INTRODUCTION TO BIOLOGICAL PSYCHIATRYzfisar/bpen/BPEN1.pdf3 Introduction Biological psychiatry occupies itself by mental disorders from biological, chemical and physical point of view

INTRODUCTION TO BIOLOGICAL PSYCHIATRY

(http://www1.lf1.cuni.cz/~zfisar/bpen/default.htm)

RNDr. Zdeněk Fišar, CSc. Department of Psychiatry

1st Faculty of Medicine, Charles University, Prague

E-mail: [email protected]

This work was supported by FRVŠ 2448/2002 grant.

Zdeněk Fišar: Introduction to Biological Psychiatry

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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

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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.


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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.

1. NEUROBIOLOGY

5

Figure 1.1. Neurone

dendritic tree dendritic spines

mitochondria

Golgi complex

ribosome

lysosomes

microtubules

axon hillock

initial segment

myelin sheath

node of Ranvier

internodium

synaptic vesicles

plasma membrane

nucleus rough endoplasmic reticulum (Nissl substance) axon telodendrium synaptic terminals

neuronal cell body (soma)


6

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

1. NEUROBIOLOGY

7

Figure 1.2. Glial cells

Figure 1.3. Myelin sheath

axon glial cell

glia

axon

paranodium nodium paranodium

node of Ranvier

astrocyte oligodendrocyte microglia


8

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.

1. NEUROBIOLOGY

9

Figure 1.4. Model of plasma membrane

peripheral glycoproteins glycolipids proteins

cholesterol integral proteins ion α-helix phospholipids channels


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Figure 1.5. Lipid bilayer and function of membrane proteins

(See: Shinitzky M.: Membrane fluidity and receptor function. In: Membrane Fluidity, M. Kates, L.A. Manson, eds., Plenum Publ. Corp. 1984, pp. 585-601.)

movement movement perpendicular in the plane to membrane of membrane

lipid bilayer in fluid state

lipid bilayer in gel state

1. NEUROBIOLOGY

11

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).


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Figure 1.6. Action potential

Figure 1.7. Frequency coding

(See: Levitan I.B. a Kaczmarek L.K.: The Neuron. Oxford Univ. Press, New York, Oxford, 1997; Ganong W.F.: Přehled lékařské fyziologie. Nakl. a vyd. H&H, 1995.)

equilibrium potential for Na+

40

∆ψ (mV) 20

0

- 20

- 40 threshold

- 60 resting potential

- 80 equilibrium potential for K+

1 2 4 8 16 32 depolarizing time (ms) stimulus

following following latency depolarization hyperpolarization

depolarizing stimulus

small short longer long large+long depolarization stimulus (mV)

+20

0

response ∆ψ (mV) +30

threshold resting potential

time (ms)

1. NEUROBIOLOGY

13

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.


14

Figure 1.8. Membrane permeability for Na+ and K+ during action potential

(see Voet D., Voetová J.G.: Biochemie. Victoria Publ., Praha, 1995.)

Figure 1.9. Ion flow during action potential

(See: Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C. Decker Inc., Toronto, Philadelphia, 1989.)

30

20

10

0

1 2 3 time (ms)

20

0

- 20

- 40

- 60

Ion

perm

eabi

lity

(mS/

cm2 )

∆ψ (m

V)

action potential

permeability for Na+

permeability for K+

Na+ channel K+ channel

resting state

depolarization

repolarization

hyperpolarization

beginning of depolarizing stimulus rapid opening of Na+ channels; slow opening of K+ channels K+ channels open; Na+ channels inactivated (refractory period) slow closing of K+ channels; removal of inactivation and closed Na+ channels

1. NEUROBIOLOGY

15

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.


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Figure 1.10. Morphology of chemical synapse

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

axon

microtubules mitochondria synaptic vesicles

presynaptic membrane

synaptic cleft postsynaptic membrane

postsynaptic cell

glia presynaptic cell

1. NEUROBIOLOGY

17

Figure 1.11. Synapses

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

axo-dendritic synapse axo-somatic synapse axo-axonic synapse button from node of Ranvier axo-axonic synapse

reverse collaterale reverse collaterale presynaptic elements en passant synaptic knob (terminal button)


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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).

