction secondary hypofunction

(desensitization)
32
2. NEUROCHEMISTRY
2.7. Receptor classification

There are many types of receptors and they can be classified by different criteria, for
example according to their pharmacological properties (it is according to activating
neurotransmitter or other agonist) or according to effectors system, which is connected
with their function (Table 2.7).
Table 2.7. Classification of receptors by their effector system

1. Receptor coupled directly to the ion channel
2. Receptor associated with G proteins
3. Receptor with intrinsic guanylyl cyclase activity
4. Receptor with intrinsic tyrosine kinase activity
2.8. Receptors coupled to ion channels

Direct coupling of the neurotransmitter receptor to the ion channel whose activity it
regulates is the simplest and the most rapid way of signal transduction. An example of
receptor with internal ion channel is GABAA receptor, nicotinic acetylcholine receptors,
or ionotropic glutamate receptors.
Nicotinic acetylcholine receptor complex is one of ligand-gated ion channels; it

contains both the acetylcholine binding site and the ion channel that is activated by
acetylcholine binding. Following receptor activation, nicotinic acetylcholine receptors as
well as ionotropic glutamate receptors increase membrane permeability for cations
Na+, K+ or Ca2+; they are excitatory receptors.
Receptor for -amino butyric acid includes chlorine (Cl-) channel, which is opened in
response to binding of GABA (Figure 2.6). Chlorine inputs into cell and
hyperpolarization of membrane occurs; so it is inhibitory receptor. There are many
modulation sites on GABAA receptor, for example benzodiazepines positively modulate
activity of this receptor.
33
Figure 2.6. GABAA receptor
barbiturates GABA, bicuculine

neurotransmitter binding site neurosteroids benzodiazepines
receptor formed
by 5 subunits
Pi
allosteric modulatory sites picrotoxin phosphorylation

Cl-
pore ~0.5 nm
34
2. NEUROCHEMISTRY
2.9. Receptors associated with G proteins

It is assumed that signal transduction mediated by receptors associated with guanyl
nucleotide-binding proteins (or G proteins) and 2nd messenger systems are altered
at mental disorders and during treatment with psychotropic drugs. Scheme for
hypothesis of second messengers in signal transduction (Figure 2.7) show that after
activation of receptor by first messenger G proteins are activated and activated G
proteins activate effectors enzymes, such as adenylyl cyclase or phospholipase C, and
second messengers are produced. Second messenger activate protein kinase of type
A, C or CaM-II, which catalyses phosphorylation of cell proteins and physiological
response to receptor activation arises. Transcription factors can be phosphorylated too,
and phosphorylated transcription factors serve as third messengers, which activate
gene expression.
According to type of 2nd messenger used there are two main pathways of signal
transduction: 1. adenylyl cyclase system; 2. phosphoinositide system.
In adenylyl cyclase system (Figure 2.8) activated receptor activates G protein, which
activates adenylyl cyclase and cyclic adenosine monophosphate (cAMP) is produced as
2nd messenger. cAMP activates protein kinase A, which phosphorylates cellular proteins
(receptors, ion channels, enzymes, transcription factors, etc.).
In phosphoinositide system (Figure 2.9) activated receptor activates G proteins,

which activate phospholipase C, and inositoltriphosphate (IP3) and diacylglycerol (DG)
are produced as 2nd messengers. DG activates protein kinase C, IP3 activate releasing
of Ca2+ from intracellular pool and Ca2+ activate many enzymes including calmoduline
and protein kinase dependent on Ca2+ and calmoduline.
2.10. Receptors with intrinsic guanylyl cyclase activity

Cyclic guanosine monophosphate (cGMP) is produced as second messenger after
activation of membrane bound or soluble form of guanylyl cyclase system (Figure
2.10). cGMP can activate protein kinase, activate or inhibit several forms of
phosphodiesterase, open up cation channels (in retina), etc.
35
Figure 2.7. Scheme for hypothesis of second messengers
first
messengers
receptors
G proteins
effector
proteins
second
messengers
protein kinase third

messengers
biological gene expression

response etc.
36
2. NEUROCHEMISTRY
Figure 2.8. Signal transduction: Adenylyl cyclase system
activated adenylyl cyclase activated Ca2+-

receptor receptor channel
forskolin

Gs Gi/o/x
s-GTP i/o/x-GTP Ca2+
free Ca2+
PKA, PKC Ca2+/CaM
ATP
5-AMP cAMP + ADP
activated protein
fosfodiesterase
ADP + Pi
protein kinase A
ATP
Gs/i/o/x G proteins, CaM calmodulin, GTP guanosine triphosphate, ATP adenosine triphosphate,
ADP adenosine diphosphate, cAMP cyclic adenosine monophosphate, 5-AMP - 5-adenosine
monophosphate, PKA protein kinase A, PKC protein kinase C
37
Figure 2.9. Signal transduction: Phosphoinositide system
receptor receptor receptor Ca2+-

with intrinsic associated with s Gq associated with Gi/o
channel
tyrosin kinase
PI-PLC1 DG PI-PLC2
PIP2 PIP2

Pi Pi
Gq q PKC Gi/o
PI-PLC
i/o
IP3 protein phosphorylation
Ca2+-dependent Ca2+
processes
IP3 receptor
endoplasmic reticulum
PI-PLC - phospholipase C specific for phosphoinositides, PIP2 - phosphatidylinositol-4,5-biphosphate,

IP3 - inositol-1,4,5-triphosphate; DG - diacylglycerol; PKC protein kinase C
38
2. NEUROCHEMISTRY
Figure 2.10. Signal transduction: Guanylyl cyclase system
GC-A
membrane bound GC-B
GC GC-C Ca2+-channel
ATP
intracellular
Ca2+ stores of Ca2+
catalytic domain
Ca2+/CaM
nNOS
soluble GC
NO
cGMP
biological
response
GC guanylyl cyclase, CaM calmodulin, NO nitric oxide, nNOS nitric oxide synthase, ATP
adenosine triphosphate, cGMP cyclic guanosine monophosphate
39
2.11. Receptor types

Basic characteristics of receptors which can be used to their classification are shown in
Table 2.8. Primary types and selected subtypes of receptors (according to the
international agreement) are summarized in Tables 2.9, 2.10, 2.11, 2.12 and 2.13.
Table 2.8. Basic characteristics of receptors

Name
Endogenous ligands and their efficiency
Selective agonists
Selective antagonists
Blockers of ion channels
Selective radioligands
Effectors cGMP (internal guanylyl cyclase)
Gi/o (K+, Ca2+, cAMP)
Gq/11 (IP3, DG)
Gs (cAMP)
internal ion channel (Na+/K+/Ca2+/Cl-)
Gen
Structure
40
2. NEUROCHEMISTRY
Table 2.9. Type 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)
P2 purinoceptors
41
Table 2.10. Subtypes of monoamine receptors

RECEPTORS Subtype Transducer Structure (aa/TM)
1-adrenoceptors 1A Gq/11 IP3/DAG 466/7
1B Gq/11 IP3/DAG 519/7
1D Gq/11 IP3/DAG 572/7
2-adrenoceptors 2A Gi/o cAMP 450/7
2B Gi/o cAMP 450/7
2C Gi/o cAMP 461/7
2D Gi/o cAMP 450/7
-adrenoceptors 1 Gs cAMP 477/7
2 Gs cAMP 413/7
3 Gs, Gi/o cAMP 408/7
dopamine D1 Gs cAMP 446/7
D2 Gi cAMP 443/7
Gq/11 IP3/DAG, K+, Ca2+
D3 Gi cAMP 400/7
D4 Gi cAMP, K+ 386/7
D5 Gs cAMP 477/7
5-hydroxytryptamine 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 cAMP 387/7
5-ht5A ? 357/7
5-ht5B ? 370/7
5-ht6 Gs cAMP 440/7
5-HT7 Gs cAMP 445/7
42
2. NEUROCHEMISTRY
Table 2.11. Subtypes of aminoacidergic receptors

