Biochemistry - Biochemistry and Biological Psychiatry...

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Unformatted text preview: Biochemistry and Biological Psychiatry Biological ass. prof. Zdeněk Fišar, CSc. Department of Psychiatry 1st Faculty of Medicine Charles University, Prague Head: prof. MUDr. Jiří Raboch, DrSc. Biochemistry and Biiological Psychiatry ological cellular neurochemistry (neurons, action potentials, synapses) intercellular signalling (neurotransmitters, receptors, growth factors) intracellular signalling (G proteins, effectors, 2nd messengers, proteinkinases, transcription factors) psychotropic drugs (antipsychotics, antidepressants) biological hypotheses of mental disorders (schizophrenia, affective disorders) Biological Psychiatry: Web Pages Biological 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) Introduction 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 (at the level of chemical synapse) are essential in the development of mental disorders. Cellular Neurochemistry Cellular Neurons Action potentials Synapses Neuron Neuron 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. 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 Synapse 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. Morphology of Chemical Synapse Chemical Synapse Signal Transduction Model of Plasma Membrane Membrane Transporters Intercellular and Intracellular Signalling Signalling Neurotransmitters Growth factors Receptors G proteins Effector systems (2nd messengers, proteinkinases, transcription factors) Criteria to Identify Neurotransmitters 1. Presence in presynaptic nerve terminal 2. Synthesis by presynaptic neuron 3. Releasing on stimulation (membrane depolarisation) 4. Producing rapid­onset 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 System Transmitter Cholinergic acetylcholine Aminoacidergic GABA, aspartic acid, glutamic acid, glycine, homocysteine Monoaminergic • Catecholamines • Indolamines • Others, related to aa Purinergic dopamine, norepinephrine, epinephrine tryptamine, serotonin histamine, taurine adenosine, ADP, AMP, ATP nitric oxide Catecholamine Biosynthesis Serotonin Biosynthesis Reuptake and Metabolism of Reuptake etabolism Monoamine Neurotransmitters onoamine Reuptake Monoamine oxidase (MAO) Catechol­O­methyltransferase (COMT) Selected Bioactive Peptides Peptide substance P, substance K (tachykinins), neurotensin, cholecystokinin (CCK), gastrin, bombesin galanin, neuromedin K, neuropeptideY (NPY), peptide YY (PYY), cortikotropin releasing hormone (CRH) growth hormone releasing hormone (GHRH), gonadotropin releasing hormone (GnRH), somatostatin, thyrotropin releasing hormone (TRH) adrenocorticotropic hormone (ACTH) growth hormone (GH), prolactin (PRL), lutenizing hormone (LH), thyrotropin (TSH) oxytocin, vasopressin Group brain and gastrointestinal peptides neuronal hypothalamic releasing factors pituitary hormones neurohypophyseal peptides atrial natriuretic peptide (ANF), vasoactive intestinal peptide neuronal and (VIP) endocrine enkephalines (met­, leu­), dynorphin, β ­endorphin opiate peptides Growth Factors in the Nervous System Neurotrophins Neurokines Fibroblast growth factors Transforming growth factor β superfamily Nerve growth factor (NGF) Brain­derived neurotrophic factor (BDNF) Neurotrophin 3 (NT3) Neurotrophin 4/5 (NT4/5) Ciliary neurotrophic factor (CNTF) Leukemia inhibitory factor (LIF) Interleukin 6 (IL­6) Cardiotrophin 1 (CT­1) FGF­1 FGF­2 Transforming growth factors β (TGFβ) Bone morphogenetic factors (BMPs) Glial­derived neurotrophic factor (GDNF) Neurturin Epidermal growth factor Epidermal growth factor (EGF) superfamily Transforming growth factor α (TGFα) Neuregilins Other growth factors Platelet­derived growth factor (PDGF) Insulin­like growth factor I (IGF­I) Membrane Receptors Receptor is macromolecule specialized on transmission of information. Receptor complex includes: 1. 2. 3. Specific binding site Internal ion channel or transduction element Effector system (ion channels or system of 2nd messengers) Regulation of receptors Regulation 1. Density of receptors (down­regulation, up­ regulation) 2. Properties of receptors (desensitisation, hypersensitivity) Receptor Classification 1. Receptor coupled directly to the ion 1. channel 2. Receptor associated with G proteins 3. Receptor with intrinsic guanylyl cyclase activity 4. Receptor with intrinsic tyrosine kinase activity 1. Receptors with Internal Ion Channel nternal on 1. Receptors with Internal Ion Channel nternal on acetylcholine Nicotinic acetylcholine receptor is made of 5 subunits, 2 of which (shown in orange) bind acetylcholine (red). membrane receptor acetylcholine 1. Receptors with internal ion channel Receptors GABAA receptor, nicotonic acetylcholine receptors, ionotropic glutamate receptors, etc. 2. Receptors Associated with G Proteins Proteins 1. adenylyl cyclase system 2. phosphoinositide