Presentation on theme: "Biochemistry and Biological Psychiatry"— Presentation transcript:
1Biochemistry and Biological Psychiatry ass. prof. Zdeněk Fišar, CSc.Department of Psychiatry1st Faculty of MedicineCharles University, PragueHead: prof. MUDr. Jiří Raboch, DrSc.Ladies and gentlemen!My name is Fišar and I will lecture about neurochemistry and biological psychiatry.
2Biochemistry and Biological Psychiatry 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)Disturbance of signal transduction through synapses play a key role in pathophysiology of mental disorders. So, I will talk about cellular neurochemistry and intercellular signalling firstly; it means I recapitulate information about neurons, synapse, neurotransmitters, receptors and growth factors. Then I will deal with intracellular signalling, it means by processes mediated by G proteins, effector enzymes, second messengers, protein kinases etc.Because most of our observations come from study of mechanisms of action of psychotropic drugs I introduce some biochemical effects of antipsychotics or antidepressants.At the close of lecture I introduce some biological hypotheses of schizophrenia or depression.
3Biological 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)All slides of my presentation you can find on Internet on web pages of 1st Faculty of Medicine. Links to information about biological psychiatry are:educational portal of our faculty;direct links are shown on the slide.
4IntroductionBiological 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.Biological psychiatry occupies itself by mental disorders from biological, chemical and physical point of view. The base of biological psychiatry is the assumption that human mind is connected with human body so that mental disorders (processes) are accompanied with biochemical changes, which can be measured. The second issue of biological psychiatry is causality of all natural processes, including human mind.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.
5Cellular Neurochemistry NeuronsAction potentialsSynapsesI will talk about cellular neurochemistry firstly.
6NeuronThe 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.The brain consists of neurons and glia. There are many different kinds of neurons and several classes of glial cells: astrocytes, oligodendrocytes, and microglia. The glia outnumber the neurons ten times or more.The neurons are the brain cells that are responsible for intracellular and intercellular signalling. Neurons share many features in common with other cells, but they are distinguished by their highly asymmetric shapes and by existence of dendrite and axon.Dendrite function is reception of signals from the other neurons.Axon is specialized for intracellular transmission of action potential from cell body to synapses.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. Nerve ending form an integral parts of synapse.Synapse mediates the signal transmission from one neuron to another. The dendritic tree is in continual flux and revises its synaptic connections in the course of life.
7Synapse Neurons communicate with one another by direct electrical couplingsecretion of neurotransmittersSynapses are specialized structures for signal transduction from one neuron to other. Chemical synapses are studied in the biological psychiatry.Neurons communicate with one another by direct electrical coupling or by the secretion of neurotransmittersSynapses are specialized structures for signal transduction from one neuron to other. Chemical synapses are studied in the biological psychiatry. Chemical synapses use neurotransmitters to signal transmission between neurons, and their function is affected both by mental disorder and by many psychotropic drugs.
8Morphology of Chemical Synapse Morphology of chemical synapse is shown on the picture. Synapse consist of presynaptic part and postsynaptic part. In presynaptic part you can see synaptic vesicles, mitochondria, microtubules, etc. Synaptic cleft forms an integral part of synapse, and surrounding glia cells support synaptic signal transduction.
9Chemical Synapse - Signal Transduction The main interest of biological psychiatry is knowledge of changes in signal transduction through chemical synapse in the mental disorder and during its treatment. It is known that many psychotropic drugs act on the level of chemical synapseOn the picture you can see basic steps in signal transduction:Depolarisation of presynaptic membrane leads to opening of voltage gated calcium channels.Calcium enters to presynaptic part and activates many enzymes. Neurotransmitters are released from synaptic vesicles by exocytosis to synaptic cleft.Calcium is rapidly removed from presynaptic part; so, reactions leading to the neurotransmitter release are effective for milliseconds only.Neurotransmitters diffuse to postsynaptic and presynaptic membrane receptors and specifically bind to them.Receptors are activated and either ion channels are opened, or activities of intracellular enzymes and 2nd messenger systems are changed. These changes lead to physiological effect of receptor activation.Temporal or spatial summation of synaptic potentials is necessary to the evocation of desirable physiological effect since the amount of neurotransmitters released from one vesicle is generally insufficient.
10Model of Plasma Membrane Plasma membranes play a key role in synaptic signal transduction. The common model of plasma membrane is shown on the picture. Plasma membranes consist of lipid bilayer (phospholipids, glycolipids, sphingomyelin, cholesterol) and integral and peripheral proteins (ion channels, receptors, enzymes, transporters).Specific receptors, ion channels, G proteins, effector enzymes, transporters and other integral proteins are necessary in signal transduction. However, lipid bilayer play an important role also, because most of membrane proteins require interaction with specific phospholipids or with cholesterol for their optimal function.