RECEPTORS Subtypes Transducer Structure (aa/TM)
GABA GABAA int. Cl- more subunits
GABAB Gi/o, Gs cAMP, cAMP, 961,941/7
K+(G), Ca2+(G)
excitatory aa NMDA int. Na+/K+/Ca2+ more subunits
(ionotropic) AMPA int. Na+/K+/Ca2+ more subunits
kainate int. Na+/K+/Ca2+ more subunits
excitatory aa mglu1 Gq/11 IP3/DAG 1194/7
(metabotropic) mglu2 Gi/o cAMP 872/7
mglu3 Gi/o cAMP 877/7
mglu5 Gq/11 IP3/DAG 1212/7
glycine glycine int. Cl- pentamer
histamine H1 Gq/11 IP3/DAG 487/7
H2 Gs cAMP 359/7
H3 Gi/o cAMP 445/7
43
Table 2.12. Subtypes of acetylcholine receptors

muscarinic M1 Gq/11, NO IP3/DAG 460/7
M2 Gi/o cAMP,K+(G) 466/7
M3 Gq/11, NO IP3/DAG 590/7
M4 Gi/o cAMP,K+(G) 479/7
M5 Gq/11, NO IP3/DAG 532/7
nicotinic 1 int. Na+/K+/Ca2+ pentamer
2 int. Na+/K+/Ca2+ pentamer
Table 2.13. Subtypes of opioid and related peptidergic receptors

opioid and mu opioid peptidergic Gi/ cAMP, 400/7
similar receptors () o K+(G),Ca2+(G)
delta opioid Gi/ cAMP, 372/7
peptidergic ( ) o K+(G),Ca2+(G)
kappa opioid Gi/ cAMP, 380/7
peptidergic () o K+(G),Ca2+(G)
N/OFQ receptor Gi/ cAMP, 370/7
o K+(G),Ca2+(G)
44
2. NEUROCHEMISTRY
2.12. Feedback and crossconnection

There are many neurotransmitters, many receptors, less G proteins and a few effector
systems. But there are many feedbacks at the cellular level and many cross-reactions at
the intracellular level. That results in divergence or convergence of signals.
Example of negative feedback in synapse (Figure 2.11):

Norepinephrine released from noradrenergic synapse can diffuse to adjacent
acetylcholinergic synapse and can activate presynaptic 2 receptors. Because 2
receptors are inhibitory receptors, activation of noradrenergic synapse can lead to
inhibition of acetylcholinergic synapse. There is great number of similar feedbacks.
Example of intracellular cross connection (Figure 2.12):

Activation of serotonin 2 receptor leads to production of diacylglycerol (DG) as 2nd
messenger and DG activates protein kinase C (PKC). PKC can phosphorylate
adenylyl cyclase and positive regulation of transduction system connected with
adrenoreceptors occurs. PKC can affect noradrenergic signal transduction through
direct phosphorylation of receptors or G proteins also.
General scheme of signal transduction implying feedbacks is shown on Figure 2.13.
45
Figure 2.11. Feedback to transmitter-releasing
NE muscarinic
ACh
2-adrenoceptor receptor (M2,M4)
(autoinhibition) (autoinhibition)
NE - ACh -
+- +-
1,2-adrenoceptors muscarinic or nicotinic

receptors
ATP adenosine ACh 2 NE muscarinic

receptor receptor
(autoinhibition)
-
-
ATP - ACh NE
+- + -
P2 purinoceptor muscarinic -
1-adrenoceptor
receptor
(See: Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C. Decker Inc., Toronto, Philadelphia,
1989.)
46
2. NEUROCHEMISTRY
Figure 2.12. Crossconnection of transducing systems on postreceptor level
5-HT2 -AR 2-AR
PI-PLC
PIP2
Gq/11 - Gs - Gi/o
IP3 + DAG AC
Ca2+
PKC
2+
+
Ca /CaM
AR adrenoceptor, G G protein, PI-PLC phosphoinositide specific phospholipase C, IP3

inositoltriphosphate, DG diacylglycerol, CaM calmodulin, AC adenylyl cyclase, PKC protein kinase
C
47
Figure 2.13. Scheme of signal transduction (implying feedback)
neurotransmitters
excitation inhibition
membrane receptors
Pi Pi Pi Pi
GGTP GGTP
G proteins
++ -
PLC, PLD, PLA2, AC effector enzymes
+- +-
+
IP3, DG, Ca2+, cAMP, FFA second messengers
+
PKC, PKA, gene protein kinases and
PKCaM expression gene expression
PP phosphoprotein phosphatases
normal
G G protein, GTP guanosine triphosphate, PLC - phospholipase C, PLD - phospholipase D, PLA2 -

phospholipase A2, AC adenylyl cyclase, IP3 inositoltriphosphate, DG diacylglycerol, cAMP cyclic
adenosine monophosphate, FFA free fatty acids, PKC protein kinase C, PKA protein kinase A,
PKCaM Ca2+ and calmodulin dependent protein kinase, PP phosphoprotein phosphatase
48
3. PSYCHOPHARMACOLOGY
3. Psychopharmacology
Psychopharmacology is very extensive branch of medicine. This chapter will emphasize
basic pharmacological concepts of action of antipsychotics and antidepressants only.
The reader should consult standard reference sources for more information from
psychopharmacology.
Psychotropic drugs are amphiphilic molecules frequently; i.e. they are soluble both in
the water phase and in the lipid bilayer. Amphiphilic drugs rapidly permeate through
plasma membrane and/or accumulate in hydrophobic interior of lipid bilayer (Figure
3.1), so, interactions are possible both with membrane macromolecules and with
cytoplasmatic or nuclear molecules.
Central nervous system drugs act primary as agonists or antagonists of

neurotransmitter receptors, inhibitors of regulatory enzymes or blockers of stimulators of
neurotransmitter membrane transporters (Table 3.1). Classification psychotropic drugs
according to effects on mental functions are shown in Table 3.2.
Figure 3.1. Interaction of amphiphilic drugs with membrane
out
membrane
in
49
Table 3.1. Potential action of psychotropics