system 3. arachidonic acid system Receptors Associated with G Proteins Receptors SYSTEM Adenylyl cyclase system Phosphoinositide Arachidonic acid system system NEURONE, 5-HT, DA, TRANSMITTER Ach NE, 5-HT, DA, Ach Histamine TRANSDUCER Gs, Gi Gp Unknown Gprotein PRIMARY EFFECTOR Adenylyl cyclase Phospholipase C Phospholipase A SECONDARY MESSENGER cAMP IP3, DAG, Ca++ Arachidonic acid SECONDARY EFFECTOR •Calcium and calmoduline •Protein kinase A dependent protein kinases •Protein kinase C •5-Lipoxygenase •12-Lipoxygenase •Cycloxygenase Types of Receptors Type System acetylcholinergic Type acetylcholine nicotinic receptors acetylcholine muscarinic receptors monoaminergic α 1­adrenoceptors α 2­adrenoceptors β ­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) Subtypes of Norepinephrine Receptors RECEPTORS ↑IP3/DAG Gq/11 ↑IP3/DAG 519/7 Gq/11 ↑IP3/DAG 572/7 α2A Gi/o cAMP 450/7 α2B Gi/o cAMP 450/7 α2C Gi/o cAMP 461/7 α2D β­adrenoceptors Gq/11 α1D α2­adrenoceptors α1A Structure (aa/TM) 466/7 α1B α1­adrenoceptors Subtype Transducer Gi/o cAMP 450/7 β1 Gs ↑cAMP 477/7 β2 Gs ↑cAMP 413/7 Subtypes of Dopamine Receptors Subtypes RECEPTORS dopamine Subtype Transducer Structure (aa/TM) 446/7 D1 Gs ↑cAMP D2 Gi 443/7 Gq/11 cAMP ↑IP3/DAG, ↑K+, ↓Ca2+ G i cAMP 400/7 D4 G i cAMP, ↑K+ 386/7 D5 Gs ↑cAMP 477/7 D3 Subtypes of Serotonin Receptors Subtypes RECEPTORS 5­HT (5­hydroxytryptamine) Subtype Transducer Structure 5­HT1A Gi/o cAMP 421/7 5­HT1B Gi/o cAMP 390/7 5­HT1D Gi/o cAMP 377/7 5­ht1E Gi/o cAMP 365/7 5­ht1F Gi/o cAMP 366/7 5­HT2A Gq/11 ↑IP3/DAG 471/7 5­HT2B Gq/11 ↑IP3/DAG 481/7 5­HT2C Gq/11 ↑IP3/DAG 458/7 5­HT3 internal cationic channel 478 5­HT4 Gs 387/7 5­ht5A ? 5­ht6 Gs ↑cAMP 357/7 ↑cAMP 440/7 Feedback to Transmitter-Releasing 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 Psychotropic Drugs Psychotropic 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 Classification of Psychotropics parameter watchfulness (vigility) effect group psychostimulant drugs negative affectivity positive hypnotic drugs positive antidepressants anxiolytics negative memory positive negative psychic integrations dysphoric drugs neuroleptics, atypical antipsychotics hallucinogenic agents positive nootropics negative amnestic drugs Main Psychotropic Drugs Main Antipsychotics Antidepressants Anxiolytics Hypnotics Cognitives Psychostimulants Hallucinogens Potential Action of Psychotropics 1. Synthesis and storage of neurotransmitters 2. Releasing of neurotransmitters 3. Receptor­neurotransmitter 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 Classification of Antipsychotics Group Conventional antipsychotics (classical neuroleptics) Atypical antipsychotics (antipsychotics of 2nd generation) Examples chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazole Mechanisms of Action of Antipsychotics Conventional antipsychotics Atypical antipsychotics • D2 receptor blockade of postsynaptic in the mesolimbic pathway • D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms; • enhanced dopamine release and 5­HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms; • other receptor­binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia Receptor Systems Affected by Atypical Antipsychotics Receptor risperidone sertindole ziprasidone loxapine zotepine clozapine olanzapine D2, 5­HT2A, 5­HT7, α1, α2 D2, 5­HT2A, 5­HT2C, 5­HT6, 5­HT7, D3, α1 D2, 5­HT2A, 5­HT1A, 5­HT1D, 5­HT2C, 5­HT7, D3, α1, NRI, SRI D2, 5­HT2A, 5­HT6, 5­HT7, D1, D4, α1, M1, H1, NRI D2, 5­HT2A, 5­HT2C, 5­HT6, 5­HT7, D1, D3, D4, α1, H1, NRI D2, 5­HT2A, 5­HT1A, 5­HT2C, 5­HT3, 5­HT6, 5­HT7, D1, D3, D4, α1, α2, M1, H1 D2, 5­HT2A, 5­HT2C, 5­HT3, 5­HT6, D1, D3, D4, D5, α1, M1­5, H1 Classification of Antidepressants Classification (based on acute pharmacological actions) (based Inhibitors of neurotransmitter catabolism • • • • Reuptake inhibitors • • • Agonists of receptors Antagonists of receptors • • monoamine oxidase inhibitors (IMAO) serotonin reuptake inhibitors (SRI) norepinephrine reuptake inhibitors (NRI) selective SRI (SSRI) selective NRI (SNRI) serotonin/norepinephrine inhibitors (SNRI) norepinephrine and dopamine reuptake inhibitors (NDRI) 5­HT1A antagonist/reuptake inhibitors (SARI) 5­HT2A ∀ α2­AR • 5­HT2 Inhibitors or stimulators of other components of signal transduction Action of SSRI SSRI Biological Hypotheses of Mental Disorders Disorders Schizophrenia Affective disorders Schizophrenia Schizophrenia Biological models of schizophrenia can be divided into four related classes: Environmental models Genetic models Neurodevelopmental models Dopamine hypothesis Schizophrenia - Genetic Models Multifactorial­polygenic threshold model: Multifactorial­polygenic 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 distribution of a continuous trait, and there may be a threshold for the clinical expression of the disease. Schizophrenia Neurodevelopmental Models A substantial group of patients, who receive 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. Basis of Classical Dopamine Hypothesis of Schizophrenia 1. 