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Biochemistry and Biological Psychiatry Department of Psychiatry 1 st Faculty of Medicine Charles University, Prague Head: Prof. MUDr. Jiří Raboch, DrSc.

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Presentation on theme: "Biochemistry and Biological Psychiatry Department of Psychiatry 1 st Faculty of Medicine Charles University, Prague Head: Prof. MUDr. Jiří Raboch, DrSc."— Presentation transcript:

1 Biochemistry and Biological Psychiatry Department of Psychiatry 1 st Faculty of Medicine Charles University, Prague Head: Prof. MUDr. Jiří Raboch, DrSc.

2 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 are essential in development of mental disorders. 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 are essential in development of mental disorders.

3 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.

4 Model of Plasma Membrane

5 Synapse Neurons communicate with one another by direct electrical coupling or by the secretion of neurotransmitters Neurons communicate with one another by direct electrical coupling or by the secretion 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.

6 Morphology of Chemical Synapse

7 Synapses

8 Chemical Synapse - Signal Transduction

9 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

10 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

11 Catecholamine Biosynthesis

12 Serotonin Biosynthesis

13 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

14 Membrane Transporters

15 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)

16 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.Transduction element 3.Effector system (2 nd messengers) Regulation of receptors: Regulation of receptors: 1.Number of receptors (down-regulation, up- regulation) 2.Properties of receptors (desensitisation, hypersensitivity)

17 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

18 GABA A Receptor

19 Receptors Associated with G Proteins adenylyl cyclase system phosphoinositide system

20 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

21 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

22 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

23 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 5B ?370/7 5-ht 6 GsGs cAMP 440/7 5-HT 7 GsGs cAMP 445/7

24 Feedback to Transmitter-Releasing

25 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

26 Interaction of Amphiphilic Drugs with Membrane

27 Potential Action of Psychotropics 1. Synthesis and storage of neurotransmitter 2. Releasing of neurotransmitter 3. Receptor-neurotransmitter interactions (blockade of receptors) 4. Catabolism of neurotransmitter 5. Reuptake of neurotransmitter 6. Transduction element (G protein) 7. Effector's system

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

29 Classification of Antipsychotics groupexamples conventional antipsychotics (classical neuroleptics) basal (sedative) antipsychotics chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine incisive antipsychotics 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

30 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

31 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

32 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

33 Action of SSRI

34 Schizophrenia Biological models of schizophrenia can be divided into three related classes: Environmental models Environmental models Genetic models Genetic models Neurodevelopmental models Neurodevelopmental models

35 Schizophrenia - Genetic Models Multifactorial-polygenic threshold model: Schizophrenia is the result of a combined effect of multiple genes interacting with variety of environmental factors; i.e. several or many genes, each of small effect, combine additively with the effects of non- inherited 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.

36 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. Genetic and no genetic risk factors that may have impacted on the developing brain during prenatal and perinatal life - pregnancy and birth complications (PBCs): viral infections in uteroviral infections in utero gluten sensitivitygluten sensitivity brain malformationsbrain malformations obstetric complicationsobstetric complications

37 Basis of Classical Dopamine Hypothesis of Schizophrenia Dopamine-releasing drugs (amphetamine, mescaline, diethyl amide of lysergic acid - LSD) can induce state closely resembling paranoid schizophrenia. Dopamine-releasing drugs (amphetamine, mescaline, diethyl amide of lysergic acid - LSD) can induce state closely resembling paranoid schizophrenia. Conventional neuroleptics, 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. Conventional neuroleptics, 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. Neuroleptics raise dopamine turnover as a result of blockade of postsynaptic dopamine receptors or as a result of desensitisation of inhibitory dopamine autoreceptors localized on cell bodies. Neuroleptics raise dopamine turnover as a result of blockade of postsynaptic dopamine receptors or as a result of desensitisation of inhibitory dopamine autoreceptors localized on cell bodies.

38 Biochemical Basis of Schizophrenia According to the 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.

39 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

40 Data for Neurotransmitter Hypothesis Tricyclic antidepressants through blockade of neurotransmitter reuptake increase neurotransmission at noradrenergic synapses MAOIs increase availability of monoamine neurotransmitters in synaptic cleft Depressive symptoms are observed after treatment by reserpine, which depletes biogenic amines in synapse

41 Neurotransmitter Hypothesis of Affective Disorders catecholamine hypothesis indolamine hypothesis cholinergic-adrenergic balance hypothesis „permissive“ hypothesis dopamine hypothesis hypothesis of biogenic amine monoamine hypothesis

42 Monoamine Hypothesis Depression was due to a deficiency of monoamine neurotransmitters, norepinephrine and serotonin. MAOI act as antidepressants by blocking of enzyme MAO, thus allowing presynaptic accumulation of monoamine neurotransmitters. Tricyclic antidepressants act as antidepressants by blocking membrane transporters ensuring reuptake of 5-HT or NE, thus causing increased extracellular neurotransmitter concentrations.

43 Permissive Biogenic Amine Hypothesis A deficit in central indolaminergic 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 indoleaminergic transmission, act as a proximate cause for affective disorders and determine their quality, catecholaminergic transmission being elevated in mania and diminished in depression.

44 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, hence many receptor hypotheses of affective disorders were formulated and tested.

45 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 (due to decreased NE release, disturbed interactions of noradrenergic, serotonergic and dopaminergic systems, etc.). Long-term antidepressant treatment causes down regulation of  1 -AR (by inhibition of NE reuptake, stimulation or blockade of receptors, regulation through serotonergic or dopaminergic systems, etc.). Transient increase of neurotransmitter availability can cause fault to mania. There is increased density of postsynaptic -AR in depression (due to decreased NE release, disturbed interactions of noradrenergic, serotonergic and dopaminergic systems, etc.). Long-term antidepressant treatment causes down regulation of  1 -AR (by inhibition of NE reuptake, stimulation or blockade of receptors, regulation through serotonergic or dopaminergic systems, etc.). Transient increase of neurotransmitter availability can cause fault to mania.

46 Postreceptor Hypotheses 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.

47 Antidepressant Treatments

48 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

49 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

50 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


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