1. synthesis and storage of neurotransmitter
2. releasing of neurotransmitter
3. receptor-neurotransmitter interactions (blockade of receptors)
4. catabolism of neurotransmitter
5. reuptake of neurotransmitter
6. transduction element (G protein)
7. effector system
Table 3.2. Classification psychotropics according to effects on mental functions

parameter effect group of examples
psychotropics
watchfulness positive psychostimulant amphetamine, amphetaminile, ephedrine,
(vigility) drugs fenmetrazine, mazindole, mezokarb,
pemoline, methylphenidate
negative hypnotic drugs barbital, amobarbital, hexobarbital;
glutethimid, metachalone, clomethiazol;
nitrazepam, flunitrazepam, triazolam;
zopiclone, zolpidem
affectivity positive antidepressants imipramine, desipramine, amitriptyline,
nortriptyline, clomipramine, maprotiline,
citalopram, fluoxetine, fluvoxamine,
mianserine, buspirone, moclobemide, Li+
anxiolytics guaifenezine, meprobamate; diazepam,
alprazolam, oxazepam; neuroleptics and
antidepressants
negative dysphoric drugs reserpine, clonidine, -methylDOPA
psychic positive neuroleptics, thioridazine, chlorpromazine,
integrations atypical chlorprotixene, levopromazine, haloperidol,
perfenazine, clozapine, amisulpride,
antipsychotics risperidone, sertindole, quetiapine,
olanzapine
negative hallucinogenic lysergid, cocaine, amphetamines,
agents ketamine, hashish, marihuana,
phencyclidine, mescaline
memory positive nootropics piracetam, pyritinol, meclophenoxate
negative amnestic drugs anticholinergics
(See: vestka J. a kol.: Psychofarmaka v klinick praxi. GRADA Publishing, 1995; Hynie S.:
Psychofarmakologie v praxi. Galn, 1995.)
50
3.1. Antipsychotics
Antipsychotics are divided into two groups (Table 3.3):
1. Conventional antipsychotics (basal or incisive)
2. Atypical antipsychotics
Incisive antipsychotics have high affinity to D2 receptors and low affinity to other
types of receptors. They affect positive symptoms of schizophrenia mainly. They bring
about extrapyramidal symptoms (EPS).
Basal antipsychotics have lower affinity to D2 receptors and higher affinity to other
receptor types beside incisive antipsychotics. They affect positive and affective
symptoms of schizophrenia. They have sedative effects, they bring about
anticholinergic, antihistaminic and cardiovascular side effect, and extrapyramidal
symptoms are less frequent.
Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of D2 and

serotonin 2A receptors, but they can affect many other types of receptors (Table 3.5).
They are much more efficient in treatment of negative symptoms of schizophrenia in
comparison with conventional antipsychotics. Atypical antipsychotics have lower side
effects (lower EPS or tardive dyskinesis)
Table 3.3. Classification of antipsychotics

group examples
basal (sedative) chlorpromazine, chlorprotixene, clopenthixole,
levopromazine, periciazine, thioridazine
antipsychotics
conventional antipsychotics droperidole, flupentixol, fluphenazine,
(classical neuroleptics) incisive fluspirilene, haloperidol, melperone,
antipsychotics oxyprothepine, penfluridol, perphenazine,
pimozide, prochlorperazine, trifluoperazine
atypical antipsychotics amisulpiride, clozapine, olanzapine,
quetiapine, risperidone, sertindole, sulpiride
(antipsychotics of 2nd generation)
(See: vestka J.: Nov (atypick) antipsychotika 2. generace. Remedia 9, 366-385, 1999.)
Table 3.4. Mechanisms of action of antipsychotics
51
conventional antipsychotics D2 receptor blockade of postsynaptic in

the mesolimbic pathway
atypical antipsychotics 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
Table 3.5. 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, 5-HT7, 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
quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1
NRI - norepinephrine reuptake inhibitor, SRI serotonin reuptake inhibitor

(See: Stahl S.M.: Psychopharmacology of Antipsychotics, Martin Dunitz, London, 1999.)
52
3.2. Antidepressants
Molecular mechanisms of action of antidepressants are much more diverse than that of
antipsychotics. Classification of antidepressants based on their acute pharmacological
actions is shown in Table 3.6. Antidepressants are amphiphilic molecules; so, they easy
permeate through the cell membrane and may affect molecules on the outer and inner
membrane surface, cytoplasmic elements and nuclear molecules (Figure 3.2).
Table 3.6. Classification of antidepressants based on acute pharmacological actions

inhibitors of neurotransmitter monoamine oxidase inhibitors (IMAO)
catabolism
reuptake inhibitors serotonin reuptake inhibitors (SRI)
norepinephrine reuptake inhibitors (NRI)
selective SRI (SSRI)
selective NRI (SNRI)
serotonin/norepinephrine (dual) inhibitors (SNRI)
norepinephrine and dopamine reuptake inhibitors (NDRI)
serotonin 2A antagonist/reuptake inhibitors (SARI)
agonists of receptors 5-HT1A
antagonists of receptors 2-AR, 5-HT2
inhibitors or stimulators of G proteins, adenylyl cyclase (AC), phospholipase (PL),
other components of signal protein kinase (PK), phosphatase, ATPase, phospholipid
transduction dependent proteins, transcription factors, 2nd a 3rd
messengers
Therapeutic response is observed after a few weeks of antidepressant treatment; so,

many adaptive changes in cellular functions occur. The neurotransmitter receptor
hypothesis of antidepressant action explains the ultimate mechanism of their
therapeutic action by receptor sensitivity changes. Currently, there is focus on the gene
expression that is activated by antidepressants (see Chapter 5).
53
Figure 3.2. Potential mechanisms of antidepressants action
transmitter
synthesis
metabolic
degradation MAO
interaction with
transport to ATPase presynaptic
vesicles synaptic vesicles autoreceptors and
heteroreceptors
releasing to
synaptic cleft
metabolic
reuptake degradation of
transporter neurotransmitter
COMT
interaction
with receptors AC PLC
PIP2
ATPase ion-channel receptor
interaction with
transducers ATP cAMP DG IP3
Ca2+
A C CaM
protein kinase
transcription
factors
nucleus
54
Table 3.7. Examples of antidepressants
group subgroup examples

tricyclic activating desipramine, nortriptyline,
(thymoleptics) protriptyline, dosulepine
sedative, anxiolytic imipramine, amitriptyline,
trimipramine, clomipramine
II. a III. generation II. generation - activating viloxazine, buspirone, amineptine,
maprotiline
II. generation - sedative, mianserine, trazodone,
anxiolytic nefazodone, pirlindol
III. generation - SSRI citalopram, fluvoxamine, fluoxetine,
sertraline, paroxetine
enhancing 5-HT uptake tianeptine
MAO inhibitors nonselective irreversible phenelzine, tranylcypromine,
isocarboxazid
selective MAOI-B irreversible deprenyl
selective MAOI-B reversibile
selective MAOI-A irreversible
selective MAOI-A reversible moclobemide, brofaromine,
toloxatone, amiflamine
thymoprophylactics lithium, carbamazepine, sodium
valproate, valpromide
(See: vestka J. a kol.: Psychofarmaka v klinick praxi. GRADA Publishing, 1995.)
55
3.3. Mechanism of action of antidepressants

Selective serotonin reuptake inhibitors (SSRI) are the most frequently used
antidepressants. Their mechanism of action on serotonergic neuron in a depressed
patient is shown on Figure 3.3.
Before treatment (Figure 3.3 A):
There is relative deficiency of 5-HT in serotonin neurone in a depressed patient.
Number of serotonin receptors is up-regulated, including presynaptic
autoreceptors as well as postsynaptic receptors.
Releasing of serotonin from synaptic knob can be affected: 1. positively by
activity of serotonin transporter or by tryptophan (serotonin precursor) availability;
2. negatively by activation both presynaptic inhibitory receptors, 5-HT1B or 2-AR,
and somatodendritic receptors, 5-HT1A.
After acute administration of SSRI (Figure 3.3 B):
A considerable part of serotonin transporters is blocked and serotonin remains
for a longer time in extracellular space. This causes serotonin to increase in the
somatodendritic area mainly.
Negative feedback mediated by inhibitory presynaptic and somatodendritic
receptors is increased and both frequency of firing of action potentials and
amount of serotonin released from presynaptic button is decreased.
After chronic treatment by SSRI (Figure 3.3 C):
The increased 5-HT at the inhibitory somatodendritic receptors causes them to
down-regulate and/or desensitise. It results in increase of frequency of firing of
action potentials and in increase of the amount of serotonin released to synaptic
cleft. The marked increase of serotonin release in the axon terminal is delayed as
compared with the processes after acute administration of SSRI. This delay may
explain why therapeutic action of antidepressants is not immediate.
The increased 5-HT at the axon terminal causes down-regulation and/or
desensitization of postsynaptic and presynaptic receptors. This desensitization
may mediate the reduction of side effects of SSRI.
Mechanism of action of 2-adrenoceptor blockers is shown on Figure 3.4; mechanism

of action of reversible inhibitors of monoamine oxidase A (RIMA) is on Figure 3.5.
56
Figure 3.3. Mechanism of action of selective serotonin reuptake inhibitors (SSRI)
A) before treatment 2-AR 5-HT1B

