Introduction To Biological Psychiatry: Rndr. Zdeněk Fišar, CSC

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. 1.2. 1.3. 1.4. 1.5. 1.6. 1.7. 2. 2.1. 2.2. 2.3. 2.4. 2.5. 2.6. 2.7. 2.8. 2.9. 2.10. 2.11. 2.12. 3. 3.1. 3.2. 3.3. 4. 4.1. 4.2. 4.3. 4.4. 4.5. 4.6. 5. 5.1. 5.2. 5.3. 5.4. 5.5. 5.6. 5.7. 6. NEURON...................................................................................................................................................... 4 GLIA ........................................................................................................................................................... 6 PLASMA MEMBRANE ................................................................................................................................... 8 ACTION POTENTIAL................................................................................................................................... 11 ION CHANNELS .......................................................................................................................................... 13 SYNAPSE ................................................................................................................................................... 15 CHEMICAL SYNAPSE ................................................................................................................................. 18 CRITERIA TO IDENTIFY NEUROTRANSMITTERS .......................................................................................... 22 CLASSICAL NEUROTRANSMITTERS ............................................................................................................ 23 NEUROPEPTIDES ....................................................................................................................................... 27 MEMBRANE TRANSPORTERS ..................................................................................................................... 28 GROWTH FACTORS .................................................................................................................................... 30 MEMBRANE RECEPTORS............................................................................................................................ 31 RECEPTOR CLASSIFICATION ...................................................................................................................... 33 RECEPTORS COUPLED TO ION CHANNELS .................................................................................................. 33 RECEPTORS ASSOCIATED WITH G PROTEINS .............................................................................................. 35 RECEPTORS WITH INTRINSIC GUANYLYL CYCLASE ACTIVITY .................................................................... 35 RECEPTOR TYPES ...................................................................................................................................... 40 FEEDBACK AND CROSSCONNECTION ......................................................................................................... 45 ANTIPSYCHOTICS ...................................................................................................................................... 51 ANTIDEPRESSANTS ................................................................................................................................... 53 MECHANISM OF ACTION OF ANTIDEPRESSANTS ......................................................................................... 56 ENVIRONMENTAL MODELS ........................................................................................................................ 60 GENETIC MODELS ..................................................................................................................................... 61 NEURODEVELOPMENTAL MODELS ............................................................................................................ 62 DELAYED ONSET OF SYMPTOMS ................................................................................................................ 63 NEURODEGENERATIVE HYPOTHESIS ......................................................................................................... 63 BIOCHEMICAL BASIS OF SCHIZOPHRENIA .................................................................................................. 64 NEUROENDOCRINE HYPOTHESES............................................................................................................... 68 NEUROCHEMICAL HYPOTHESES ................................................................................................................ 70 NEUROTRANSMITTER HYPOTHESES ........................................................................................................... 71 RECEPTOR HYPOTHESES ............................................................................................................................ 73 POSTRECEPTOR HYPOTHESES .................................................................................................................... 76 MOLECULAR AND CELLULAR THEORY OF DEPRESSION.............................................................................. 77 MOLECULAR MECHANISM OF ACTION OF ANTIDEPRESSANT TREATMENTS ................................................ 77
NEUROCHEMISTRY .................................................................................................................................... 22
PSYCHOPHARMACOLOGY....................................................................................................................... 49
SCHIZOPHRENIA ......................................................................................................................................... 59
AFFECTIVE DISORDERS............................................................................................................................ 68
LABORATORY SURVEY IN PSYCHIATRY ............................................................................................ 79 REFERENCES....................................................................................................................................................... 83
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.
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
Figure 1.1. Neurone
dendritic tree
dendritic spines
neuronal cell body (soma) mitochondria plasma membrane nucleus Golgi complex ribosome lysosomes microtubules rough endoplasmic reticulum (Nissl substance) axon axon hillock initial segment myelin sheath node of Ranvier internodium
synaptic vesicles telodendrium
synaptic terminals
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
Figure 1.2. Glial cells
astrocyte
oligodendrocyte
microglia
Figure 1.3. Myelin sheath
axon
glial cell
node of Ranvier glia axon
paranodium
nodium
paranodium
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
Figure 1.4. Model of plasma membrane
peripheral proteins
glycoproteins
glycolipids
cholesterol phospholipids
integral proteins
ion channels
-helix
Figure 1.5. Lipid bilayer and function of membrane proteins
lipid bilayer in fluid state
movement perpendicular to membrane
movement in the plane 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.)
