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Biochemistry and Biological Psychiatry ass. prof. Zdeněk Fišar , CSc. Department of Psychiatry 1 st Faculty of Medicine Charles University, Prague Head: prof. MUDr. Jiří Raboch, DrSc. Biochemistry and B iological P sychiatry

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Biochemistry and Biological Psychiatry

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Biochemistry and biological psychiatry l.jpg

Biochemistry and Biological Psychiatry

ass. prof. Zdeněk Fišar, CSc.

Department of Psychiatry

1st Faculty of Medicine

Charles University, Prague

Head: prof. MUDr. Jiří Raboch, DrSc.


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Biochemistry and Biological Psychiatry

  • cellular neurochemistry (neurons, action potentials, synapses)

  • intercellular signalling (neurotransmitters, receptors, growth factors)

  • intracellular signalling (G proteins, effectors, 2nd messengers, proteinkinases, transcription factors)

  • psychotropic drugs (antipsychotics, antidepressants)

  • biological hypotheses of mental disorders (schizophrenia, affective disorders)


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Biological Psychiatry: Web Pages

1. Educational portal of our faculty:

  • http://connect.lf1.cuni.cz

  • http://portal.lf1.cuni.cz/

    (section Psychiatry, Psychology, Sexuology)

    2. Direct links:

  • http://www.lf1.cuni.cz/zfisar/psychiatry/

    (presentation of lectures from psychiatry)

  • http://psych.lf1.cuni.cz/bpen/default.htm

    (teaching material from biological psychiatry)


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Introduction

  • Biological psychiatry studies disorders in human mind from the neurochemical, neuroendocrine and genetic point of view mainly.

  • It is postulated that changes in brain signal transmission (at the level of chemical synapse) are essential in the development of mental disorders.


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Cellular Neurochemistry

  • Neurons

  • Action potentials

  • Synapses


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Neuron

The neurons are the brain cells that are responsible for intracellular and intercellular signalling.

Action potential is large and rapidly reversible fluctuation in the membrane potential, that propagate along the axon.

At the end of axon there are many nerve endings (synaptic terminals, presynaptic parts, synaptic buttons, knobs). Nerve ending form an integral parts of synapse.

Synapse mediates the signal transmission from one neuron to another.


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Synapse

  • Neurons communicate with one another by

    • direct electrical coupling

    • secretion of neurotransmitters

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


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Morphology of Chemical Synapse


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Chemical Synapse - Signal Transduction


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Model of Plasma Membrane


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Membrane Transporters


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Intercellular and Intracellular Signalling

  • Neurotransmitters

  • Growth factors

  • Receptors

  • G proteins

  • Effectorsystems (2nd messengers, proteinkinases, transcription factors)


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Criteria to Identify Neurotransmitters

  • There are two main groups of neurotransmitters:

  • classical neurotransmitters

  • neuropeptides


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Selected Classical Neurotransmitters

nitric oxide


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Catecholamine Biosynthesis


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Serotonin Biosynthesis


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Reuptake and Metabolism of Monoamine Neurotransmitters

  • Reuptake

  • Monoamine oxidase (MAO)

  • Catechol-O-methyltransferase (COMT)


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Selected Bioactive Peptides


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Growth Factors in the Nervous System


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Membrane Receptors

  • Receptor is macromolecule specialized on transmission of information.

  • Receptor complex includes:

    • Specific binding site

    • Internal ion channel or transduction element

    • Effector system (ion channels or system of 2nd messengers)


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Regulation of receptors

  • Density of receptors (down-regulation, up-regulation)

  • Properties of receptors (desensitisation, hypersensitivity)


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Receptor Classification

  • Receptor coupled directly to the ion channel

  • Receptor associated with G proteins

  • Receptor with intrinsic guanylyl cyclase activity

  • Receptor with intrinsic tyrosine kinase activity


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1. Receptors with Internal Ion Channel


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acetylcholine

membrane

receptor

acetylcholine

1. Receptors with Internal Ion Channel

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


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1. Receptors with internal ion channel