1. NEUROBIOLOGY

19

Figure 1.12. Chemical synapse - signal transduction

PRESYNAPTIC PART action potential

- Ca2+ entry through voltage-gated channel

- Ca2+-catalysed reaction → exocytosis

- Inactivation of intracellular Ca2+

- Diffusion of neurotransmitter

- Reaction with receptors of postsynaptic cell and changes in membrane permeability

Ca2+


20

Figure 1.13. Excitation and inhibition postsynaptic potentials

(See: Netter F.H.: Physiology and Functional Neuroanatomy. Nervous System I. CIBA-GEIGY Ltd., Basle, 1989.)

Na+ K+ Cl- K+

0 4 8 12 16time (ms)

∆ψ (mV)

-65

-70

resulted ion current

excitation postsynaptic potential

time (ms) 0 4 8 12 16

-70

-65

∆ψ (mV)

resulted ion current

inhibition postsynaptic potential

synaptic vesicles

synaptic cleft (released transmitters)

postsynaptic membrane

excitation synapse inhibition synapse

1. NEUROBIOLOGY

21

Figure 1.14. Summation of excitation and inhibition

excitation

inhibition

B) Temporal summation of excitation

excitation

inhibition

A) Insufficient excitation

excitation

inhibition

C) Spatial summation of excitation

excitation presynaptic inhibition

inhibition postsynaptic inhibition

inhibition D) Excitation + inhibition


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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

2. NEUROCHEMISTRY

23

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: γ-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.


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Table 2.2. Selected classical neurotransmitters

System Transmitter Precursor

cholinergic acetylcholine choline+acetylcoenzym A

GABA glucose → glutamate

aspartic acid glucose+glutamine; glutamate

glutamic acid glucose+glutamine; aspartate

glycine serine

aminoacidergic

homocysteine cysteine→cystine

monoaminergic

dopamine tyrosine→DOPA→dopamine

norepinephrine →norepinephrine→epinephrine

catecholamines

epinephrine

tryptamine indolamines

serotonin tryptophan→5-hydroxytryptophan

histamine histidine others, related to aa

taurine cysteine→cysteamine

adenosine

ADP

AMP

purinergic

ATP

2. NEUROCHEMISTRY

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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


26

Figure 2.2. Catecholamine biosynthesis

L-tyrosine

tyrosine hydroxylase L-DOPA (3,4-dihydroxyphenylalanine)

DOPA decarboxylase dopamine (DA)

dopamine-β-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)

2. NEUROCHEMISTRY

27

2.3. Neuropeptides It was identified a great number of neuropeptides (Table 2.3) and new neuropeptides

are discovered continually. β-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 cholecystokinin (CCK) gastrin bombesin

brain and gastrointestinal peptides

galanin neuromedin K neuropeptideY (NPY) peptide YY (PYY)

neuronal

cortikotropin releasing hormone (CRH) growth hormone releasing hormone (GHRH) gonadotropin releasing hormone (GnRH) somatostatin thyrotropin releasing hormone (TRH)

hypothalamic releasing factors

adrenocorticotropic hormone (ACTH) growth hormone (GH) prolactin (PRL) lutenizing hormone (LH) thyrotropin (TSH)

pituitary hormones

oxytocin vasopressin neurohypophyseal peptides

atrial natriuretic peptide (ANF) vasoactive intestinal peptide (VIP) neuronal and endocrine

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

opiate peptides


28

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

2. NEUROCHEMISTRY

29

Figure 2.4. Membrane transporters

GLIA PRESYNAPTIC

ion channel receptor

POSTSYNAPTIC

- Na+/Cl- dependent transporter

- vesicular transporter

- Na+ dependent transporter

ion pump

ion channel

synaptic vesicle

autoreceptor transporter transmitter

ADP ATP


30

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 β superfamily Transforming growth factors β (TGFβ)

Bone morphogenetic factors (BMPs)

Glial-derived neurotrophic factor (GDNF)

Neurturin

Epidermal growth factor superfamily Epidermal growth factor (EGF)

Transforming growth factor α (TGFα)

Neuregilins

Other growth factors Platelet-derived growth factor (PDGF)

Insulin-like growth factor I (IGF-I)

2. NEUROCHEMISTRY

31

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)


32

Figure 2.5. Adaptation of receptors

reactive hyperfunction (upregulation)

balance

secondary hyperfunction

adaptive hypofunction (desensitization)

secondary hypofunction

RECEPTOR

NEUROTRANSMITTER

2. NEUROCHEMISTRY

33

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 γ-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.