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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).
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Figure 1.6. Action potential equilibrium potential for Na+ 40 (mV) 20 0 - 20 - 40 threshold - 60 resting potential - 80 equilibrium potential for K+ latency 1 depolarizing stimulus following depolarization 2 following hyperpolarization 16 32
4 8 time (ms)
Figure 1.7. Frequency coding depolarization stimulus (mV) +20 0 response (mV) +30 threshold resting potential time (ms) depolarizing stimulus small short longer long large+long
(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.)
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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.
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Figure 1.8. Membrane permeability for Na+ and K+ during action potential action potential 20 permeability for Na+ 20 permeability for K+ 10 0 - 20 - 40 - 60 0 1 2 3 time (ms) (mV)
30 Ion permeability (mS/cm2)
(see Voet D., Voetov J.G.: Biochemie. Victoria Publ., Praha, 1995.)
Figure 1.9. Ion flow during action potential Na+ channel resting state K+ channel 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
depolarization
repolarization
hyperpolarization
(See: Atwood H.L., MacKay W.A.: Essentials of Neurochemistry. B.C. Decker Inc., Toronto, Philadelphia, 1989.)
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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.
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Figure 1.10. Morphology of chemical synapse glia axon microtubules mitochondria synaptic vesicles presynaptic membrane synaptic cleft postsynaptic membrane presynaptic cell
postsynaptic cell
(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972)
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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 synaptic knob (terminal button)
axo-axonic synapse
(See: Nmeek S. a kol.: Neurobiologie, Avicenum, Praha 1972; modified.)
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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).
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1. NEUROBIOLOGY
Figure 1.12. Chemical synapse - signal transduction
PRESYNAPTIC PART
action potential
Ca2+
- 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
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Figure 1.13. Excitation and inhibition postsynaptic potentials
excitation synapse
inhibition synapse
synaptic vesicles synaptic cleft (released transmitters) postsynaptic membrane
Na+
K+
Cl-
K+
resulted ion current (mV) -65 excitation postsynaptic potential
-70
time (ms) 8 12
16
-65 -70 (mV) 0 4 8 12 time (ms) 16
inhibition postsynaptic potential
resulted ion current
(See: Netter F.H.: Physiology and Functional Neuroanatomy. Nervous System I. CIBA-GEIGY Ltd., Basle, 1989.)
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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 excitation
inhibition presynaptic inhibition
inhibition
postsynaptic 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
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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.
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Table 2.2. Selected classical neurotransmitters System cholinergic aminoacidergic Transmitter acetylcholine GABA aspartic acid glutamic acid glycine homocysteine monoaminergic catecholamines dopamine norepinephrine epinephrine indolamines tryptamine serotonin others, related to aa histamine taurine purinergic adenosine ADP AMP ATP tryptophan5-hydroxytryptophan histidine cysteinecysteamine tyrosineDOPAdopamine norepinephrineepinephrine Precursor choline+acetylcoenzym A glucose glutamate glucose+glutamine; glutamate glucose+glutamine; aspartate serine cysteinecystine
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2. NEUROCHEMISTRY
Figure 2.1. Synthesis and release of acetylcholine
AXON
axoplasmic transport of choline acetyltransferase (synthesized in soma) glucose uptake choline uptake glucose metabolism mitochondrial enzymes acetyl-CoA + choline choline acetyltransferase acetylcholine + CoA vesicles free acetylcholine (cytoplasmic)
NERVE TERMINAL
SYNAPTIC CLEFT
released acetylcholine hydrolysis by acetylcholinesterase choline + acetate
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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)
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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 substance P, substance K (tachykinins) neurotensin cholecystokinin (CCK) gastrin bombesin galanin neuromedin K neuropeptideY (NPY) peptide YY (PYY) cortikotropin releasing hormone (CRH) growth hormone releasing hormone (GHRH) gonadotropin releasing hormone (GnRH) somatostatin thyrotropin releasing hormone (TRH) adrenocorticotropic hormone (ACTH) growth hormone (GH) prolactin (PRL) lutenizing hormone (LH) thyrotropin (TSH) oxytocin vasopressin atrial natriuretic peptide (ANF) vasoactive intestinal peptide (VIP) enkephalines (met-, leu-) dynorphin -endorphin Group brain and gastrointestinal peptides
neuronal
hypothalamic releasing factors
pituitary hormones
neurohypophyseal peptides neuronal and endocrine opiate peptides
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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
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2. NEUROCHEMISTRY
Figure 2.4. Membrane transporters
GLIA
PRESYNAPTIC
ion pump
ADP ATP
ion channel synaptic vesicle autoreceptor transporter transmitter
ion channel
receptor
POSTSYNAPTIC - Na+/Cl- dependent transporter - vesicular transporter - Na+ dependent transporter
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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 Transforming growth factor superfamily
FGF-1 FGF-2 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)
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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)
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Figure 2.5. Adaptation of receptors
secondary hyperfunction
reactive hyperfunction (upregulation)
balance RECEPTOR
NEUROTRANSMITTER
adaptive hypofunction (desensitization)
secondary hypofunction
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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.
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Figure 2.6. GABAA receptor
neurotransmitter binding site
barbiturates neurosteroids
GABA, bicuculine benzodiazepines
receptor formed by 5 subunits
Pi
allosteric modulatory sites picrotoxin
Cl-
phosphorylation
pore ~0.5 nm
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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.
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Figure 2.7. Scheme for hypothesis of second messengers first messengers
receptors
G proteins
effector proteins
second messengers
protein kinase
third messengers
biological response
gene expression etc.
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2. NEUROCHEMISTRY
Figure 2.8. Signal transduction: Adenylyl cyclase system
activated receptor forskolin
adenylyl cyclase
activated receptor
Ca2+channel