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


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2. Receptors Associated with G Proteins

  • adenylyl cyclase system

  • phosphoinositide system

  • arachidonic acid system


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Receptors Associated with G Proteins


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Types of Receptors


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Subtypes of Norepinephrine Receptors


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Subtypes of Dopamine Receptors


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Subtypes of Serotonin Receptors


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Feedback to Transmitter-Releasing


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Crossconnection of Transducing Systems on Postreceptor Level

AR – adrenoceptor

G – G protein

PI-PLC – phosphoinositide specific phospholipase C

IP3 – inositoltriphosphate

DG – diacylglycerol

CaM – calmodulin

AC – adenylyl cyclase

PKC – protein kinase C


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Psychotropic Drugs

Biochemical hypotheses of mental disorders are based on the study of mechanisms of action of psychotropic drugs at the level of:

  • chemical synapse

  • intracellular processes connected with signal transduction


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Classification of Psychotropics


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Main Psychotropic Drugs

  • Antipsychotics

  • Antidepressants

  • Anxiolytics

  • Hypnotics

  • Cognitives

  • Psychostimulants

  • Hallucinogens


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Potential Action of Psychotropics


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Classification of Antipsychotics


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Mechanisms of Action of Antipsychotics


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Receptor Systems Affected by Atypical Antipsychotics


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Classification of Antidepressants(based on acute pharmacological actions)


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Action of SSRI


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Biological Hypotheses of Mental Disorders

  • Schizophrenia

  • Affective disorders


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Schizophrenia

Biological models of schizophrenia can be divided into four related classes:

  • Environmental models

  • Genetic models

  • Neurodevelopmental models

  • Dopamine hypothesis


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Schizophrenia - Genetic Models

Multifactorial-polygenic threshold model:

  • Schizophrenia is the result of a combined effect of multiple genes interacting with variety of environmental factors.

  • The liability to schizophrenia is linked to one end of the distribution of a continuous trait, and there may be a threshold for the clinical expression of the disease.


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Schizophrenia - Neurodevelopmental Models

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


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Basis of Classical Dopamine Hypothesis of Schizophrenia

  • Dopamine-releasing drugs (amphetamine, mescaline, LSD) can induce state closely resembling paranoid schizophrenia.

  • Antipsychotics, that are effective in the treatment of schizophrenia, have in common the ability to inhibit the dopaminergic system by blocking action of dopamine in the brain.

  • Antipsychotics raise dopamine turnover.


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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.


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Biological Psychiatry and Affective Disorders


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Data for Neurotransmitter Hypothesis


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Monoamine Hypothesis

Depression was due to a deficiency of monoamine neurotransmitters, norepinephrine and serotonin.

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


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Permissive Biogenic Amine Hypothesis

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


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Receptor Hypotheses

  • The common final result of chronic treatment by majority of antidepressants is the down-regulation or up-regulation of postsynaptic or presynaptic receptors.

  • The delay of clinical response corresponds with these receptor alterations.


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Receptor Hypotheses

Receptor catecholamine hypothesis:

  • Supersensitivity of catecholamine receptors in the presence of low levels of serotonin is the biochemical basis of depression.

    Classical norepinephrine receptor hypothesis:

  • There is increased density of postsynaptic -AR in depression. Long-term antidepressant treatment causes down regulation of 1-AR. Transient increase of neurotransmitter availability can cause fault to mania.


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Neurotransmitter Regulation of Mood and Behavior

Motivation

Pleasure

Reward

Alertness

Energy

Dopamine

Norepinephrine

Attention

Interest

Obsession

Compulsion

Mood

Anxiety

Serotonin

Nutt 2008


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Postreceptor Hypotheses

Neurotrophic hypothesis(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.

Duman et al. 1997


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Neurotrophic Effects of Antidepressants

Nestler et al. 2002


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Antidepressant Treatments


Thank you for your attention web pages http connect lf1 cuni cz http portal lf1 cuni cz l.jpg

Thank you for your attentionWeb pages:http://connect.lf1.cuni.czhttp://portal.lf1.cuni.cz


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