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

cellular neurochemistrycellular neurochemistry (neurons, action (neurons, action potentials, synapses)potentials, synapses)

intercellular signallingintercellular signalling (neurotran (neurotranssmitters, mitters, receptors, growth factors)receptors, growth factors)

intracellular signallingintracellular signalling (G proteins, (G proteins, effectors, 2effectors, 2ndnd messengers, messengers, proteinkinases, proteinkinases, transcription factors)transcription factors)

psychotropic drugspsychotropic drugs (antipsychotics, (antipsychotics, antidepressants)antidepressants)

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

Biological Psychiatry: Web PagesBiological Psychiatry: Web Pages

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IntroductionIntroduction

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.

Cellular NeurochemistryCellular Neurochemistry

NNeuronseurons AAction potentialsction potentials SSynapsesynapses

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

NNeurotransmitterseurotransmitters GGrowth factorsrowth factors RReceptorseceptors G proteinsG proteins EEffectorffector ssystems (ystems (22ndnd messengers, messengers,

proteinkinases, proteinkinases, transcription factors)transcription factors)

Criteria to Identify Neurotransmitters Criteria to Identify Neurotransmitters

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

There are two main groups of neurotransmitters:• classical neurotransmitters • neuropeptides

Selected Classical Neurotransmitters Selected Classical Neurotransmitters

System Transmitter

Cholinergic acetylcholine

Aminoacidergic GABA, aspartic acid, glutamic acid, glycine, homocysteine

Monoaminergic• Catecholamines dopamine, norepinephrine,

epinephrine• Indolamines tryptamine, serotonin• Others, related to

aahistamine, taurine

Purinergic adenosine, ADP, AMP, ATP

nitric oxide

Catecholamine Biosynthesis Catecholamine Biosynthesis

Serotonin Biosynthesis Serotonin Biosynthesis

Reuptake and MReuptake and Metabolism of etabolism of MMonoamine onoamine NNeurotransmitterseurotransmitters

ReuptakeReuptake Monoamine oxidase (MAO)Monoamine oxidase (MAO) Catechol-Catechol-OO-methyltransferase (COMT)-methyltransferase (COMT)

Selected Bioactive Peptides Selected Bioactive Peptides Peptide Group

substance P, substance K (tachykinins), neurotensin, cholecystokinin (CCK), gastrin, bombesin

brain and gastrointestinal peptides

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

neuronal

cortikotropin releasing hormone (CRH)hypothalamic releasing factors

growth hormone releasing hormone (GHRH), gonadotropin releasing hormone (GnRH), somatostatin, thyrotropin releasing hormone (TRH)

adrenocorticotropic hormone (ACTH)pituitary hormonesgrowth hormone (GH), prolactin (PRL), lutenizing

hormone (LH), thyrotropin (TSH)

oxytocin, vasopressin neurohypophyseal peptides

atrial natriuretic peptide (ANF), vasoactive intestinal peptide (VIP)

neuronal and endocrine

enkephalines (met-, leu-), dynorphin, -endorphin opiate peptides

Growth Factors in the Nervous System Growth Factors in the Nervous System Neurotrophins Nerve growth factor (NGF)

Brain-derived neurotrophic factor (BDNF)Neurotrophin 3 (NT3)Neurotrophin 4/5 (NT4/5)

Neurokines Ciliary neurotrophic factor (CNTF)Leukemia inhibitory factor (LIF)Interleukin 6 (IL-6)Cardiotrophin 1 (CT-1)

Fibroblast growth factors

FGF-1FGF-2

Transforming growth factor superfamily

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)

Membrane Receptors Membrane Receptors

ReceptorReceptor is macromolecule is macromolecule specialized on transmission of specialized on transmission of information.information.

Receptor complex includes:Receptor complex includes:

1.1. Specific binding siteSpecific binding site

2.2. Internal ion channel or tInternal ion channel or transduction ransduction elementelement

3.3. Effector system (Effector system (ion channels or ion channels or system of system of 22ndnd messengers) messengers)

Regulation of receptorsRegulation of receptors

1.1. DensityDensity of receptors (down-regulation, of receptors (down-regulation, up-regulation)up-regulation)

2.2. Properties of receptors Properties of receptors (desensitisation, hypersensitivity)(desensitisation, hypersensitivity)