Gs s-GTP

Gi/o/x i/o/x-GTP Ca2+
PKA, PKC ATP
Ca2+/CaM
free Ca2+
5-AMP fosfodiesterase
cAMP + ADP activated protein
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
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Figure 2.9. Signal transduction: Phosphoinositide system
receptor with intrinsic channel tyrosin kinase
receptor associated with s Gq PI-PLC1 DG PIP2
receptor associated with Gi/o PI-PLC2 PIP2
Ca2+-
Pi PI-PLC
Pi Gq

Gi/o i/o
PKC
IP3
protein phosphorylation
Ca2+-dependent processes
Ca2+ 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
membrane bound GC
GC-A GC-B GC-C
Ca2+-channel
ATP Ca2+ catalytic domain Ca2+/CaM
intracellular stores of Ca2+
nNOS soluble GC cGMP NO
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 acetylcholinergic monoaminergic Type acetylcholine nicotinic receptors acetylcholine muscarinic receptors 1-adrenoceptors 2-adrenoceptors -adrenoceptors dopamine receptors serotonin receptor aminoacidergic GABA receptors glutamate ionotropic receptors glutamate metabotropic receptors glycine receptors histamine receptors peptidergic purinergic opioid receptors other peptide receptors adenosine receptors (P1 purinoceptors) P2 purinoceptors
41
Table 2.10. Subtypes of monoamine receptors RECEPTORS 1-adrenoceptors Subtype 1A 1B 1D 2A 2B 2C 2D 1 2 3 D1 D2 D3 D4 D5 5-HT1A 5-HT1B 5-HT1D 5-ht1E 5-ht1F 5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT4 5-ht5A 5-ht5B 5-ht6 5-HT7 Transducer Gq/11 IP3/DAG Gq/11 IP3/DAG Gq/11 IP3/DAG Gi/o cAMP Gi/o cAMP Gi/o cAMP Gi/o cAMP Gs cAMP Gs cAMP Gs, Gi/o cAMP Gs cAMP Gi cAMP Gq/11 IP3/DAG, K+, Ca2+ Gi cAMP Gi cAMP, K+ Gs cAMP Gi/o cAMP Gi/o cAMP Gi/o cAMP Gi/o cAMP Gi/o cAMP Gq/11 IP3/DAG Gq/11 IP3/DAG Gq/11 IP3/DAG internal cationic channel Gs cAMP ? ? Gs cAMP Gs cAMP Structure (aa/TM) 466/7 519/7 572/7 450/7 450/7 461/7 450/7 477/7 413/7 408/7 446/7 443/7 400/7 386/7 477/7 421/7 390/7 377/7 365/7 366/7 471/7 481/7 458/7 478 387/7 357/7 370/7 440/7 445/7
2-adrenoceptors
-adrenoceptors
dopamine
5-hydroxytryptamine
42
2. NEUROCHEMISTRY
Table 2.11. Subtypes of aminoacidergic receptors RECEPTORS GABA Subtypes GABAA GABAB int. ClGi/o, Gs cAMP, cAMP, K+(G), Ca2+(G) excitatory aa (ionotropic) excitatory aa (metabotropic) NMDA AMPA kainate mglu1 mglu2 mglu3 mglu4 mglu5 mglu6 mglu7 mglu8 glycine histamine glycine H1 H2 H3 int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ Gq/11 Gi/o Gi/o Gi/o Gq/11 Gi/o Gi/o Gi/o int. ClGq/11 Gs Gi/o IP3/DAG cAMP cAMP IP3/DAG cAMP cAMP cAMP IP3/DAG cAMP cAMP cAMP more subunits more subunits more subunits 1194/7 872/7 877/7 912/7 1212/7 877/7 915/7 908/7 pentamer 487/7 359/7 445/7 Transducer Structure (aa/TM) more subunits 961,941/7
43