11Membrane Transporters Not only receptors, ion channels, G proteins and effectors but also neurotransmitter transporters are necessary for synaptic transmission.Removing of neurotransmitters from synaptic cleft is key step in synaptic signal transmission. Generally, neurotransmitters are removed from synaptic cleft by enzymatic degradation or by active transport to presynaptic button or to surrounding glia cells.The main way of acetylcholine removing from synaptic cleft is metabolism by acetylcholinesterase. But for majority of neurotransmitters speculated in biochemical hypothesis of mental disorders there are specific membrane transporters.There are three main classes of membrane transporters:Transporters dependent on sodium and chlorine: they are embedded in the presynaptic membrane mainly. They transport serotonin, norepinephrine or dopamine back into presynaptic part and neurotransmitters may be stored in vesicles and repeatedly released in response to action potential.Vesicular transporters: they carries neurotransmitters into synaptic vesicles; their function is important to prevent neurotransmitter degradation.Sodium dependent transporters: they are localized in the membrane of glia cells, and transport neurotransmitters such as gama-aminobutyric acid (GABA), glutamate or aspartate into glia cells; neurotransmitters are metabolized and metabolites may be used in synthesis of new neurotransmitters in presynaptic part.
12Intercellular and Intracellular Signalling NeurotransmittersGrowth factorsReceptorsG proteinsEffector systems (2nd messengers, proteinkinases, transcription factors)So, it was brief information about synapses, and now I will talk about intracellular signalling, i.e. about neurotransmitters, receptors and growth factors.
13Criteria to Identify Neurotransmitters Presence in presynaptic nerve terminalSynthesis by presynaptic neuronReleasing on stimulation (membrane depolarisation)Producing rapid-onset and rapidly reversible responses in the target cellExistence of specific receptorA multitude of chemicals called neurotransmitters mediate intercellular communication in the nervous system. Although they exhibit great diversity in many of their properties, all are stored in vesicles in nerve terminals and are released to the extracellular space via process requiring calcium ions. Their action is terminated by reuptake into presynaptic terminal or glia cells or by catabolism in synaptic cleft or in presynaptic terminal. Criteria to identify neurotransmitters are shown in the Table:neurotransmitters must be present in presynaptic nerve terminals and they are synthesised by presynaptic neuron;neurotransmitters are released in response to membrane depolarization and produce rapid and specific response in the target cell;there is specific receptor to every neurotransmitter.From the chemical point of view are neurotransmitters monoamines, amino acids and peptides. There are two main groups of neurotransmitters:classical neurotransmitters;neuropeptides;Nitric oxide has a special role in neurotransmission.There are two main groups of neurotransmitters:classical neurotransmittersneuropeptides
14Selected Classical Neurotransmitters SystemTransmitterCholinergicacetylcholineAminoacidergicGABA, aspartic acid, glutamic acid, glycine, homocysteineMonoaminergicCatecholaminesdopamine, norepinephrine, epinephrineIndolaminestryptamine, serotoninOthers, related to aahistamine, taurinePurinergicadenosine, ADP, AMP, ATPAll classical neurotransmitters are synthesized in nerve terminals.The first molecule to be implicated as neurotransmitter was acetylcholine (ACh). It was demonstrated that acetylcholine is the transmitter at neuromuscular synapses, as well as at a variety of neuron-neuron synapses. ACh is synthesized from choline and acetyl‑coenzyme A in the nerve endings; reaction is catalyzed by the enzyme choline acetyltransferase. ACh is rapidly degraded in synaptic cleft by the enzyme acetylcholinesterase.There are three major amino acid neurotransmitters in the nervous system: gama-aminobutyric acid (GABA), glycine and glutamic acid. GABA and glycine are inhibitory neurotransmitters; glutamate and aspartate are excitatory neurotransmitters.Monoamine neurotransmitters, such as dopamine, norepinephrine or serotonin are the most important neurotransmitters in pathophysiology of mental disorders and in mechanisms of action of psychotropic drugs. They are divided to catecholamines (dopamine, norepinephrine), indolamines (serotonin), and others.Specific properties have nitric oxide, which does not interact with membrane receptors but diffuse to target intracellular receptor.nitric oxide
15Catecholamine Biosynthesis Dopamine or norepinephrine biosynthesis is summarized on this slide.Catecholamines are generally synthesized from tyrosine.Dopamine is formed by hydroxylation and decarboxylation of tyrosine; norepinephrine is formed by hydroxylation of dopamine.
16Serotonin Biosynthesis Serotonin biosynthesis is shown on this slide.Indolamines (serotonin and tryptamine) are generally synthesized from tryptophan by hydroxylation and decarboxylation.Chemical term of serotonin is 5-hydroxytryptamine, abbreviation 5-HT. The abbreviation 5-HT will be used on next slides.
17Reuptake and Metabolism of Monoamine Neurotransmitters Monoamine oxidase (MAO)Catechol-O-methyltransferase (COMT)Action both of catecholamines and indolamines on target cells is terminated by removing from synaptic cleft by specific transporters; the active transport of neurotransmitters from extracellular space into synapse is called reuptake.The major enzymes involved in the catabolism of dopamine or norepinephrine is monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT). Serotonin is metabolized by monoamino oxidase.Most of antidepressants either increase availability of neurotransmitters in synapse by inhibition of catabolising enzymes, or prolong monoamine neurotransmitters action by inhibiting their high affinity reuptake system.