5-HT1A
5-HT1A
TRP
5-HT1B
5-HT2A
5-HT
5-HT2C
MAO
5-HIAA 5-HT3
SERT 5-HT4
...
B) acute administration of SSRI 2-AR 5-HT1B
5-HT1A
TRP
5-HT
MAO
5-HIAA
SERT
C) chronic treatment by SSRI 2-AR
5-HT1A
TRP
5-HT
MAO
5-HIAA
SERT
57
Figure 3.4. Mechanism of action of 2-adrenoceptor blockers
NE or 5-HT
neurone presynaptic
2-AR 2-AR 2-AR
NE or 5-HT
NORMAL DEPRESSION AFTER TREATMENT

density and sensitivity of 2-AR blockade
presynaptic 2-AR NE or 5-HT transmission
NE or 5-HT transmission
Figure 3.5. Mechanism of action of reversible inhibitors of MAO-A (RIMA)

TYRAMINE
TYRAMINE
TYRAMINE
TYRAMINE
TYRAMINE
RIMA
serotonin dopamine phenylethylamine

norepinephrine MAO-A tyramine MAO-B benzylamine
epinephrine tryptamine methylhistamine
TYRAMINE
TYRAMINE
TYRAMINE
RIMA
TYRAMINE
TYRAMINE
MAO-A MAO-B
58
4. SCHIZOPHRENIA
4. Schizophrenia
Schizophrenia is specific human disease. It is group of diseases characterized by

delusions, hallucinations, disorganized speech, grossly disorganized or catatonic
behaviour, of negative symptoms (Table 4.1). Symptoms of schizophrenia can be
subcategorized into:
1. Positive symptoms
2. Negative symptoms
3. Cognitive symptoms
4. Aggressive/hostile symptoms
5. Depressive/anxious symptoms
In this chapter, environmental, genetic, neurodevelopmental and biochemical
hypotheses of schizophrenia are presented. Classification, clinical description and
criteria for diagnosis of schizophrenia are not described.
For practical purposes the descriptive psychopathology of schizophrenia can be treated

in three sections:
1. Purely positive symptoms (hallucinations and other abnormal experiences,
delusions and catatonia)
2. What used to be referred to as psychological deficit, purely negative symptoms
impaired attention, intelligence, memory, perception and will.
3. Traditional psychopathological groupings containing positive and negative
symptoms (mixed) thought disorder and disturbances of emotions.
Table 4.1. Positive and negative symptoms of schizophrenia

negative positive
alogia hallucination
affective flattening delusions
avolition apathy bizarre behaviour
anhedonia asociality positive formal thought disorder
attentional impairment
Biological models of schizophrenia can be divided into three related classes:

59
Environmental models
Genetic models
Neurodevelopmental models
4.1. Environmental models

Environmental models suppose that either stress or physical factors are the main
evoking phenomenon in schizophrenia (Table 4.2).
Table 4.2. Environmental models of schizophrenia

Model of evocative influence of complex social demands:
There are four criteria for schizophrenia-evoking stress:
1. A situation demanding action or decision
2. Complexity or ambiguity of the information supplied to deal with the task
3. Unless resolved, the situation demanding action or decision persist
4. The subject has no escape route available
Most stresses of this nature will be non-pathogenic; a schizophrenia-evoking effect
occurs only in conjunction with a specific genetic liability.
Non-psychosocial environmental model:
An unspecified number of varieties of physical factors will be sufficient to produce the
specific cerebral lesions and dysfunction thought to be characteristic of schizophrenia,
regardless of the presence or absence of a genetic susceptibility (see
Neurodevelopmental models below).
(See: Jablensky A.: Schizophrenia: the epidemiological horizon. In: Schizophrenia, Hirsch S.R. and
Weinberger D.R., eds., Blackwell Science, pp. 206-252, 1995.)
60
4. SCHIZOPHRENIA
4.2. Genetic models

Evidence for a genetic contribution to schizophrenia comes from twin and familiar
studies. The genetic factors in schizophrenia have specificity as they do not increase
the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is
clinically or phenotypically heterogeneous, but whether this variety is paralleled by
etiological heterogeneity or to what extent is problematic. Genetic models are
summarized in Table 4.3. Published data indicates that monogenic models could be
rejected and multifactorial threshold model or mixed models are favoured.
Table 4.3 Genetic models

Distinct heterogeneity model:
Schizophrenia is a collection of several separate diseases, each associated with single
major locus (SML) that may be inherited either dominantly or recessively. In addition,
there are sporadic, environmentally caused cases.
Monogenic models (single major locus models):
Schizophrenia might be a single-gene dominant disorder with highly variable
expression or reduced penetrance of the trait; i.e. all cases of schizophrenia share the
same single major locus (SML).
Multifactorial-polygenic threshold model:
Schizophrenia is the result of a combined effect of multiple genes interacting with
variety of environmental factors; i.e. several or many genes, each of small effect,
combine additively with the effects of non-inherited 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.
A mixed or combined model:
The model includes the elements of some, or all, of the above three.
(See: Jablensky A.: Schizophrenia: the epidemiological horizon. In: Schizophrenia, Hirsch S.R. and
Weinberger D.R., eds., Blackwell Science, pp. 206-252, 1995; Asherson P., Mant R., McGuffin P.:
Genetics and schizophrenia. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell
Science, pp. 253-274, 1995.)
61
4.3. Neurodevelopmental models

The leading hypothesis for the aetiology of schizophrenia is related to disturbance in
normal brain development. The principal assumption is that normal brain development
is disrupted in specific ways at critical periods and the resulting lesion produces the
symptoms of schizophrenia only through interaction with the normal maturation
processes in the brain, which occur in late adolescence or early adulthood.
Neurodevelopmental hypothesis states that:

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.
The neurodevelopmental model therefore directs attention to both genetic and no

genetic risk factors that may have impacted on the developing brain during prenatal
and perinatal life; pregnancy and birth complications (PBCs) are considered in
psychiatry:
viral infections in utero
gluten sensitivity
brain malformations
obstetric complications
Genetic contribution to schizophrenia development consists in wrong genetic program
for the normal formation of synapses and migration of neurons in the developing brain.
These risk factors may have the final common effect on nerve growth factors reduction
resulting in structural abnormalities, selection of wrong neurons to survive in the fetal
brain, neuron migration to the wrong places, neuron inervation of wrong targets or mix-
up of the nurturing signals.
62
4. SCHIZOPHRENIA
4.4. Delayed onset of symptoms

We can propound the question, why is the illness manifestation delayed typically for
about two decades after birth? Delayed onset of symptoms of schizophrenia (in early
adult) can be explained by different mechanisms:
1. There is an additional pathological process occurring around the time of onset of
the clinical symptoms
2. An interaction between a static developmental defect and normal developmental
events that occur in early adulthood is necessary
It is supposed that onset of schizophrenia can be initiated by wrong organization,
elimination and restructuring of synapses during adolescence, which may be or not
secondary to the maldevelopment in utero.
4.5. Neurodegenerative hypothesis

