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- 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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- cellular neurochemistry (neurons, action potentials, synapses)
- intercellular signalling (neurotransmitters, receptors, growth fact=
ors)
- 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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- 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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- 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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- Neurons
- Action potentials
- Synapses
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- Neuron
- The neurons are the brain cells that are responsible for intracellu=
lar
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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- 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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- Neurotransmitters
- Growth factors
- Receptors
- G proteins
- Effector systems (2nd messengers, proteinkinases, transc=
ription
factors)
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- Reuptake
- Monoamine oxidase (MAO)
- Catechol-O-methyltransferase (COMT)
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- Receptor is macromolecule specialized on transmission of informatio=
n.
- Receptor complex includes:
- Specific binding site
- Internal ion channel or transduction element
- Effector system (ion channels or system of 2nd messenge=
rs)
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- Density of receptors (down-regulation, up-regulation)
- Properties of receptors (desensitisation, hypersensitivity)
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- 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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- 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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- Antipsychotics
- Antidepressants
- Anxiolytics
- Hypnotics
- Cognitives
- Psychostimulants
- Hallucinogens
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- Schizophrenia
- Affective disorders
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- Biological models of schizophrenia can be divided into four related
classes:
- Environmental models
- Genetic models
- Neurodevelopmental models
- Dopamine hypothesis
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- 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 distribu=
tion
of a continuous trait, and there may be a threshold for the clinical
expression of the disease.
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- A substantial group of patients, who receive diagnosis of schizophr=
enia
in adult life, have experienced a disturbance of the orderly develo=
pment
of the brain decades before the symptomatic phase of the illness.=
li>
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- Dopamine-releasing drugs (amphetamine, mescaline, LSD) can induce s=
tate
closely resembling paranoid schizophrenia.
- Antipsychotics, that are effective in the treatment of schizophreni=
a,
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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- 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 receptor=
s.
This increased activity can be localized in specific brain regions.=
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- 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 sym=
ptoms
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 pathophysi=
ology
of affective disorders.
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- 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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- The common final result of chronic treatment by majority of
antidepressants is the down-regulation or up-regulation of postsyna=
ptic
or presynaptic receptors.
- The delay of clinical response corresponds with these receptor
alterations.
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- 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 b-AR in depression. Long-term antidepressant treatment
causes down regulation of b1-AR. Transient increase of neurotransmit=
ter
availability can cause fault to mania.
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- Neurotrophic hypothesis (molecular and cellular theory) of depressi=
on:
- 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 stre=
ss
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 antidepress=
ant
treatment leads to increase in expression of BDNF and his receptor =
trkB
through elevated function of serotonin and norepinephrine systems.<=
/li>
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