Biochemistry and Biochemistry and Biological Biological Psychiatry Psychiatry ass. prof. ass. prof. Zdeněk Fišar Zdeněk Fišar , CSc. , CSc. Department of Psychiatry Department of Psychiatry 1 1 st st Faculty of Medicine Faculty of Medicine Charles University, Prague Charles University, Prague Head: prof. MUDr. Jiří Raboch, Head: prof. MUDr. Jiří Raboch, DrSc. DrSc.
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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:
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Biochemistry and Biochemistry and Biological PsychiatryBiological Psychiatry
ass. prof. ass. prof. Zdeněk FišarZdeněk Fišar, CSc., CSc.
Department of PsychiatryDepartment of Psychiatry11stst Faculty of Medicine Faculty of Medicine
Charles University, PragueCharles University, PragueHead: prof. MUDr. Jiří Raboch, DrSc.Head: prof. MUDr. Jiří Raboch, DrSc.
Biochemistry and Biochemistry and BBiological iological PPsychiatrysychiatry
2. Direct links:2. Direct links: http://www.lf1.cuni.cz/zfisar/psychiatry/http://www.lf1.cuni.cz/zfisar/psychiatry/
(presentation of lectures from psychiatry)(presentation of lectures from psychiatry) http://psych.lf1.cuni.cz/bpen/default.htmhttp://psych.lf1.cuni.cz/bpen/default.htm
(teaching material from biological psychiatry)(teaching material from biological psychiatry)
Biological psychiatry studies disorders Biological psychiatry studies disorders in human mind from the in human mind from the neurochemical, neuroendocrine and neurochemical, neuroendocrine and genetic point of view mainly. genetic point of view mainly.
It is postulated that changes in brain It is postulated that changes in brain signal transmission (at the level of signal transmission (at the level of chemical synapse) are essential in the chemical synapse) are essential in the development of mental disorders.development of mental disorders.
NeuronNeuron The The neuronsneurons are the are the
brain cells that are brain cells that are responsible for responsible for intracellular and intracellular and intercellular signalling.intercellular signalling.
Action potentialAction potential is is large and rapidly large and rapidly reversible fluctuation in reversible fluctuation in the membrane potential, the membrane potential, that propagate along the that propagate along the axon.axon.
At the end of axon there At the end of axon there are many are many nerve nerve endingsendings (synaptic (synaptic terminals, presynaptic terminals, presynaptic parts, synaptic buttons, parts, synaptic buttons, knobs). Nerve ending knobs). Nerve ending form an integral parts of form an integral parts of synapse. synapse.
SynapseSynapse mediates the mediates the signal transmission from signal transmission from one neuron to another.one neuron to another.
SynapseSynapse
Neurons communicate with one Neurons communicate with one another by another by • direct electrical couplingdirect electrical coupling• secretion of neurotransmitterssecretion of neurotransmitters
SynapsesSynapses are specialized structures are specialized structures for signal transduction from one for signal transduction from one neuron to other. Chemical synapses neuron to other. Chemical synapses are studied in the biological are studied in the biological psychiatry.psychiatry.
Morphology of Chemical Synapse Morphology of Chemical Synapse
Chemical Chemical Synapse - Synapse -
Signal Signal Transduction Transduction
Model of Plasma Membrane Model of Plasma Membrane
Membrane Membrane Transporters Transporters
Intercellular and Intracellular Intercellular and Intracellular SignallingSignalling
Subtypes of Norepinephrine Subtypes of Norepinephrine Receptors Receptors
RECEPTORS Subtype Transducer Structure (aa/TM)
1-adrenoceptors 1A Gq/11 IP3/DAG 466/7
1B Gq/11 IP3/DAG 519/7
1D Gq/11 IP3/DAG 572/7
2-adrenoceptors 2A Gi/o cAMP 450/7
2B Gi/o cAMP 450/7
2C Gi/o cAMP 461/7
2D Gi/o cAMP 450/7
-adrenoceptors 1 Gs cAMP 477/7
2 Gs cAMP 413/7
3 Gs, Gi/o cAMP 408/7
Subtypes of Dopamine ReceptorsSubtypes of Dopamine Receptors
RECEPTORS Subtype Transducer Structure (aa/TM)
dopamine D1 Gs cAMP 446/7
D2 Gi
Gq/11 cAMPIP3/DAG, K+, Ca2+
443/7
D3 Gi cAMP 400/7