34

Figure 2.6. GABAA receptor

Pi

Cl-

barbiturates GABA, bicuculine neurotransmitter binding site neurosteroids benzodiazepines

allosteric modulatory sites picrotoxin phosphorylation pore ~0.5 nm

receptor formed by 5 subunits

2. NEUROCHEMISTRY

35

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.


36

Figure 2.7. Scheme for hypothesis of second messengers

receptors

G proteins

effector proteins

second messengers

protein kinase

biological response

gene expression etc.

first messengers

third messengers

2. NEUROCHEMISTRY

37

Figure 2.8. Signal transduction: Adenylyl cyclase system

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

free Ca2+ PKA, PKC Ca2+/CaM

5´-AMP

fosfodiesterase protein kinase A

γ γ β β Gs Gi/o/x αs-GTP αi/o/x-GTP Ca2+

activated adenylyl cyclase activated Ca2+- receptor receptor channel forskolin

ATP

cAMP + ADP

activated protein

ADP + Pi

ATP


38

Figure 2.9. Signal transduction: Phosphoinositide system

PI-PLC - phospholipase C specific for phosphoinositides, PIP2 - phosphatidylinositol-4,5-biphosphate, IP3 - inositol-1,4,5-triphosphate; DG - diacylglycerol; PKC – protein kinase C

γ γ Pi Pi β β

Gq αq PKC Gi/o PI-PLCγ αi/o

IP3 protein phosphorylation

Ca2+-dependent Ca2+

processes IP3 receptor

endoplasmic reticulum

receptor receptor receptor Ca2+- with intrinsic associated with s Gq associated with Gi/o channel tyrosin kinase PI-PLCβ1 DG PI-PLCβ2

PIP2 PIP2

2. NEUROCHEMISTRY

39

Figure 2.10. Signal transduction: Guanylyl cyclase system

GC – guanylyl cyclase, CaM – calmodulin, NO – nitric oxide, nNOS – nitric oxide synthase, ATP – adenosine triphosphate, cGMP – cyclic guanosine monophosphate

GC-A GC-B GC-C Ca2+-channel

Ca2+

Ca2+/CaM

nNOS

NO cGMP

biological response

ATP

catalytic domain

soluble GC

membrane bound GC

intracellular stores of Ca2+


40

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

cGMP (internal guanylyl cyclase)

Gi/o (K+↑, Ca2+↓, cAMP↓)

Gq/11 (IP3, DG)

Gs (cAMP↑)

Effectors

internal ion channel (Na+/K+/Ca2+/Cl-)

Gen

Structure

2. NEUROCHEMISTRY

41

Table 2.9. Type of receptors

System Type

acetylcholine nicotinic receptors acetylcholinergic

acetylcholine muscarinic receptors

α1-adrenoceptors

α2-adrenoceptors

β-adrenoceptors

dopamine receptors

monoaminergic

serotonin receptor

GABA receptors

glutamate ionotropic receptors

glutamate metabotropic receptors

glycine receptors

aminoacidergic

histamine receptors

opioid receptors peptidergic

other peptide receptors

adenosine receptors (P1 purinoceptors) purinergic

P2 purinoceptors


42

Table 2.10. Subtypes of monoamine receptors

RECEPTORS Subtype Transducer Structure (aa/TM)α1A Gq/11 ↑IP3/DAG 466/7 α1B Gq/11 ↑IP3/DAG 519/7

α1-adrenoceptors

α1D Gq/11 ↑IP3/DAG 572/7 α2A Gi/o cAMP 450/7 α2B Gi/o cAMP 450/7 α2C Gi/o cAMP 461/7