Table 2.12. Subtypes of acetylcholine receptors RECEPTORS muscarinic Subtypes M1 M2 M3 M4 M5 nicotinic 1 2 3 4 6 7 8 9 Gq/11, NO Gi/o Gq/11, NO Gi/o Gq/11, NO int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ int. Na+/K+/Ca2+ Transducer IP3/DAG cAMP,K+(G) IP3/DAG cAMP,K+(G) IP3/DAG Structure (aa/TM) 460/7 466/7 590/7 479/7 532/7 pentamer pentamer pentamer pentamer pentamer pentamer pentamer pentamer
Table 2.13. Subtypes of opioid and related peptidergic receptors RECEPTORS opioid and similar receptors () delta opioid peptidergic ( ) kappa opioid peptidergic () N/OFQ receptor Subtypes mu opioid peptidergic Gi/
o
Transducer cAMP, K+(G),Ca2+(G) cAMP, K+(G),Ca2+(G) cAMP, K+(G),Ca2+(G) cAMP, K+(G),Ca2+(G)
Structure (aa/TM) 400/7 372/7 380/7 370/7
Gi/
o
Gi/
o
Gi/
o
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
2-adrenoceptor (autoinhibition)
ACh
muscarinic receptor (M2,M4) (autoinhibition)
NE
ACh
+-
+1,2-adrenoceptors
muscarinic or nicotinic receptors
ATP
adenosine receptor (autoinhibition)
ACh
NE
muscarinic receptor
ACh NE
ATP
+-
+
muscarinic receptor
P2 purinoceptor
1-adrenoceptor -
(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
AC +
Gi/o
IP3 + DAG
Ca2+
Ca /CaM
2+
PKC
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 effector enzymes
++ +-
+second messengers protein kinases and gene expression phosphoprotein phosphatases normal
PLC, PLD, PLA2, AC + IP3, DG, Ca2+, cAMP, FFA
+
PKC, PKA, PKCaM PP gene expression
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 watchfulness (vigility) effect positive negative group of psychotropics psychostimulant drugs hypnotic drugs examples
amphetamine, amphetaminile, ephedrine, fenmetrazine, mazindole, mezokarb, pemoline, methylphenidate barbital, amobarbital, hexobarbital; glutethimid, metachalone, clomethiazol; nitrazepam, flunitrazepam, triazolam; zopiclone, zolpidem imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, citalopram, fluoxetine, fluvoxamine, mianserine, buspirone, moclobemide, Li+ guaifenezine, meprobamate; diazepam, alprazolam, oxazepam; neuroleptics and antidepressants reserpine, clonidine, -methylDOPA thioridazine, chlorpromazine, chlorprotixene, levopromazine, haloperidol, perfenazine, clozapine, amisulpride, risperidone, sertindole, quetiapine, olanzapine lysergid, cocaine, amphetamines, ketamine, hashish, marihuana, phencyclidine, mescaline piracetam, pyritinol, meclophenoxate anticholinergics
affectivity
positive
antidepressants
anxiolytics negative positive dysphoric drugs neuroleptics, atypical antipsychotics hallucinogenic agents nootropics amnestic drugs
psychic integrations
negative memory positive negative
(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 basal (sedative) antipsychotics conventional antipsychotics (classical neuroleptics) incisive antipsychotics atypical antipsychotics (antipsychotics of 2nd generation) examples
chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride
(See: vestka J.: Nov (atypick) antipsychotika 2. generace. Remedia 9, 366-385, 1999.)
Table 3.4. Mechanisms of action of antipsychotics