D4 Gi cAMP, K+ 386/7
D5 Gs cAMP 477/7
Subtypes of Serotonin ReceptorsSubtypes of Serotonin ReceptorsRECEPTORS Subtype Transducer Structure
5-HT(5-hydroxytryptamine)
5-HT1A Gi/o cAMP 421/7
5-HT1B Gi/o cAMP 390/7
5-HT1D Gi/o cAMP 377/7
5-ht1E Gi/o cAMP 365/7
5-ht1F Gi/o cAMP 366/7
5-HT2A Gq/11 IP3/DAG 471/7
5-HT2B Gq/11 IP3/DAG 481/7
5-HT2C Gq/11 IP3/DAG 458/7
5-HT3 internal cationic channel
478
5-HT4 Gs cAMP 387/7
5-ht5A ? 357/7
5-ht6 Gs cAMP 440/7
5-HT7 Gs cAMP 445/7
Feedback to Transmitter-Releasing Feedback to Transmitter-Releasing
Crossconnection of Transducing Crossconnection of Transducing Systems on Postreceptor Level Systems on Postreceptor Level
AR – adrenoceptorG – G proteinPI-PLC – phosphoinositide
specific phospholipase CIP3 – inositoltriphosphateDG – diacylglycerolCaM – calmodulinAC – adenylyl cyclasePKC – protein kinase C
Psychotropic DrugsPsychotropic Drugs
Biochemical hypotheses of mental disorders Biochemical hypotheses of mental disorders are based on the study of mechanisms of are based on the study of mechanisms of action of action of psychotropic drugspsychotropic drugs at the level of: at the level of:
• chemical synapsechemical synapse
• intracellular processes connected with intracellular processes connected with signal transductionsignal transduction
Classification of Psychotropics Classification of Psychotropics parameter effect group
Potential Action of Psychotropics Potential Action of Psychotropics 1. Synthesis and storage of
neurotransmitters2. Releasing of neurotransmitters3. Receptor-neurotransmitter
interactions (agonists, antagonists)4. Catabolism of neurotransmitters5. Reuptake of neurotransmitters6. Transduction element (G protein)7. Effector's system8. Transcription factor activity and gene
expression
Classification of Antipsychotics Classification of Antipsychotics
Schizophrenia is the result of a combined Schizophrenia is the result of a combined effect of multiple genes interacting with effect of multiple genes interacting with variety of environmental factors. variety of environmental factors.
The liability to schizophrenia is linked to The liability to schizophrenia is linked to one end of the distribution of a continuous one end of the distribution of a continuous trait, and there may be a threshold for the trait, and there may be a threshold for the clinical expression of the disease.clinical expression of the disease.
A substantial group of patients, who A substantial group of patients, who receive diagnosis of schizophrenia in receive diagnosis of schizophrenia in adult life, have experienced a adult life, have experienced a disturbance of the orderly development disturbance of the orderly development of the brain decades before the of the brain decades before the symptomatic phase of the illness.symptomatic phase of the illness.
Basis of Classical Dopamine Basis of Classical Dopamine Hypothesis of Schizophrenia Hypothesis of Schizophrenia
1.1. Dopamine-releasing drugs (amphetamine, Dopamine-releasing drugs (amphetamine, mescaline, LSD) can induce state closely mescaline, LSD) can induce state closely resembling paranoid schizophrenia.resembling paranoid schizophrenia.
2.2. AntipsychoticsAntipsychotics, that are effective in the , that are effective in the treatment of schizophrenia, have in treatment of schizophrenia, have in common the ability to inhibit the common the ability to inhibit the dopaminergic system by blocking action of dopaminergic system by blocking action of dopamine in the brain.dopamine in the brain.
Classical Dopamine Hypothesis of Classical Dopamine Hypothesis of SchizophreniaSchizophrenia
PPsychotic symptoms are related to sychotic symptoms are related to dopaminergic hyperactivity in the dopaminergic hyperactivity in the brain. Hyperactivity of dopaminergic brain. Hyperactivity of dopaminergic systems during schizophrenia is result systems during schizophrenia is result of increased sensitivity and density of of increased sensitivity and density of dopamine D2 receptors. This increased dopamine D2 receptors. This increased activity can be localized in specific activity can be localized in specific brain regions.brain regions.