α2-adrenoceptors

α2D Gi/o cAMP 450/7 β1 Gs ↑cAMP 477/7 β2 Gs ↑cAMP 413/7

β-adrenoceptors

β3 Gs, Gi/o ↑cAMP 408/7 D1 Gs ↑cAMP 446/7 D2 Gi

Gq/11 cAMP ↑IP3/DAG, ↑K+, ↓Ca2+

443/7

D3 Gi cAMP 400/7 D4 Gi cAMP, ↑K+ 386/7

dopamine

D5 Gs ↑cAMP 477/7 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-hydroxytryptamine

5-HT7 Gs ↑cAMP 445/7

2. NEUROCHEMISTRY

43

Table 2.11. Subtypes of aminoacidergic receptors

RECEPTORS Subtypes Transducer Structure (aa/TM)

GABAA int. Cl- more subunits GABA

GABAB Gi/o, Gs cAMP, ↑cAMP,

↑K+(G), ↑Ca2+(G)

961,941/7

NMDA int. Na+/K+/Ca2+ more subunits

AMPA int. Na+/K+/Ca2+ more subunits

excitatory aa

(ionotropic)

kainate int. Na+/K+/Ca2+ more subunits

mglu1 Gq/11 ↑IP3/DAG 1194/7

mglu2 Gi/o cAMP 872/7



mglu5 Gq/11 ↑IP3/DAG 1212/7



excitatory aa

(metabotropic)


glycine glycine int. Cl- pentamer

H1 Gq/11 ↑IP3/DAG 487/7

H2 Gs ↑cAMP 359/7

histamine

H3 Gi/o cAMP 445/7


44

Table 2.12. Subtypes of acetylcholine receptors


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

muscarinic

M5 Gq/11, NO ↑IP3/DAG 532/7

α1 int. Na+/K+/Ca2+ pentamer







nicotinic


Table 2.13. Subtypes of opioid and related peptidergic receptors


mu opioid peptidergic

(µ)

Gi/

o

cAMP,

↑K+(G),↓Ca2+(G)

400/7

delta opioid

peptidergic (δ )

Gi/

o

cAMP,

↑K+(G),↓Ca2+(G)

372/7

kappa opioid

peptidergic (κ)

Gi/

o

cAMP,

↑K+(G),↓Ca2+(G)

380/7

opioid and

similar receptors

N/OFQ receptor Gi/

o

cAMP,

↑K+(G),↓Ca2+(G)

370/7

2. NEUROCHEMISTRY

45

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 α2 receptors. Because α2

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.


46

Figure 2.11. Feedback to transmitter-releasing

(See: Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C. Decker Inc., Toronto, Philadelphia, 1989.)

-

-

α2-adrenoceptor (autoinhibition)

NE

NE

α1,2-adrenoceptors

+ -

muscarinic receptor (M2,M4) (autoinhibition)

muscarinic or nicotinic receptors

ACh

ACh

+ -

-

α2

muscarinic receptor

ACh

ACh

muscarinic receptor

NE

NE

α1-adrenoceptor

+ -

- -

-

adenosine receptor (autoinhibition)

P2 purinoceptor

+ -

ATP

ATP

2. NEUROCHEMISTRY

47

Figure 2.12. Crossconnection of transducing systems on postreceptor level

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

PKC

AC

5-HT2 β-AR α2-AR

Ca2+

Ca2+/CaM

IP3 + DAG

PIP2

Gq/11 Gs Gi/o

PI-PLC

-

+

+

-


48

normal

Pi

++ -

+

+

excitation inhibition

GαGTP GαGTP

IP3, DG, Ca2+, cAMP, FFA

PLC, PLD, PLA2, AC

gene expression

PKC, PKA, PKCaM

PP

neurotransmitters membrane receptors G proteins effector enzymes second messengers protein kinases and gene expression phosphoprotein phosphatases

+-+-

Pi Pi Pi

Figure 2.13. Scheme of signal transduction (implying feedback)