Receptor Classification Receptor Classification

1.1. Receptor coupled directly to the ion Receptor coupled directly to the ion channelchannel

2.2. Receptor associated with G proteinsReceptor associated with G proteins

3.3. Receptor with intrinsic guanylyl Receptor with intrinsic guanylyl cyclase activitycyclase activity

4.4. Receptor with intrinsic tyrosine Receptor with intrinsic tyrosine kinase activitykinase activity

1. 1. Receptors with Receptors with IInternal nternal IIon on CChannelhannel

1. 1. Receptors with Receptors with IInternal nternal IIon on CChannelhannel

acetylcholine

membrane

receptor

acetylcholine

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

1. 1. Receptors with internal ion channelReceptors with internal ion channel

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

2. 2. Receptors Receptors Associated with Associated with

G ProteinsG Proteins

1. adenylyl cyclase system

2. phosphoinositide system

3. arachidonic acid system

Receptors Associated with G ProteinsReceptors Associated with G Proteins

SYSTEMAdenylyl cyclase system

Phosphoinositide system

Arachidonic acid system

NEURO-TRANSMITTER

NE, 5-HT, DA, Ach

NE, 5-HT, DA, Ach Histamine

TRANSDUCER Gs, Gi GpUnknown G-protein

PRIMARY EFFECTOR

Adenylyl cyclase Phospholipase C Phospholipase A

SECONDARY MESSENGER

cAMP IP3, DAG, Ca++ Arachidonic acid

SECONDARY EFFECTOR

•Protein kinase A

•Calcium and calmoduline dependent protein kinases •Protein kinase C

•5-Lipoxygenase•12-Lipoxygenase•Cycloxygenase

TypeTypess of Receptors of Receptors System Type

acetylcholinergic acetylcholine nicotinic receptors

acetylcholine muscarinic receptors

monoaminergic 1-adrenoceptors

2-adrenoceptors

-adrenoceptors

dopamine receptors

serotonin receptor

aminoacidergic GABA receptors

glutamate ionotropic receptors

glutamate metabotropic receptors

glycine receptors

histamine receptors

peptidergic opioid receptors

other peptide receptors

purinergic adenosine receptors (P1 purinoceptors)

P2 purinoceptors

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

watchfulness (vigility)

positive psychostimulant drugs

negative hypnotic drugs

affectivity positive antidepressants

anxiolytics

negative dysphoric drugs

psychic integrations

positive neuroleptics, atypical antipsychotics

negative hallucinogenic agents

memory positive nootropics

negative amnestic drugs

Main PsychoMain Psychotropictropic Drugs Drugs

AntipsychoticsAntipsychotics AntidepressantsAntidepressants AnxiolyticsAnxiolytics HypnoticsHypnotics CognitivesCognitives PsychostimulantsPsychostimulants HallucinogensHallucinogens

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

Group Examples

Conventional antipsychotics(classical neuroleptics)

chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine

droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine

Atypical antipsychotics(antipsychotics of 2nd generation)

amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazole

Mechanisms of Action of Mechanisms of Action of Antipsychotics Antipsychotics

Conventional antipsychotics

D2 receptor blockade of postsynaptic in the mesolimbic pathway

Atypical antipsychotics

D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms;

enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms;

other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

Receptor Systems Affected by Atypical AntipsychoticsReceptor Systems Affected by Atypical Antipsychotics

risperidone D2, 5-HT2A, 5-HT7, 1, 2

sertindole D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1

ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, 1, NRI, SRI

loxapine D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, M1, H1, NRI

zotepine D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, 1, H1, NRI

clozapine D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1

olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, 1, M1-5, H1

quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1

aripiprazole D2, 5-HT2A, 5-HT1A, 1, 2, H1

Classification of AntidepressantsClassification of Antidepressants (based on acute pharmacological actions)(based on acute pharmacological actions)

Inhibitors of neurotransmitter catabolism

• monoamine oxidase inhibitors (IMAO)

Reuptake inhibitors

• serotonin reuptake inhibitors (SRI)• norepinephrine reuptake inhibitors (NRI)• selective SRI (SSRI)• selective NRI (SNRI)• serotonin/norepinephrine inhibitors (SNRI)• norepinephrine and dopamine reuptake

inhibitors (NDRI)• 5-HT2A antagonist/reuptake inhibitors (SARI)

Agonists of receptors

• 5-HT1A

Antagonists of receptors

2-AR• 5-HT2

Inhibitors or stimulators of other components of signal transduction

Action of Action of SSRISSRI

Biological Hypotheses of Mental Biological Hypotheses of Mental DisordersDisorders

SSchizophreniachizophrenia AAffective disordersffective disorders

SchizophreniaSchizophrenia

Biological modelsBiological models of schizophrenia of schizophrenia can be divided into can be divided into fourfour related related classes:classes:

Environmental modelsEnvironmental models Genetic modelsGenetic models Neurodevelopmental modelsNeurodevelopmental models Dopamine hypothesisDopamine hypothesis

Schizophrenia - Genetic Models Schizophrenia - Genetic Models

Multifactorial-polygenic threshold Multifactorial-polygenic threshold modelmodel::

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.

Schizophrenia - Schizophrenia - Neurodevelopmental Models Neurodevelopmental Models

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.

3.3. AntipsychoticsAntipsychotics raise dopamine turnover. raise dopamine turnover.

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

NEUROCHEMISTRY neurotransmitters availability, metabolism

receptors number, affinity, sensitivity

postreceptor processes

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.

Permissive Biogenic Amine Permissive Biogenic Amine Hypothesis Hypothesis

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.

Classical norepinephrine receptor Classical norepinephrine receptor hypothesishypothesis::

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

cellularcellular theory) theory) of depressionof depression:: Transcription factor, Transcription factor, cAMP response element-cAMP response element-

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

Nestler et al. 2002

Antidepressant TreatmentsAntidepressant Treatments

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