Biological Psychiatry and Biological Psychiatry and Affective Disorders Affective Disorders
BIOLOGY genetics vulnerability to mental disorders
stress increased sensitivity
chronobiology desynchronisation of biological rhythms
G proteins, 2nd messengers, phosphorylation, transcription
IMMUNONEURO-ENDOCRINOLOGY
HPA (hypothalamic-pituitary-adrenocortical) system
increased activity during depression
immune function different changes during depression
Data for Neurotransmitter Data for Neurotransmitter Hypothesis Hypothesis
1. Tricyclic antidepressants through blockade of neurotransmitter reuptake increase neurotransmission at noradrenergic and serotonergic 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
Monoamine Hypothesis Monoamine Hypothesis
Depression was due to a deficiency of Depression was due to a deficiency of monoamine neurotransmitters, monoamine neurotransmitters, norepinephrine and serotonin.norepinephrine and serotonin.
AAdvanced monoamine theorydvanced monoamine theory:: serotonin or serotonin or norepinephrine levels in the brain are norepinephrine levels in the brain are regulated by MAO-A activity mainly. However, regulated by MAO-A activity mainly. However, specific symptoms of depression or mania are specific symptoms of depression or mania are related to changes in the activity of related to changes in the activity of monoamine transporters in specific brain monoamine transporters in specific brain regions. So, both MAO-A activity and density regions. So, both MAO-A activity and density of transporters are included in the of transporters are included in the pathophysiology of affective disorders.pathophysiology of affective disorders.
A deficit in central A deficit in central serotonergicserotonergic transmission transmission permits affective disorder, but is insufficient permits affective disorder, but is insufficient for its cause; changes in central for its cause; changes in central catecholaminergic transmission, when they catecholaminergic transmission, when they occur in the context of a deficit in occur in the context of a deficit in serotonergicserotonergic transmission, act as a transmission, act as a proximate cause for affective disorders and proximate cause for affective disorders and determine their qualitydetermine their quality ( (catecholaminergic catecholaminergic transmission being elevated in mania and transmission being elevated in mania and diminished in depressiondiminished in depression))..
Receptor Hypotheses Receptor Hypotheses
The common final result of chronic The common final result of chronic treatment by majority of treatment by majority of antidepressants is the down-antidepressants is the down-regulation or up-regulation of regulation or up-regulation of postsynaptic or presynaptic receptors. postsynaptic or presynaptic receptors.
The delay of clinical response The delay of clinical response corresponds with these receptor corresponds with these receptor alterations.alterations.
Receptor HypothesesReceptor HypothesesRReceptor catecholamine hypothesiseceptor catecholamine hypothesis:: Supersensitivity of catecholamine receptors Supersensitivity of catecholamine receptors
in the presence of low levels of serotonin is in the presence of low levels of serotonin is the biochemical basis of depression.the biochemical basis of depression.
There is increased density of postsynaptic There is increased density of postsynaptic -AR in depression-AR in depression.. Long-term Long-term antidepressant treatment causes down antidepressant treatment causes down regulation of regulation of 11-AR-AR. . Transient increase of Transient increase of neurotransmitter availability can cause neurotransmitter availability can cause fault to mania.fault to mania.
Neurotransmitter Regulation of Neurotransmitter Regulation of Mood and BehaviorMood and Behavior
Nutt 2008
MotivationPleasureReward
AlertnessEnergy
ObsessionCompulsion
Dopamine Norepinephrine
Serotonin
Mood
AttentionInterest
Anxiety
Postreceptor Hypotheses Postreceptor Hypotheses Neurotrophic hypothesisNeurotrophic hypothesis (m(molecular and olecular and
binding proteinbinding protein (CREB), is one intracellular target (CREB), is one intracellular target of long-term antidepressant treatment and of long-term antidepressant treatment and brain-brain-derived neurotrophic factorderived neurotrophic factor (BDNF) is one (BDNF) is one target gene of CREB. Chronic stress leads to target gene of CREB. Chronic stress leads to decrease in expression of BDNF in hippocampus. decrease in expression of BDNF in hippocampus. Long-term increase in levels of glucocorticoids, Long-term increase in levels of glucocorticoids, ischemia, neurotoxins, hypoglycaemia etc. ischemia, neurotoxins, hypoglycaemia etc. decreases neuron survival. Long-term decreases neuron survival. Long-term antidepressant treatment leads to increase in antidepressant treatment leads to increase in expression of BDNF and his receptor trkB through expression of BDNF and his receptor trkB through elevated function of serotonin and norepinephrine elevated function of serotonin and norepinephrine systems.systems.
Duman et al. 1997
Neurotrophic Effects of AntidepressantsNeurotrophic Effects of Antidepressants