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

3. PSYCHOPHARMACOLOGY

49

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

in

membrane


50

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 psychotropics

examples

positive psychostimulant drugs

amphetamine, amphetaminile, ephedrine, fenmetrazine, mazindole, mezokarb, pemoline, methylphenidate

watchfulness (vigility)

negative hypnotic drugs barbital, amobarbital, hexobarbital; glutethimid, metachalone, clomethiazol; nitrazepam, flunitrazepam, triazolam; zopiclone, zolpidem

antidepressants imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, citalopram, fluoxetine, fluvoxamine, mianserine, buspirone, moclobemide, Li+

positive

anxiolytics guaifenezine, meprobamate; diazepam, alprazolam, oxazepam; neuroleptics and antidepressants

affectivity

negative dysphoric drugs reserpine, clonidine, α-methylDOPA positive neuroleptics,

atypical antipsychotics

thioridazine, chlorpromazine, chlorprotixene, levopromazine, haloperidol, perfenazine, clozapine, amisulpride, risperidone, sertindole, quetiapine, olanzapine

psychic integrations

negative hallucinogenic agents

lysergid, cocaine, amphetamines, ketamine, hashish, marihuana, phencyclidine, mescaline

positive nootropics piracetam, pyritinol, meclophenoxate memory negative amnestic drugs anticholinergics

(See: Švestka J. a kol.: Psychofarmaka v klinické praxi. GRADA Publishing, 1995; Hynie S.: Psychofarmakologie v praxi. Galén, 1995.)


51

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)

antipsychotics

chlorpromazine, chlorprotixene, clopenthixole,

levopromazine, periciazine, thioridazine

conventional antipsychotics

(classical neuroleptics) incisive

antipsychotics

droperidole, flupentixol, fluphenazine,

fluspirilene, haloperidol, melperone,

oxyprothepine, penfluridol, perphenazine,

pimozide, prochlorperazine, trifluoperazine

atypical antipsychotics

(antipsychotics of 2nd generation)

amisulpiride, clozapine, olanzapine,

quetiapine, risperidone, sertindole, sulpiride

(See: Švestka J.: Nová (atypická) antipsychotika 2. generace. Remedia 9, 366-385, 1999.)

Table 3.4. Mechanisms of action of antipsychotics


52

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, α1, α2

sertindole D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, α1

ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, α1, NRI, SRI

loxapine D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, α1, M1, H1, NRI

zotepine D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, α1, H1, NRI

clozapine D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D1, D3, D4, α1, α2, M1, H1

olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, α1, M1-5, H1

quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, α1, α2, H1

NRI - norepinephrine reuptake inhibitor, SRI – serotonin reuptake inhibitor

(See: Stahl S.M.: Psychopharmacology of Antipsychotics, Martin Dunitz, London, 1999.)


53

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

catabolism

monoamine oxidase inhibitors (IMAO)

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 α2-AR, 5-HT2

inhibitors or stimulators of

other components of signal

transduction

G proteins, adenylyl cyclase (AC), phospholipase (PL),

protein kinase (PK), phosphatase, ATPase, phospholipid

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).


54

Figure 3.2. Potential mechanisms of antidepressants action

transporter COMT

transmitter synthesis metabolic degradation transport to vesicles releasing to synaptic cleft reuptake interaction with receptors interaction with transducers

interaction with presynaptic autoreceptors and heteroreceptors metabolic degradation of neurotransmitter

MAO

ATPase synaptic vesicles

PLC AC

ATP cAMP DG IP3

PIP2

ATPase ion-channel receptor

nucleus

protein kinase

Ca2+

transcription factors

A C CaM


55

Table 3.7. Examples of antidepressants

group subgroup examples

activating desipramine, nortriptyline, protriptyline, dosulepine

tricyclic (thymoleptics)

sedative, anxiolytic imipramine, amitriptyline, trimipramine, clomipramine

II. generation - activating viloxazine, buspirone, amineptine, maprotiline

II. generation - sedative, anxiolytic

mianserine, trazodone, nefazodone, pirlindol

III. generation - SSRI citalopram, fluvoxamine, fluoxetine, sertraline, paroxetine

II. a III. generation

enhancing 5-HT uptake tianeptine

nonselective irreversible phenelzine, tranylcypromine, isocarboxazid

selective MAOI-B irreversible deprenyl

selective MAOI-B reversibile

selective MAOI-A irreversible

MAO inhibitors

selective MAOI-A reversible moclobemide, brofaromine, toloxatone, amiflamine

thymoprophylactics lithium, carbamazepine, sodium valproate, valpromide

(See: Švestka J. a kol.: Psychofarmaka v klinické praxi. GRADA Publishing, 1995.)


