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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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1 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.

2 Biochemistry and Biological Psychiatry cellular neurochemistry (neurons, action potentials, synapses) cellular neurochemistry (neurons, action potentials, synapses) intercellular signalling (neurotransmitters, receptors, growth factors) intercellular signalling (neurotransmitters, receptors, growth factors) intracellular signalling (G proteins, effectors, 2 nd messengers, proteinkinases, transcription factors) intracellular signalling (G proteins, effectors, 2 nd messengers, proteinkinases, transcription factors) psychotropic drugs (antipsychotics, antidepressants) psychotropic drugs (antipsychotics, antidepressants) biological hypotheses of mental disorders (schizophrenia, affective disorders) biological hypotheses of mental disorders (schizophrenia, affective disorders)

3 Biological Psychiatry: Web Pages 1. Educational portal of our faculty: (section Psychiatry, Psychology, Sexuology) 2. Direct links: (presentation of lectures from psychiatry) (teaching material from biological psychiatry)

4 Introduction Biological psychiatry studies disorders in human mind from the neurochemical, neuroendocrine and genetic point of view mainly. 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. It is postulated that changes in brain signal transmission (at the level of chemical synapse) are essential in the development of mental disorders.

5 Cellular Neurochemistry Neurons Neurons Action potentials Action potentials Synapses Synapses

6 Neuron The neurons are the brain cells that are responsible for intracellular and intercellular signalling. 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. 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. 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. Synapse mediates the signal transmission from one neuron to another.

7 Synapse Neurons communicate with one another by Neurons communicate with one another by direct electrical couplingdirect electrical coupling secretion of neurotransmitterssecretion of neurotransmitters Synapses are specialized structures for signal transduction from one neuron to other. Chemical synapses are studied in the biological psychiatry. Synapses are specialized structures for signal transduction from one neuron to other. Chemical synapses are studied in the biological psychiatry.

8 Morphology of Chemical Synapse

9 Chemical Synapse - Signal Transduction

10 Model of Plasma Membrane

11 Membrane Transporters

12 Intercellular and Intracellular Signalling Neurotransmitters Neurotransmitters Growth factors Growth factors Receptors Receptors G proteins G proteins Effector systems (2 nd messengers, proteinkinases, transcription factors) Effector systems (2 nd messengers, proteinkinases, transcription factors)

13 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

14 Selected Classical Neurotransmitters SystemTransmitter Cholinergicacetylcholine AminoacidergicGABA, aspartic acid, glutamic acid, glycine, homocysteine Monoaminergic Catecholaminesdopamine, norepinephrine, epinephrine Indolaminestryptamine, serotonin Others, related to aa histamine, taurine Purinergicadenosine, ADP, AMP, ATP nitric oxide

15 Catecholamine Biosynthesis

16 Serotonin Biosynthesis

17 Reuptake and Metabolism of Monoamine Neurotransmitters Reuptake Reuptake Monoamine oxidase (MAO) Monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT) Catechol-O-methyltransferase (COMT)

18 Selected Bioactive Peptides PeptideGroup 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 hormones growth 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

19 Growth Factors in the Nervous System NeurotrophinsNerve growth factor (NGF) Brain-derived neurotrophic factor (BDNF) Neurotrophin 3 (NT3) Neurotrophin 4/5 (NT4/5) NeurokinesCiliary neurotrophic factor (CNTF) Leukemia inhibitory factor (LIF) Interleukin 6 (IL-6) Cardiotrophin 1 (CT-1) Fibroblast growth factors FGF-1 FGF-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 factorsPlatelet-derived growth factor (PDGF) Insulin-like growth factor I (IGF-I)

20 Membrane Receptors Receptor is macromolecule specialized on transmission of information. Receptor is macromolecule specialized on transmission of information. Receptor complex includes: Receptor complex includes: 1.Specific binding site 2.Internal ion channel or transduction element 3.Effector system (ion channels or system of 2 nd messengers)

21 Regulation of receptors 1.Density of receptors (down-regulation, up-regulation) 2.Properties of receptors (desensitisation, hypersensitivity)

22 Receptor Classification 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

23 1. Receptors with Internal Ion Channel

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

25 1. Receptors with internal ion channel GABA A receptor, nicotonic acetylcholine receptors, ionotropic glutamate receptors, etc.