51
conventional antipsychotics atypical antipsychotics
D2 receptor blockade of postsynaptic in the mesolimbic pathway D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms; enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms; other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia
Table 3.5. Receptor systems affected by atypical antipsychotics risperidone sertindole ziprasidone loxapine zotepine clozapine olanzapine quetiapine D2, 5-HT2A, 5-HT7, 1, 2 D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1 D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, 1, NRI, SRI D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, M1, H1, NRI D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, 1, H1, NRI D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1 D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, 1, M1-5, H1 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 antagonists of receptors inhibitors or stimulators of other components of signal transduction 5-HT1A 2-AR, 5-HT2 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).
53
Figure 3.2. Potential mechanisms of antidepressants action
transmitter synthesis metabolic degradation transport to vesicles releasing to synaptic cleft reuptake interaction with receptors transporter AC ATPase synaptic vesicles
MAO
interaction with presynaptic autoreceptors and heteroreceptors metabolic degradation of neurotransmitter PLC PIP2 IP3
COMT
ATPase ion-channel receptor interaction with ATP transducers
cAMP DG
Ca2+ A C CaM protein kinase transcription factors
nucleus
54
Table 3.7. Examples of antidepressants group tricyclic (thymoleptics) activating sedative, anxiolytic II. a III. generation II. generation - activating II. generation - sedative, anxiolytic III. generation - SSRI enhancing 5-HT uptake MAO inhibitors nonselective irreversible subgroup examples desipramine, nortriptyline, protriptyline, dosulepine imipramine, amitriptyline, trimipramine, clomipramine viloxazine, buspirone, amineptine, maprotiline mianserine, trazodone, nefazodone, pirlindol citalopram, fluvoxamine, fluoxetine, sertraline, paroxetine tianeptine phenelzine, tranylcypromine, isocarboxazid
selective MAOI-B irreversible deprenyl selective MAOI-B reversibile selective MAOI-A irreversible selective MAOI-A reversible thymoprophylactics moclobemide, brofaromine, toloxatone, amiflamine 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 5-HT1A 2-AR TRP 5-HT1B 5-HT1A 5-HT1B 5-HT2A 5-HT2C 5-HT3 SERT 5-HT4 ...
5-HT MAO 5-HIAA
B) acute administration of SSRI 5-HT1A
2-AR TRP
5-HT1B
5-HT MAO 5-HIAA SERT
C) chronic treatment by SSRI 5-HT1A
2-AR 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 NE or 5-HT transmission presynaptic 2-AR NE or 5-HT transmission
Figure 3.5. Mechanism of action of reversible inhibitors of MAO-A (RIMA)
TYRAMINE
TYRAMINE
TYRAMINE
serotonin norepinephrine epinephrine
MAO-A
dopamine tyramine tryptamine
TYRAMINE
RIMA
MAO-B
phenylethylamine benzylamine methylhistamine
TYRAMINE
TYRAMINE
TYRAMINE
MAO-A
MAO-B
TYRAMINE
TYRAMINE
RIMA
TYRAMINE
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 alogia affective flattening avolition apathy anhedonia asociality attentional impairment hallucination delusions bizarre behaviour positive formal thought disorder positive
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 mixup 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 norepinephrine serotonin monoaminoxidase revisited dopamine GABAergic glutamatergic peptidergic membrane 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 + 3 GABA -
Glu +
sensory input
striatum
thalamus
DA substantia nigra, area ventralis tegmenti + excitatory action - inhibitory action
B) direct pathways (positive feedback) cerebral cortex behaviour
Glu +
2 GABA +
Glu +
thalamus sensory input
striatum
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 (NMDA antag.) LSD (5-HT2 agon.)
ACh GABA
atropine (M1 antagonist)
amphetamine (DA releaser)
5-HT
nucleus raphe
DA
substantia nigra, area ventralis tegmenti
NE
locus 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-methylD-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 stress chronobiology neurotransmitters receptors postreceptor processes hypothalamic-pituitaryadrenocortical system immune function vulnerability to mental disorders increased sensitivity desynchronisation of biological rhythms availability, metabolism number, affinity, sensitivity G proteins, 2nd messengers, phosphorylation, transcription increased activity during depression different changes during depression
NEUROCHEMISTRY
IMMUNONEUROENDOCRINOLOGY
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 longterm, 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.)
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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 receptors availability metabolism number or density affinity sensitivity postreceptor systems number and activity of G proteins effector enzymes 2nd messengers systems protein kinases phosphatases transcription factors
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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
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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.
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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 adrenergic receptor system 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 treatment by antidepressants ? depression
ACh - acetylcholine, GABA - -amino butyric acid, DA - dopamine, AR adrenoceptors. - increased, - decreased
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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 5HT 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.
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Figure 5.1. Classical noradrenergic receptor hypothesis
5-HT
5-HT
5-HT
NE
NE
NE
DA
DA
DA
DEPRESSION 5-HT NE reuptake NE DA 5-HT NE preNE - receptors postsynaptic DA
MANIA
(See: Lopez D. et al.: The Essential Brain. Current Topics Sci. Med. Merck 1991.)
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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 signalamplification 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 brainderived 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.)
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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 serum cholesterol (3,7-6,5 mmol/l) and lipemia (58 g/l) 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 glycaemia blood picture determination of metabolites of psychotropics in urine or in blood lithemia (0,4-1,2 mmol/l), function of thyroid and kidney (serum creatinine, urea), pH of urine, molality, clearance, serum mineralogram (Na, K) determination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, dopamine metabolite), hydroxyindolacetic acid (HIAA, serotonin metabolite), methoxyhydroxyphenylglycole (MHPG, norepinephrine metabolite) neurotransmitter receptors and transporters cerebrospinal fluid: pH, tension, elements, abundance of globulins (by electrophoresis) neuroendocrinne stimulative or suppressive tests: dexamethasone suppressive test (DST), TRH test, fenfluramine test prolactin determination increased during treatment with neuroleptics research diagnosis of progressive paralysis, depressive disorders research during lithiotherapy diabetes mellitus during pharmacotherapy control or toxicology before pharmacotherapy and in alcoholics Indication brain disease at atherosclerosis
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6. LABORATORY SURVEY IN PSYCHIATRY
Table 6.2. Recommended laboratory survey in selected psychiatric cases