56

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 α2-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 α2-adrenoceptor blockers is shown on Figure 3.4; mechanism

of action of reversible inhibitors of monoamine oxidase A (RIMA) is on Figure 3.5.


57

5-HT1A 5-HT1B 5-HT2A 5-HT2C 5-HT3 5-HT4

...

5-HT1A TRP

5-HT

MAO

5-HIAA

SERT

A) before treatment α2-AR 5-HT1B

C) chronic treatment by SSRI α2-AR

TRP

5-HT

MAO

5-HIAA

SERT

5-HT1A

5-HT1A TRP

5-HT

MAO

5-HIAA

SERT

B) acute administration of SSRI α2-AR 5-HT1B

Figure 3.3. Mechanism of action of selective serotonin reuptake inhibitors (SSRI)


58

Figure 3.4. Mechanism of action of α2-adrenoceptor blockers

Figure 3.5. Mechanism of action of reversible inhibitors of MAO-A (RIMA)

presynaptic α2-AR α2-AR α2-AR

NORMAL DEPRESSION ↑ density and sensitivity of

presynaptic α2-AR ↓ NE or 5-HT transmission

AFTER TREATMENT α2-AR blockade

↑ NE or 5-HT transmission

NE or 5-HT

NE or 5-HT neurone

serotonin dopamine phenylethylaminenorepinephrine tyramine benzylamine epinephrine tryptamine methylhistamine

TYR

AM

INE

RIM

A

MAO-BMAO-A

TYR

AM

INE

TYR

AM

INE

TYR

AM

INE

TYR

AM

INE

TYR

AM

INE

RIM

A

MAO-BMAO-A

TYR

AM

INE

TYR

AM

INE

TYR

AM

INE

TYR

AM

INE

4. SCHIZOPHRENIA

59

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:


60

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.)

4. SCHIZOPHRENIA

61

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.)


62

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.

4. SCHIZOPHRENIA

63

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.


64

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.

4. SCHIZOPHRENIA

65

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.


66

Figure 4.1. Excitatory and inhibitory influence of dopamine on the direct and

indirect pathways

Glu – glutamate, DA – dopamine, GABA - γ-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.)

+ excitatory action - inhibitory action

cerebral cortex

striatum

substantia nigra, area ventralis tegmenti

thalamus sensory input

behaviour

Glu + Glu +

DA -

3 GABA

-

cerebral cortex

striatum


thalamus sensory input

behaviour

Glu + Glu +

DA +

2 GABA

+

A) „indirect“ pathways (negative feedback)

B) „direct“ pathways (positive feedback)

4. SCHIZOPHRENIA

67

cortex

GluGlu


DA

striatum

ACh

GABA

nucleus raphe

5-HT

locus coeruleus

NE

GABA

LSD (5-HT2 agonist) muscimol (GABAA agonist)

PCP (NMDA antagonist)

atropine (M1 antagonist)

PCP (NMDA antag.)

LSD

(5-HT2 agon.)

amphetamine (DA releaser)

Figure 4.2. Potential psychogenic pathways and sites of action of psychotogenic

and antipsychotic agents

LSD – diethyl amid of lysergic acid, PCP – phencyclidine, 5-HT – serotonin, Glu – glutamate, DA – dopamine, GABA – γ-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.)


68

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

genetics vulnerability to mental disorders stress increased sensitivity

BIOLOGY

chronobiology desynchronisation of biological rhythms

neurotransmitters availability, metabolism receptors number, affinity, sensitivity

NEUROCHEMISTRY

postreceptor processes G proteins, 2nd messengers, phosphorylation, transcription

hypothalamic-pituitary-adrenocortical system

increased activity during depression

IMMUNONEURO- ENDOCRINOLOGY

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

5. AFFECTIVE DISORDERS

69

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.)


70

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

availability neurotransmitters

metabolism

number or density

affinity

receptors

sensitivity

number and activity of G proteins

effector enzymes

2nd messengers systems

protein kinases

phosphatases

postreceptor systems

transcription factors


71

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


72

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.