Recent post mortem studies on schizophrenics described a multitude of morphological
changes in different brain structures. The most often reported structural alterations are
in the limbic system, mainly in hippocampal formation and parahippocampal and
cingulate gyri. However, other structures such as the thalamus, frontal and temporal
cortex and basal ganglia seem to be affected too.
Neurodegenerative hypothesis of schizophrenia suggest an ongoing

neurodegenerative processes with loss of neuronal function during the course of the
disease. Excitotoxic hypothesis proposes that neurons degenerate as a consequence of
excessive glutamatergic neurotransmission.
Combined neurodevelopmental/neurodegenerative hypothesis suggest that

schizophrenia may be a neurodegenerative process superimposed on a
neurodevelopmental abnormality.
63
4.6. Biochemical basis of schizophrenia

The biochemical hypotheses of schizophrenia are orientated towards the role of
neurotransmitters and their receptors; dopamine, serotonin, glutamate, GABA,
norepinephrine and so on are considered (Table 4.4). Dopamine plays a key role in
biochemical hypotheses of schizophrenia. Dopamine hypothesis of schizophrenia was
formulated almost 40 years ago by Randrup and Munkvad (1965) and plays a
prominent role in schizophrenia research hitherto. Basis or motives for dopamine
hypothesis are summarized in Table 4.5.
According to the 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.
Table 4.4. Biochemical hypotheses of schizophrenia

classical dopamine GABAergic
norepinephrine glutamatergic
serotonin peptidergic
monoaminoxidase membrane
revisited dopamine transmethylation
Table 4.5. Basis of classical dopamine hypothesis of schizophrenia

Dopamine-releasing drugs (amphetamine, mescaline, diethyl amide of lysergic acid -
LSD) can induce state closely resembling paranoid schizophrenia.
Conventional neuroleptic drugs, 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.
Neuroleptics raise dopamine turnover as a result of blockade of postsynaptic dopamine
receptors or as a result of desensitisation of inhibitory dopamine autoreceptors localized
on cell bodies.
64
4. SCHIZOPHRENIA
Revised dopamine hypothesis of schizophrenia postulate that a reduced striatal

inhibition on the thalamus, caused by either an increased dopaminergic or a reduced
glutamatergic tone, should lead to an increase in arousal and psychomotor activity and
to an increased sensory input transmitted to the cortex. If a certain threshold is
exceeded the integrative capacity of the cortex will become insufficient and this will lead
to positive symptoms of schizophrenia. An excessive dopaminergic function may also
lead to a disintegration of motor functions. This inhibitory function of the striatum
appears to be exerted via the indirect pathways (Figure 4.1 A). The direct pathways
(Figure 4.1 B) should be able to mediate the excitatory glutamatergic input from the
cortex to the thalamus; the dopamine input in the direct pathways appears to be
excitatory, and dopamine should thus be behaviourally stimulating also via the direct
pathways.
Hypothetical scheme of interactions, leading to psychotogenic responses, is shown in

Figure 4.2.
65
Figure 4.1. Excitatory and inhibitory influence of dopamine on the direct and
indirect pathways
A) indirect pathways (negative feedback)
cerebral cortex behaviour
Glu + Glu +
3 GABA
striatum thalamus sensory input
-
DA -
substantia nigra,
area ventralis tegmenti + excitatory action
- inhibitory action
B) direct pathways (positive feedback)
cerebral cortex behaviour
Glu + Glu +
2 GABA
striatum thalamus sensory input
+
DA +
substantia nigra,
area ventralis tegmenti
Glu glutamate, DA dopamine, GABA - -amino butyric acid
(See: Carlsson A.: The dopamine theory revisited. In: Schizophrenia, Hirsch S.R. and Weinberger D.R.,
eds., Blackwell Science, pp. 379-400, 1995.)
66
4. SCHIZOPHRENIA
Figure 4.2. Potential psychogenic pathways and sites of action of psychotogenic

and antipsychotic agents
LSD (5-HT2 agonist) muscimol (GABAA agonist)

PCP (NMDA antagonist)
cortex
GABA Glu Glu
striatum
PCP ACh
(NMDA antag.)
atropine
(M1 antagonist)
LSD GABA
(5-HT2 agon.)
amphetamine
(DA releaser)
5-HT DA NE
nucleus raphe substantia nigra, locus

area ventralis tegmenti coeruleus
LSD diethyl amid of lysergic acid, PCP phencyclidine, 5-HT serotonin, Glu glutamate, DA
dopamine, GABA -amino butyric acid, ACh acetylcholine, NE norepinephrine, NMDA N-methyl-
D-aspartate
(See: Carlsson A.: The dopamine theory revisited. In: Schizophrenia, Hirsch S.R. and Weinberger D.R.,
eds., Blackwell Science, pp. 379-400, 1995.)
67
5. Affective disorders
Mood disorders are characterized by depression, mania, or both. In this chapter,

biochemical hypothesis of affective disorders are presented. Classification, clinical
description and criteria for diagnosis of disorders of mood are not described.
Depression and mania are thought to be heterogeneous illnesses that can result from
dysfunction of several neurotransmitter or metabolic systems. Approaches of biological
psychiatry to the affective disorders are summarized in Table 5.1.
Table 5.1 Biological psychiatry and affective disorders

BIOLOGY genetics vulnerability to mental disorders
stress increased sensitivity
chronobiology desynchronisation of biological
rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
receptors number, affinity, sensitivity
postreceptor processes G proteins, 2nd messengers,
phosphorylation, transcription
IMMUNONEURO- hypothalamic-pituitary- increased activity during
ENDOCRINOLOGY adrenocortical system depression
immune function different changes during
depression
Theoretical and clinical studies have provided evidence that the monoamine
neurotransmitter systems are involved in the treatment of affective disorders. These
studies have led to a series of hypotheses concerning the mechanism of the action of
antidepressant treatments, as well as pathophysiology of depression, that have focused
on alterations in brain levels of serotonin and norepinephrine or their receptors.
Studies at the level of neurotransmitters and receptors have not generated a compelling
model of antidepressant action or the pathophysiology of depression. For example,
common action of antidepressant treatments at the level of monoamines or their
receptors was not identified so far. It is possible that there is more than a single
mechanism by which antidepressant treatments exert their therapeutic actions.
An updated hypothesis suggests that postreceptor intracellular targets mediate the long-
term, therapeutic action of antidepressant treatments.
5.1. Neuroendocrine hypotheses
68
5. AFFECTIVE DISORDERS
Changes in the activity of the hypothalamic-pituitary-adrenal (HPA) axis or

hypothalamic-pituitary-thyroid (HPT) axis were observed during depression. An
increased function of the HPA axis was described in more than 50% of depressed
patients. Abnormalities of the HPA axis in patients with depression are summarized in
Table 5.2.
The dexamethasone suppression test (DST) is used to determine the sensitivity of

the HPA axis to negative feedback. 1 mg of dexamethasone is usually administered at
23:00 h and plasma cortisol is monitored following morning. In healthy subjects
dexamethasone suppresses plasma cortisol. DST was suggested as test for diagnosis
of major depressive disorder, since increased function of HPA axis can be expressed in
reduced decrease of ACTH and cortisol levels after dexamethasone administration. But
it was demonstrated that DST test is unsufficiently specific.
Table 5.2. Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis in patients

with depression
cortisol hypersecretion
increased urinary free cortisol
increased CSF corticotrophin releasing factor
increased circulating ACTH
abnormal circadian rhythms of cortisol
abnormal dexamethasone suppression
decreased glucocorticoid receptor sensitivity
decreased release of ACTH to CRF
increased adrenal gland size
CSF cerebrospinal fluid, ACTH adrenocorticotrophic hormone, CRF corticotrophin-releasing factor
(See: Trimble M.R.: Biological Psychiatry. 2nd ed., John Wiley & Sons, New York, 1996.)
69
Neuroendocrine hypothesis of affective disorders were formulated on the base of

abnormalities in HPA axis function and disturbed glucocorticoid feedback in depression
(Table 5.3).
Table 5.3. Neuroendocrine hypotheses of affective disorders