1. 2. 3. Dopamine­releasing drugs (amphetamine, mescaline, LSD) can induce state closely resembling paranoid schizophrenia. 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. Antipsychotics raise dopamine turnover. Classical Dopamine Hypothesis of Schizophrenia 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. Biological Psychiatry and Affective Disorders neurotransmitters desynchronisation of biological rhythms availability, metabolism number, affinity, sensitivity postreceptor processes ENDOCRINOLOGY increased sensitivity receptors IMMUNONEURO­ vulnerability to mental disorders chronobiology NEUROCHEMISTRY genetics stress BIOLOGY G proteins, 2nd messengers, phosphorylation, transcription HPA (hypothalamic­ increased activity during depression pituitary­adrenocortical) system immune function different changes during depression 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 Monoamine Hypothesis Depression was due to a deficiency of monoamine 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 MAO­A 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 MAO­A activity and density of transporters are included in the pathophysiology of affective disorders. Permissive Biogenic Amine Hypothesis A deficit in central serotonergic transmission A deficit in central 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). Receptor Hypotheses The common final result of chronic treatment by majority of antidepressants is the down­regulation or up­regulation of postsynaptic or presynaptic receptors. The delay of clinical response corresponds with these receptor alterations. Receptor Hypotheses Receptor 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 β­AR in depression. Long­term antidepressant treatment causes down regulation of β1­AR. Transient increase of neurotransmitter availability can cause fault to mania. Neurotransmitter Regulation of Mood and Behavior Mood Dopamine Motivation Pleasure Reward Alertness Energy Attention Interest Norepinephrine Mood Anxiety Obsession Compulsion Serotonin Nutt 2008 Postreceptor Hypotheses Neurotrophic hypothesis (molecular and cellular theory) Neurotrophic hypothesis of depression: Transcription factor, cAMP response element­binding protein (CREB), is one intracellular target of long­term antidepressant treatment and brain­derived neurotrophic factor (BDNF) is one target gene of CREB. Chronic stress leads to decrease in expression of BDNF in hippocampus. Long­term increase in levels of glucocorticoids, ischemia, neurotoxins, hypoglycaemia etc. decreases neuron survival. Long­term 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 Neurotrophic Effects of Antidepressants Neurotrophic Nestler et al. 2002 Antidepressant Treatments Antidepressant Laboratory Survey in Psychiatry Laboratory survey methods in psychiatry coincide with internal and neurological methods: Classic and special biochemical and neuroendocrine tests Immunological tests Electrocardiography (ECG) Electroencephalography (EEG) Computed tomography (CT) Nuclear magnetic resonance (NMR) Phallopletysmography Classic and Special Biochemical Tests Test Indication serum cholesterol (3,7­6,5 mmol/l) and lipemia (5­8 g/l) brain disease at atherosclerosis thyroid disorder, hyperparathyreosis or cholesterolemia, TSH, T3, T4, blood pressure, hypothyroidism can be an mineralogram (calcemia, phosphatemia) undesirable side effect of Li­ hepatic tests: bilirubin (total < 17mmol/l), cholesterol, therapy before pharmacotherapy and in aminotranspherase (AST, ALT, TZR, TVR), alkaline alcoholics phosphatase glycaemia diabetes mellitus blood picture during pharmacotherapy determination of metabolites of psychotropics in control or toxicology urine or in blood lithemia (0,4­1,2 mmol/l), function of thyroid and kidney (serum creatinine, urea), pH of urine, molality, during lithiotherapy clearance, serum mineralogram (Na, K) Classic and Special Biochemical Tests Test Indication determination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, DA metabolite), hydroxyindolacetic acid (HIAA, 5­HT metabolite), methoxyhydroxyphenylglycole (MHPG, NE metabolite) research neurotransmitter receptors and transporters research cerebrospinal fluid: pH, tension, elements, abundance of globulins (by electrophoresis) neuroendocrinne stimulative or suppressive tests: dexamethasone suppressive test (DST), TRH test, fenfluramine test prolactin determination diagnosis of progressive paralysis, … depressive disorders increased during treatment with neuroleptics Thank you for your attention Thank Web pages: http://connect.lf1.cuni.cz http://portal.lf1.cuni.cz http://portal.lf1.cuni.cz ...
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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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