26 2. Receptors Associated with G Proteins 1.adenylyl cyclase system 2.phosphoinositide system 3.arachidonic acid system

27 Receptors Associated with G Proteins SYSTEM Adenylyl cyclase system Phosphoinositide system Arachidonic acid system NEURO- TRANSMITTER NE, 5-HT, DA, Ach Histamine TRANSDUCERG s, G i GpGp Unknown G- protein PRIMARY EFFECTOR Adenylyl cyclasePhospholipase CPhospholipase A SECONDARY MESSENGER cAMPIP 3, DAG, Ca++Arachidonic acid SECONDARY EFFECTOR Protein kinase A Calcium and calmoduline dependent protein kinases Protein kinase C 5-Lipoxygenase 12-Lipoxygenase Cycloxygenase

28 Types of Receptors SystemType acetylcholinergicacetylcholine nicotinic receptors acetylcholine muscarinic receptors monoaminergic  1 -adrenoceptors  2 -adrenoceptors -adrenoceptors dopamine receptors serotonin receptor aminoacidergicGABA receptors glutamate ionotropic receptors glutamate metabotropic receptors glycine receptors histamine receptors peptidergicopioid receptors other peptide receptors purinergicadenosine receptors (P 1 purinoceptors) P 2 purinoceptors

29 Subtypes of Norepinephrine Receptors RECEPTORSSubtypeTransducerStructure (aa/TM)  1 -adrenoceptors 1A G q/11 IP 3 /DAG 466/7  1B G q/11 IP 3 /DAG 519/7  1D G q/11 IP 3 /DAG 572/7  2 -adrenoceptors 2A G i/o cAMP450/7  2B G i/o cAMP450/7  2C G i/o cAMP461/7  2D G i/o cAMP450/7 -adrenoceptors11 GsGs cAMP 477/7 22 GsGs cAMP 413/7 33 G s, G i/o cAMP 408/7

30 Subtypes of Dopamine Receptors RECEPTORSSubtypeTransducerStructure (aa/TM) dopamineD1GsGs cAMP 446/7 D2G i G q/11 cAMP IP 3 /DAG, K +, Ca /7 D3GiGi cAMP400/7 D4GiGi cAMP, K + 386/7 D5GsGs cAMP 477/7

31 Subtypes of Serotonin Receptors RECEPTORSSubtypeTransducerStructure 5-HT (5-hydroxytryptamine) 5-HT 1A G i/o cAMP421/7 5-HT 1B G i/o cAMP390/7 5-HT 1D G i/o cAMP377/7 5-ht 1E G i/o cAMP365/7 5-ht 1F G i/o cAMP366/7 5-HT 2A G q/11 IP 3 /DAG 471/7 5-HT 2B G q/11 IP 3 /DAG 481/7 5-HT 2C G q/11 IP 3 /DAG 458/7 5-HT 3 internal cationic channel478 5-HT 4 GsGs cAMP 387/7 5-ht 5A ?357/7 5-ht 6 GsGs cAMP 440/7 5-HT 7 GsGs cAMP 445/7

32 Feedback to Transmitter-Releasing

33 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

34 Psychotropic Drugs Biochemical hypotheses of mental disorders are based on the study of mechanisms of action of psychotropic drugs at the level of: chemical synapsechemical synapse intracellular processes connected with signal transductionintracellular processes connected with signal transduction

35 Classification of Psychotropics parametereffectgroup watchfulness (vigility) positivepsychostimulant drugs negativehypnotic drugs affectivitypositiveantidepressants anxiolytics negativedysphoric drugs psychic integrations positiveneuroleptics, atypical antipsychotics negativehallucinogenic agents memorypositivenootropics negativeamnestic drugs

36 Main Psychotropic Drugs Antipsychotics Antipsychotics Antidepressants Antidepressants Anxiolytics Anxiolytics Hypnotics Hypnotics Cognitives Cognitives Psychostimulants Psychostimulants Hallucinogens Hallucinogens

37 Potential Action of Psychotropics 1. Synthesis and storage of neurotransmitters 2. Releasing of neurotransmitters 3. Receptor-neurotransmitter interactions (agonists, antagonists) 4. Catabolism of neurotransmitters 5. Reuptake of neurotransmitters 6. Transduction element (G protein) 7. Effector's system 8. Transcription factor activity and gene expression

38 Classification of Antipsychotics GroupExamples 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 2 nd generation) amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazole

39 Mechanisms of Action of 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-HT 2A 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

40 Receptor Systems Affected by Atypical Antipsychotics risperidone D2, 5-HT 2A, 5-HT 7,  1,  2 sertindole D2, 5-HT 2A, 5-HT 2C, 5-HT 6, 5-HT 7, D3,  1 ziprasidoneD2, 5-HT 2A, 5-HT 1A, 5-HT 1D, 5-HT 2C, 5- HT 7, D3,  1, NRI, SRI loxapine D2, 5-HT 2A, 5-HT 6, 5-HT 7, D1, D4,  1, M 1, H 1, NRI zotepineD2, 5-HT 2A, 5-HT 2C, 5-HT 6, 5-HT 7, D1, D3, D4,  1, H 1, NRI clozapineD2, 5-HT 2A, 5-HT 1A, 5-HT 2C, 5-HT 3, 5- HT 6, 5-HT 7, D1, D3, D4,  1,  2, M 1, H 1 olanzapineD2, 5-HT 2A, 5-HT 2C, 5-HT 3, 5-HT 6, D1, D3, D4, D5,  1, M 1-5, H 1 quetiapine D2, 5-HT 2A, 5-HT 6, 5-HT 7,  1,  2, H 1 aripiprazole D2, 5-HT 2A, 5-HT 1A,  1,  2, H 1