Endocrine abnormalities associated with depression are results of increased releasing
of CRF both in hypothalamus and out of them.
Disturbed glucocorticoid feedback in depression is caused by lower density of
corticosteroid receptors in hippocampus and hypothalamus during depression (i.e. by
disturbed regulation of gene expression of these receptors).
5.2. Neurochemical hypotheses

There are evidences that signal transmission through chemical synapse is disturbed in
the affective disorders. Changes in neurotransmitters, membrane receptors and
postreceptor pathways are studied during mental illness and its treatment. The
neurochemical parameters studied in affective disorders are summarized in Table 5.4.
Table 5.4. Neurochemical parameters studied in affective disorders

neurotransmitters availability
metabolism
receptors number or density
affinity
sensitivity
postreceptor systems number and activity of G proteins
effector enzymes
2nd messengers systems
protein kinases
phosphatases
transcription factors
70
5.3. Neurotransmitter hypotheses

Discovery of the tricyclic antidepressant drugs supported hypothesis about significant
role for the biogenic amine, particularly NE and 5-HT in the ethiopathogenesis of
affective disorders. Reduced activity of the serotonergic and noradrenergic systems has
been reported in subgroups of patients with major depression, but this has not been
observed in all depressed patients.
Initial neurotransmitter hypotheses were supported by effect of tricyclic antidepressants

on reuptake of NE and 5-HT, effect of monoamine oxidase inhibitors (MAOI) on
catabolism of monoamine neurotransmitters and effect of reserpine on vesicular
transport of neurotransmitters (Table 5.5). Reuptake inhibition results in an enrichment
of the NE and 5-HT in the synaptic cleft. Similar effect can be achieved with MAO
inhibitors. For many years this effect was considered to be the precondition for
antidepressant activity. The first major theory about the biological ethiology of
depression was monoamine hypothesis supposing that:
Depression was due to a deficiency of monoamine neurotransmitters, norepinephrine
and serotonin. MAOI act as antidepressants by blocking of enzyme MAO, thus allowing
presynaptic accumulation of monoamine neurotransmitters. Tricyclic antidepressants
act as antidepressants by blocking membrane transporters ensuring reuptake of 5-HT
or NE, thus causing increased extracellular neurotransmitter concentrations.
Table 5.5. Data for neurotransmitter hypothesis

1. Tricyclic antidepressants through blockade of neurotransmitter reuptake increase
neurotransmission at noradrenergic synapses
2. MAOIs increase availability of monoamine neurotransmitters in synaptic cleft
3. Depressive symptoms are observed after treatment by reserpine, which depletes
biogenic amines in synapse
71
In addition to the role of noradrenergic and serotonergic systems in depression,

cholinergic and dopaminergic and others systems were considered, so, many
neurotransmitter hypotheses were formulated (Table 5.6).
Table 5.6. Neurotransmitter hypothesis of affective disorders

catecholamine hypothesis
indolamine hypothesis
cholinergic-adrenergic balance hypothesis
permissive hypothesis
dopamine hypothesis
hypothesis of biogenic amine
monoamine hypothesis
Permissive biogenic amine hypothesis persists as part of more recent hypothesis:

A deficit in central indolaminergic 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 indoleaminergic transmission, act as a proximate
cause for affective disorders and determine their quality, catecholaminergic
transmission being elevated in mania and diminished in depression.
However, neither the catecholamine nor the serotonin hypothesis could be confirmed in
depressive patients. Clinically, the onset of the antidepressant action differs from the
biochemical effects; the uptake inhibition occurs suddenly, whereas the therapeutic
effect needs two or three weeks of pharmacotherapy. Furthermore, depletion of 5-HT or
NE in healthy individuals does not induce clinically significant depressive
symptomatology. These are reasons why receptor and postreceptor events are
observed during affective disorders and their treatment at present time.
72
5.4. Receptor hypotheses

The neurotransmitter receptor hypothesis posits that disturbance occurs in function of
receptors for the key monoamine neurotransmitters. Such wrong receptor function may
be caused by depletion of monoamine neurotransmitters, by abnormalities in the
receptor, or by problems with signal transduction on postreceptor level.
The common final result of chronic treatment by majority of antidepressants is the

down-regulation or up-regulation of postsynaptic or presynaptic receptors (Table 5.7).
The delay of clinical response corresponds with these receptor alterations, hence many
receptor hypotheses of affective disorders were formulated and tested.
Table 5.7. Effect of depression and antidepressant treatment on receptor sensitivity

system receptor system treatment by depression
antidepressants
adrenergic 1-AR (postsynaptic, exc.)
2-AR (presynaptic, inh.)
2-AR (postsynaptic, inh.)
1-AR (postsynaptic, exc.)
serotonergic 5-HT2 (exc.)
5-HT1A (somatodendritic ?
autoreceptors, inh.)
5-HT1A (postsynaptic, inh.)
5-HT1B (terminal autoreceptors, inh.)
other ACh
GABA
DA
corticosteroid receptors
ACh - acetylcholine, GABA - -amino butyric acid, DA - dopamine, AR adrenoceptors.

- increased, - decreased
73
When activated by catecholamines, the presynaptic 2-adrenergic receptors can inhibit

NE or 5-HT release. Some antidepressants reduce sensitivity of brain
2-adrenoreceptors. Hypothesis about role of presynaptic 2-AR was formulated:
There is increased density of presynaptic 2-adrenergic receptors in high affinity state in
depression.
Several lines of evidence indicate that an enhancement of 5-HT neurotransmission

might underlie the therapeutic response to different types of antidepressant treatment,
so, general serotonin receptor hypothesis was suggested:
Depression is connected with these abnormalities in serotonin receptors:
5-HT2 up-regulation
5-HT1A desensitisation
Abnormal signal transduction following 5-HT binding to receptor
Very elegant but not confirmed was receptor catecholamine hypothesis:

Supersensitivity of catecholamine receptors in the presence of low levels of serotonin is
the biochemical basis of depression.
The common result of chronic treatment by majority of antidepressants is the down

regulation of -adrenergic receptors, which can be modulated by interaction with the 5-
HT system, DA system, neuropeptides and hormones. Classical norepinephrine
receptor hypothesis of affective disorders was formulated (Figure 5.1):
There is increased density of postsynaptic -AR in depression (due to decreased NE
release, disturbed interactions of noradrenergic, serotonergic and dopaminergic
systems, etc.). Long-term antidepressant treatment causes down regulation of 1-AR
(by inhibition of NE reuptake, stimulation or blockade of receptors, regulation through
serotonergic or dopaminergic systems, etc.). Transient increase of neurotransmitter
availability can cause fault to mania.
Apparently paradoxical increase of intracellular cAMP levels were observed at
decreased density of -AR, so increased cAMP system activity seems to be
fundamental in therapeutic action of antidepressants. So, postreceptor hypotheses of
affective disorders are tested at present time.
74
Figure 5.1. Classical noradrenergic receptor hypothesis
5-HT 5-HT 5-HT
h
e i
f j
NE NE NE
DA DA DA
c d g
DEPRESSION
5-HT
NE reuptake
NE
DA 5-HT NE NE - receptors
pre- postsynaptic DA
k
MANIA
(See: Lopez D. et al.: The Essential Brain. Current Topics Sci. Med. Merck 1991.)
75
5.5. Postreceptor hypotheses