73

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 antidepressants

depression

β1-AR (postsynaptic, exc.) ↓ ↑

α2-AR (presynaptic, inh.) ↓ ↑

α2-AR (postsynaptic, inh.) ↑ ↓

adrenergic

α1-AR (postsynaptic, exc.) ↑

5-HT2 (exc.) ↓ ↑

5-HT1A (somatodendritic autoreceptors, inh.)

↓ ↓?

5-HT1A (postsynaptic, inh.) ↑ ↓

serotonergic

5-HT1B (terminal autoreceptors, inh.) ↓

ACh ↓ ↑

GABA ↑ ↓

DA ↑ ↓

other

corticosteroid receptors ↑ ↓

ACh - acetylcholine, GABA - γ-amino butyric acid, DA - dopamine, AR – adrenoceptors. ↑ - increased, ↓ - decreased


74

When activated by catecholamines, the presynaptic α2-adrenergic receptors can inhibit

NE or 5-HT release. Some antidepressants reduce sensitivity of brain

α2-adrenoreceptors. Hypothesis about role of presynaptic α2-AR was formulated:

There is increased density of presynaptic α2-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 β-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 β-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 β1-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 β-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.


75

Figure 5.1. Classical noradrenergic receptor hypothesis

(See: Lopez D. et al.: The Essential Brain. Current Topics Sci. Med. Merck 1991.)

5-HT

NE

DA

5-HT

NE

DA

DA 5-HT NE NE - receptors

NE reuptake

pre- postsynaptic

DEPRESSION

5-HT

NE

DA

MANIA

DA

NE

5-HT


76

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.


77

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.


78

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.)

6. LABORATORY SURVEY IN PSYCHIATRY

79

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


80

Table 6.1. Classic and special biochemical tests

Test Indication

serum cholesterol (3,7-6,5 mmol/l) and lipemia (5-

8 g/l)

brain disease at atherosclerosis

cholesterolemia, TSH, T3, T4, blood pressure,

mineralogram (calcemia, phosphatemia)

thyroid disorder,

hyperparathyreosis or

hypothyroidism can be an

undesirable side effect of lithium

therapy

hepatic tests: bilirubin (total < 17mmol/l),

cholesterol, aminotranspherase (AST, ALT, TZR,

TVR), alkaline phosphatase

before pharmacotherapy and in

alcoholics

glycaemia diabetes mellitus

blood picture during pharmacotherapy

determination of metabolites of psychotropics in

urine or in blood

control or toxicology

lithemia (0,4-1,2 mmol/l), function of thyroid and

kidney (serum creatinine, urea), pH of urine,

molality, clearance, serum mineralogram (Na, K)

during lithiotherapy

determination of neurotransmitter metabolites, e.g.

homovanilic acid (HVA, dopamine metabolite),

hydroxyindolacetic acid (HIAA, serotonin

metabolite), methoxyhydroxyphenylglycole

(MHPG, norepinephrine metabolite)

research

neurotransmitter receptors and transporters research

cerebrospinal fluid: pH, tension, elements,

abundance of globulins (by electrophoresis)

diagnosis of progressive

paralysis, …

neuroendocrinne stimulative or suppressive tests:

dexamethasone suppressive test (DST), TRH test,

fenfluramine test

depressive disorders

prolactin determination increased during treatment with

neuroleptics

6. LABORATORY SURVEY IN PSYCHIATRY

81

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 prolactin, nephric function, EEG, cranium Rtg or CT, special test on laxative

cranium Rtg

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


82

Table 6.3. Immunological tests

Test Indication

venereal disease research laboratories

(VDRL) Test

syphilis

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

antibodies

Epstein-Barr virus (EBV, infectious

mononucleosis) and Cytomegalovirus

(CMV, seronegative mononucleosis), …

antinuclear antibodies and lupus

erytematosus cell preparation

systemic lupus erytematodes

83

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INTRODUCTION TO BIOLOGICAL PSYCHIATRYzfisar/bpen/BPEN1.pdf3 Introduction Biological psychiatry occupies itself by mental disorders from biological, chemical and physical point of view