Alcoholism and drug dependence blood picture + differential serum electrolytes, glycaemia, S-urea, creatinine hepatic tests: GGT, AST, ALT, AF total protein, S-albumin prothrombine time serum Ca, P lithic acid toxicological survey of urine alcoholemia screening on syphilis (RRR, BWR) ECG thorax Rtg urine + deposit ordure S-ammonia cranium Rtg or CT HIV survey Anorexia blood picture + differential FW hepatic tests thorax Rtg ECG serum minerals and electrolytes total protein urine + deposit special survey: cortisolemia, thyroid tests, serum prolactin, nephric function, EEG, cranium Rtg or CT, special test on laxative Bulimia glycaemia serum Ca, P ECG toxicological survey of urine special test on laxative Atypical psychosis blood picture + differential serum electrolytes, glycaemia, S-urea, creatinine hepatic tests: GGT, AST, ALT, AF glycaemia nephric function (N-urea, S-creatinine) serum Ca, P thyroidal tests cortisolemia screening on syphilis (RRR, BWR) and Lyme Borreliosis think on hypovitaminosis B12 HIV test at risk person urine + deposit toxicological survey of urine uropophyrine and porphobilinogene in urine thorax Rtg ECG EEG or CT Dementia blood picture + differential serum electrolytes, glycaemia, S-urea, creatinine hepatic tests: GGT, AST, ALT, AF thyroidal tests screening on syphilis (RRR, BWR) think on hypovitaminosis B12 urine + deposit HIV tests cranium Rtg ECG EEG or CT Malign neuroleptic syndrome all basic blood and urine tests S-creatine kinase myoglobin in urine lumbal puncture to rule out CNS infection ECG thorax Rtg
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Table 6.3. Immunological tests Test venereal disease research laboratories (VDRL) Test rapid reagine reaction (RRR) antibodies against Borrelia Burgdorferi complement fixative test antibodies against HIV hepatic tests (ALT, AST) specific test on antigen EBV and antibodies antinuclear antibodies and lupus erytematosus cell preparation syphilis Lyme Borreliosis brucellosis HIV infection hepatitis Epstein-Barr virus (EBV, infectious mononucleosis) and Cytomegalovirus (CMV, seronegative mononucleosis), systemic lupus erytematodes syphilis Indication
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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.
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Introduction To Biological Psychiatry: Rndr. Zdeněk Fišar, CSC