The introduction of new, more selective antidepressants led to new reflection upon the
mechanism of their action. Most promising are recent investigations of the second
messenger systems, the adenylyl cyclase system, the phosphatidylinositol system,
G proteins, transcription factors etc. Modulation of receptor sensitivity, either
down-regulation or up-regulation, is most probably dependent on the second and third
messenger systems. Selected postreceptor hypotheses are shown in Table 5.8.
Table 5.8. Postreceptor hypotheses

Second messenger dysbalance hypothesis:
Affective disorders arise from the dysbalance of the two major intraneuronal signal-
amplification systems, with depression resulting from a hypofunction of the AC-cAMP
kinases pathway together with dominance of the PLC-CaM/C kinases system, and
mania resulting from the converse.
G protein hypothesis:
They are changes either density or function of subunits of G proteins during depression.
(e.g. increase of Gs protein)
Molecular model of affective disorders:
Clinical heterogeneity observed at depressed patients can be explained by changes in
signal transduction pathways which regulate two or more different neurotransmitter
systems and which affect the neuron activity. G proteins, phosphatases and
transcription factors are studied mainly.
Molecular and cellular theory of depression:
Transcription factor, cAMP response element-binding protein (CREB), is one
intracellular target of long-term antidepressant treatment and brain-derived 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.
76
5.6. Molecular and cellular theory of depression

Recent studies have begun to characterize the action of stress and antidepressant
treatments on signal transduction at postreceptor level. Long-term antidepressant
treatments result in the sustained activation of the cAMP system in specific brain
regions, including the increased function and expression of the transcription factor
cAMP response element-binding protein (CREB). The activated cAMP system leads to
the regulation of specific target genes, including the increased expression of brain-
derived neurotrophic factor (BDNF) in hippocampus and cortex.
It was found that stress can decrease the expression of BDNF and lead to atrophy of
the same populations of stress-vulnerable hippocampal neurons. Decreased size and
impaired function of these neurons may be involved in depression; this possibility is
supported by clinical imaging studies, which demonstrate a decreased volume of certain
brain structures. These findings constitute the framework for a molecular and cellular
hypothesis of depression (Table 5.8), which assume that stress-induced vulnerability
and therapeutic action of antidepressant treatments occur via intracellular mechanisms
that decrease or increase, respectively, neurotrophic factors necessary for the survival
and function of particular neurons. This hypothesis also explains how stress and other
types of neuronal insult can lead to depression in vulnerable individuals.
5.7. Molecular mechanism of action of antidepressant treatments

A model for the molecular mechanism of action of antidepressant treatments is shown
on Figure 5.2. Antidepressant treatment causes inhibition of serotonin and
norepinephrine reuptake or breakdown. Short-term antidepressant treatment increase
extracellular levels of serotonin and norepinephrine. Long-term treatment leads to
decrease in the function and expression of serotonin and norepinephrine receptors, to
increase in the cAMP signal transduction and to increase in expression of CREB.
Increased activity of the cAMP signal transduction cascade indicates that the functional
output of 5-HT and NE are up-regulated, even though levels of certain 5-HT and NE
receptors are down-regulated. Expression of BDNF and its receptor trkB is also
increased by long-term antidepressant treatment, so increased neuronal survival,
function, and remodelling of synaptic architecture are provided.
77
Figure 5.2. A model for the molecular mechanism of action of antidepressant

treatments
Antidepressant treatments (AT)
Inhibition of serotonin and norepinephrine reuptake or breakdown.
Short-Term AT: Increase in levels of serotonin or norepinephrine.
Long-Term AT: Decrease in the function and expression of 5-HT and NE

receptors.
Increase in the cAMP signal transduction pathway (increased
levels of adenylyl cyclase and PKA and translocation of PKA to
the cell nucleus).
Increase in expression of the transcription factor CREB (cAMP
response element-binding protein); it is suggested that CREB is
a common postreceptor target for antidepressants.
(See: Duman et al.: A Molecular and Cellular Theory of Depression. Arch. Gen. Psychiatry, 1997; 54:
597-606.)
78
6. LABORATORY SURVEY IN PSYCHIATRY
6. Laboratory survey in psychiatry
Biochemical, immunological, genetic, electrophysiological and neuroendocrine

parameters are studied in mental disorders. Laboratory survey methods in psychiatry
coincide with internal and neurological methods:
Classic and special biochemical and neuroendocrine tests
Immunological tests
Electrocardiography (ECG)
Electroencephalography (EEG)
Computed tomography (CT)
Nuclear magnetic resonance (NMR)
Phallopletysmography
79
Table 6.1. Classic and special biochemical tests

Test Indication
serum cholesterol (3,7-6,5 mmol/l) and lipemia (5- brain disease at atherosclerosis
8 g/l)
cholesterolemia, TSH, T3, T4, blood pressure, thyroid disorder,
mineralogram (calcemia, phosphatemia) hyperparathyreosis or
hypothyroidism can be an
undesirable side effect of lithium
therapy
hepatic tests: bilirubin (total < 17mmol/l), before pharmacotherapy and in
cholesterol, aminotranspherase (AST, ALT, TZR, alcoholics
TVR), alkaline phosphatase
glycaemia diabetes mellitus
blood picture during pharmacotherapy
determination of metabolites of psychotropics in control or toxicology
urine or in blood
lithemia (0,4-1,2 mmol/l), function of thyroid and during lithiotherapy
kidney (serum creatinine, urea), pH of urine,
molality, clearance, serum mineralogram (Na, K)
determination of neurotransmitter metabolites, e.g. research
homovanilic acid (HVA, dopamine metabolite),
hydroxyindolacetic acid (HIAA, serotonin
metabolite), methoxyhydroxyphenylglycole
(MHPG, norepinephrine metabolite)
neurotransmitter receptors and transporters research
cerebrospinal fluid: pH, tension, elements, diagnosis of progressive
abundance of globulins (by electrophoresis) paralysis,
neuroendocrinne stimulative or suppressive tests: depressive disorders
dexamethasone suppressive test (DST), TRH test,
fenfluramine test
prolactin determination increased during treatment with
neuroleptics
80
6. LABORATORY SURVEY IN PSYCHIATRY
Table 6.2. Recommended laboratory survey in selected psychiatric cases