41 Classification of Antidepressants (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-HT 2A antagonist/reuptake inhibitors (SARI) Agonists of receptors 5-HT 1A Antagonists of receptors  2 -AR 5-HT 2 Inhibitors or stimulators of other components of signal transduction

42 Action of SSRI

43 Biological Hypotheses of Mental Disorders Schizophrenia Schizophrenia Affective disorders Affective disorders

44 Schizophrenia Biological models of schizophrenia can be divided into four related classes: Environmental models Environmental models Genetic models Genetic models Neurodevelopmental models Neurodevelopmental models Dopamine hypothesis Dopamine hypothesis

45 Schizophrenia - Genetic Models Multifactorial-polygenic threshold model: Schizophrenia is the result of a combined effect of multiple genes interacting with variety of environmental factors. 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. 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.

46 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.

47 Basis of Classical Dopamine Hypothesis of Schizophrenia 1. Dopamine-releasing drugs (amphetamine, mescaline, LSD) can induce state closely resembling paranoid schizophrenia. 2. 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. 3. Antipsychotics raise dopamine turnover.

48 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.

49 Biological Psychiatry and Affective Disorders BIOLOGYgenetics vulnerability to mental disorders stress increased sensitivity chronobiology desynchronisation of biological rhythms NEUROCHEMISTRYneurotransmitters availability, metabolism receptors number, affinity, sensitivity postreceptor processes G proteins, 2 nd messengers, phosphorylation, transcription IMMUNONEURO- ENDOCRINOLOGY HPA (hypothalamic- pituitary- adrenocortical) system increased activity during depression immune function different changes during depression

50 Data for Neurotransmitter 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

51 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.

52 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).

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

54 Receptor Hypotheses Receptor catecholamine hypothesis: Supersensitivity of catecholamine receptors in the presence of low levels of serotonin is the biochemical basis of depression. 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. 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.

55 Neurotransmitter Regulation of Mood and Behavior Nutt 2008 Motivation Pleasure Reward Alertness Energy Obsession Compulsion Dopamine Norepinephrine Serotonin Mood Attention Interest Anxiety

56 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. 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

57 Neurotrophic Effects of Antidepressants Nestler et al. 2002

58 Antidepressant Treatments

59 Laboratory Survey in Psychiatry Laboratory survey methods in psychiatry coincide with internal and neurological methods: Laboratory survey methods in psychiatry coincide with internal and neurological methods: Classic and special biochemical and neuroendocrine tests Classic and special biochemical and neuroendocrine tests Immunological tests Immunological tests Electrocardiography (ECG) Electrocardiography (ECG) Electroencephalography (EEG) Electroencephalography (EEG) Computed tomography (CT) Computed tomography (CT) Nuclear magnetic resonance (NMR) Nuclear magnetic resonance (NMR) Phallopletysmography Phallopletysmography

60 Classic and Special Biochemical Tests TestIndication serum cholesterol (3,7-6,5 mmol/l) and lipemia (5-8 g/l) brain disease at atherosclerosis cholesterolemia, TSH, T3, T4, blood pressure, mineralogram (calcemia, phosphatemia) thyroid disorder, hyperparathyreosis or hypothyroidism can be an undesirable side effect of Li-therapy hepatic tests: bilirubin (total < 17mmol/l), cholesterol, aminotranspherase (AST, ALT, TZR, TVR), alkaline phosphatase before pharmacotherapy and in alcoholics glycaemiadiabetes mellitus blood pictureduring pharmacotherapy determination of metabolites of psychotropics in urine or in blood control or toxicology lithemia (0,4-1,2 mmol/l), function of thyroid and kidney (serum creatinine, urea), pH of urine, molality, clearance, serum mineralogram (Na, K) during lithiotherapy

61 Classic and Special Biochemical Tests TestIndication determination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, DA metabolite), hydroxyindolacetic acid (HIAA, 5- HT metabolite), methoxyhydroxyphenylglycole (MHPG, NE metabolite) research neurotransmitter receptors and transportersresearch cerebrospinal fluid: pH, tension, elements, abundance of globulins (by electrophoresis) diagnosis of progressive paralysis, … neuroendocrinne stimulative or suppressive tests: dexamethasone suppressive test (DST), TRH test, fenfluramine test depressive disorders prolactin determination increased during treatment with neuroleptics

62 Thank you for your attention Web pages:


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