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INTRODUCTION TO BIOLOGICAL PSYCHIATRY

RNDr. Zdenk Fiar, CSc.

This work was supported by FRV 2448/2002 grant.

Zdenk Fiar: Introduction to Biological Psychiatry

LABORATORY SURVEY IN PSYCHIATRY ............................................................................................ 79 REFERENCES....................................................................................................................................................... 83

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.1. Neurone

synaptic vesicles telodendrium

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.2. Glial cells

Figure 1.3. Myelin sheath

node of Ranvier glia axon

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.4. Model of plasma membrane

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.5. Lipid bilayer and function of membrane proteins

lipid bilayer in fluid state

movement perpendicular to membrane

movement in the plane of membrane

lipid bilayer in gel state

Zdenk Fiar: Introduction to Biological Psychiatry

Zdenk Fiar: Introduction to Biological Psychiatry

30 Ion permeability (mS/cm2)

Zdenk Fiar: Introduction to Biological Psychiatry

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

Figure 1.11. Synapses

axo-somatic synapse reverse collaterale axo-axonic synapse

button from node of Ranvier reverse collaterale

presynaptic elements en passant synaptic knob (terminal button)

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

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.12. Chemical synapse - signal transduction

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 1.13. Excitation and inhibition postsynaptic potentials

synaptic vesicles synaptic cleft (released transmitters) postsynaptic membrane

resulted ion current (mV) -65 excitation postsynaptic potential

-65 -70 (mV) 0 4 8 12 time (ms) 16

inhibition postsynaptic potential

resulted ion current

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 excitation

inhibition presynaptic inhibition

Zdenk Fiar: Introduction to Biological Psychiatry

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 2.1. Synthesis and release of acetylcholine

released acetylcholine hydrolysis by acetylcholinesterase choline + acetate

Zdenk Fiar: Introduction to Biological Psychiatry

hypothalamic releasing factors

neurohypophyseal peptides neuronal and endocrine opiate peptides

Zdenk Fiar: Introduction to Biological Psychiatry

Figure 2.4. Membrane transporters

ion channel synaptic vesicle autoreceptor transporter transmitter

POSTSYNAPTIC - Na+/Cl- dependent transporter - vesicular transporter - Na+ dependent transporter

Zdenk Fiar: Introduction to Biological Psychiatry

Fibroblast growth factors Transforming growth factor superfamily

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)

Zdenk Fiar: Introduction to Biological Psychiatry