Alcoholism and drug dependence Atypical psychosis
blood picture + differential blood picture + differential
serum electrolytes, glycaemia, S-urea, creatinine serum electrolytes, glycaemia, S-urea,
creatinine
hepatic tests: GGT, AST, ALT, AF hepatic tests: GGT, AST, ALT, AF
total protein, S-albumin glycaemia
prothrombine time nephric function (N-urea, S-creatinine)
serum Ca, P serum Ca, P
lithic acid thyroidal tests
toxicological survey of urine cortisolemia
alcoholemia screening on syphilis (RRR, BWR) and Lyme
Borreliosis
screening on syphilis (RRR, BWR) think on hypovitaminosis B12
ECG HIV test at risk person
thorax Rtg urine + deposit
urine + deposit toxicological survey of urine
ordure uropophyrine and porphobilinogene in urine
S-ammonia thorax Rtg
cranium Rtg or CT ECG
HIV survey EEG or CT
Anorexia Dementia
blood picture + differential blood picture + differential
FW serum electrolytes, glycaemia, S-urea,
creatinine
hepatic tests hepatic tests: GGT, AST, ALT, AF
thorax Rtg thyroidal tests
ECG screening on syphilis (RRR, BWR)
serum minerals and electrolytes think on hypovitaminosis B12
total protein urine + deposit
urine + deposit HIV tests
special survey: cortisolemia, thyroid tests, serum cranium Rtg
prolactin, nephric function, EEG, cranium Rtg or CT,
special test on laxative
Bulimia ECG
glycaemia EEG or CT
serum Ca, P Malign neuroleptic syndrome
ECG all basic blood and urine tests
toxicological survey of urine S-creatine kinase
special test on laxative myoglobin in urine
lumbal puncture to rule out CNS infection
ECG
thorax Rtg
81
Table 6.3. Immunological tests

Test Indication
venereal disease research laboratories syphilis
(VDRL) Test
rapid reagine reaction (RRR) syphilis
antibodies against Borrelia Burgdorferi Lyme Borreliosis
complement fixative test brucellosis
antibodies against HIV HIV infection
hepatic tests (ALT, AST) hepatitis
specific test on antigen EBV and Epstein-Barr virus (EBV, infectious
antibodies mononucleosis) and Cytomegalovirus
(CMV, seronegative mononucleosis),
antinuclear antibodies and lupus systemic lupus erytematodes
erytematosus cell preparation
82
REFERENCES
(RECOMMENDED LITERATURE)
Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C.Decker Inc., Toronto-Philadelphia, 1989.
Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th Ed., edited by G.J.Siegel et
al., Lippincott-Raven, Philadelphia, New York, 1999.
Caron M.G.: TiPS Receptor and Ion Channel Nomenclature Supplement, 1996.
Duman et al.: A Molecular and Cellular Theory of Depression. Arch. Gen. Psychiatry, 1997; 54: 597-606.
Fiar Z.: Biochemick hypotzy afektivnch poruch, Galn, Praha 1998.
Fiar Z., Jirk R.: Vybran kapitoly z biologick psychiatrie, GRADA, Praha, 2001.
Ganong W.F.: Pehled lkask fyziologie. Nakl. a vyd. H&H, 1995.
Hschl C.: Psychiatrie pro praktick lkae, H&H, Jinoany, 1996
Hschl C., Libiger J., vestka J. et al.: Psychiatrie. Tigis, 2002.
Hynie S.: Psychofarmakologie v praxi. Galn, Praha, 1995.
Kotyk A., Janek K.: Membrane Transport. Academia, Praha, 1977.
Levitan I.B., Kaczmarek L.K.: The Neuron. Cell and Molecular Biology. Second Edition, Oxford
Univ. Press, New York, Oxford, 1997.
Nmeek S., Lodin Z., Wolf J., Vyskoil F.: Neurobiologie, Avicenum, zdrav. nakl., Praha, 1972.
Raboch J., Zvolsk P. et al.: Psychiatrie. Galn, Karolinum, 2001.
Randrup A., Munkvad I.: Special antagonism of amphetamine-induced abnormal behaviour. Inhibition of
stereotyped activity with increase of some normal activities. Psychopharmacologia, 7: 416-422, 1965.
Schizophrenia, edited by S.R. Hirsch and D.R. Weinberger, Blackwell Science, 1995.
Shinitzky M.: Membrane fluidity and receptor function. In: Membrane Fluidity (M. Kates, L.A. Manson,
eds.), Plenum Publ. Corp., pp. 585-601, 1984.
Stahl S.M.: Psychopharmacology of Antipsychotics, Martin Dunitz, London, 1999.
Stahl S.M.: Essentials Psychopharmacology, Cambridge Univ. Press, cambridge, 2000.
vestka J. a kol.: Psychofarmaka v klinick praxi. Grada, Praha, 1995
vestka J.: Nov (atypick) antipsychotika 2. generace. Remedia 9, 366-385, 1999.
The Essential Brain. Current Topics in Science and Medicine. Merck, 1991.
The RBI Handbook of Receptor Classification and Signal Transduction, 3rd Ed., edited by K.J.Watling,
RBI, Natick, 1998.
TiPS Receptor and Ion Channel Nomenclature Supplement 2000, 11th Ed., compiled by S.P.H.Alexander
and J.A.Peters.
Trimble M.R.: Biological Psychiatry. 2nd ed., John Wiley & Sons, New York, 1996.
Vina O.: Psychofarmaka. Minimum pro praxi. Triton, Praha, 1998.
Voyet D., Voyetov J.G.: Biochemie. Victoria Publishing a.s., Praha, 1995.
Zvolsk P.: Rozvoj genetiky v psychiatrii. Avicenum, Praha, 1990.
83

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INTRODUCTION TO BIOLOGICAL PSYCHIATRY

RNDr. Zdenk Fiar, CSc.

This work was supported by FRV 2448/2002 grant.

Biological psychiatry studies disorders in human mind from the neurochemical,

Apportionable parts of this teaching material are dedicated to essence of neurobiology

Cytoskeleton is important part of neuron. Cytoskeleton is heterogeneous network of

Figure 1.1. Neurone

dendritic tree dendritic

plasma Golgi complex

Table 1.1. Functions of glia

Figure 1.2. Glial cells

astrocyte oligodendrocyte microglia

Figure 1.3. Myelin sheath

axon glial cell

paranodium nodium paranodium

1.3. Plasma membrane

Plasma membranes consist of (Figure 1.4):

Main properties of lipid bilayer are included in model of fluid mosaic:

Figure 1.4. Model of plasma membrane

peripheral glycoproteins glycolipids

cholesterol integral proteins ion -helix

Figure 1.5. Lipid bilayer and function of membrane proteins

1.4. Action potential

Specific properties of axonal membranes allowing signal transmission in the form of

Figure 1.6. Action potential

Figure 1.7. Frequency coding

1.5. Ion channels

permeability for Na+

Figure 1.9. Ion flow during action potential

Na+ channel K+ channel

rapid opening of Na+

Table 1.2. Intercellular communication

Neurosecretion is a more complex process. Stimulation of cells is followed by an

Figure 1.10. Morphology of chemical synapse

glia presynaptic cell

(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972)

Figure 1.11. Synapses

button from node of

(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972; modified.)

1.7. Chemical synapse

Table 1.3. Basic steps in signal transduction

Release of neurotransmitters is closely linked to the entry of calcium. With repetitive

Following neurotransmitter release postsynaptic or presynaptic membrane receptors are

Temporal and/or spatial summation of synaptic potentials is necessary to the evocation

Figure 1.12. Chemical synapse - signal transduction

PRESYNAPTIC PART action potential

c - Ca entry through voltage-gated channel

d - Ca -catalysed reaction exocytosis

Figure 1.13. Excitation and inhibition postsynaptic potentials

excitation synapse inhibition synapse

Figure 1.14. Summation of excitation and inhibition

B) Temporal summation of excitation

C) Spatial summation of excitation

excitation presynaptic inhibition

inhibition postsynaptic inhibition

2.1. Criteria to identify neurotransmitters

Table 2.1. Criteria to identify neurotransmitter

2.2. Classical neurotransmitters

The first molecule to be implicated as neurotransmitter was acetylcholine (Ach). It was

Catecholamines (dopamine, norepinephrine and epinephrine) are synthesized from

Table 2.2. Selected classical neurotransmitters

Figure 2.1. Synthesis and release of acetylcholine

AXON axoplasmic transport