18Selected Bioactive Peptides Groupsubstance P, substance K (tachykinins), neurotensin, cholecystokinin (CCK), gastrin, bombesinbrain and gastrointestinal peptidesgalanin, neuromedin K, neuropeptideY (NPY), peptide YY (PYY),neuronalcortikotropin releasing hormone (CRH)hypothalamic releasing factorsgrowth 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, vasopressinneurohypophyseal peptidesatrial natriuretic peptide (ANF), vasoactive intestinal peptide (VIP)neuronal and endocrineenkephalines (met-, leu-), dynorphin, -endorphinopiate peptidesIt was about classical neurotransmitters. Second main group of neurotransmitters are neuropeptides.It was identified a great number of neuropeptides as neurotransmitters and new peptide neurotransmitters are discovered continually. Selected neuropeptides are shown in the Table; e.g. beta-endorphin is important in psychiatry, since it has a role in pain and in stress. All neuropeptides are synthesized in the cell body.The action of neuropeptides in the synaptic cleft is terminated by peptidases; there is no reuptake for neuropeptides.Neuropeptides are co-transmitters usually; it means they are released along with some classical neurotransmiter such as serotonin, norepinephrine or dopamine. Transduction mechanism of neuropeptides is coupled with G proteins.
19Growth 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 factorsFGF-1FGF-2Transforming growth factor superfamilyTransforming growth factors (TGF)Bone morphogenetic factors (BMPs)Glial-derived neurotrophic factor (GDNF)NeurturinEpidermal growth factor superfamilyEpidermal growth factor (EGF)Transforming growth factor (TGF)NeuregilinsOther growth factorsPlatelet-derived growth factor (PDGF)Insulin-like growth factor I (IGF-I)Growth factors are extremely important in neurotransmission.Growth factors are proteins that stimulate cellular proliferation and promote cellular survival. They are essential for nervous system development and function. They are released from different cell; after interaction of neurotrophins with membrane receptors changes in activity of intracellular enzymes occur leading to changes in gene expression and production of cellular molecules.Mechanism of action of growth factors is similar to action of neurotransmitters, but they are not released in response to membrane depolarization and to changes of intracellular calcium levels.There are 6 major classes of growth factors, which act within nervous system. From the psychiatry point of view neurotrophins and neurokines are most important.Neurokines are mediators which interconnect central nervous, and endocrine systems.Neurotrophins support the survival and phenotypic specificity of subsets of neurons. Brain-derived neurotrophic factor (BDNF) has a role in stress response, depression and in action of antidepressants.
20Membrane ReceptorsReceptor is macromolecule specialized on transmission of information.Receptor complex includes:Specific binding siteInternal ion channel or transduction elementEffector system (ion channels or system of 2nd messengers)Receptor is macromolecule specialized on transmission of information. It is defined as binding site with functional relationships.Receptor complex includes:Specific binding site;Internal ion channel or transduction element;Effector system (ion channels or system of 2nd messengers).Activation of receptors with internal ion channel leads to rapid change in membrane potential.Activation of receptors connected with G proteins leads to slower response through activation of effector system.Effector system includes G protein activated ion channels or G protein activated enzymes (adenylyl cyclase or phospholipase); G protein activated enzymes generate 2nd messengers and second messengers activate protein kinases. Phosphorylation of cellular proteins by protein kinase leads to physiological effects of receptor activation.
21Regulation of receptors Density of receptors (down-regulation, up-regulation)Properties of receptors (desensitisation, hypersensitivity)Receptors are able to adapt their properties to increased or decreased activation. Changes in the density of receptors are known mechanism of their adaptation.But response to receptor activation can be altered at unchanged density of receptors too. Regulation of properties of receptors consists of decreased or increased activity of post receptor events.
22Receptor Classification Receptor coupled directly to the ion channelReceptor associated with G proteinsReceptor with intrinsic guanylyl cyclase activityReceptor with intrinsic tyrosine kinase activityThere are many types of receptors and they can be classified by different criteria, e.g. according to their pharmacological properties or according to effector system, which is connected with their function. Classification according to effector system is shown on the slide:Receptor coupled directly to the ion channel.Receptor associated with G proteins.Receptor with intrinsic guanylyl cyclase activity.Receptor with intrinsic tyrosine kinase activity (they are receptors for growth factors).Receptors coupled to ion channels or associated with G proteins are studied in biological psychiatry.
231. Receptors with Internal Ion Channel Direct coupling of the neurotransmitter receptor to the ion channel whose activity it regulates is the simplest and the most rapid way of signal transduction. An example of receptor with internal ion channel is GABAA receptor, nicotinic acetylcholine receptors, or ionotropic glutamate receptors.Following receptor activation, nicotinic acetylcholine receptors as well as ionotropic glutamate receptors increase membrane permeability for sodium, potassium or calcium; they are excitatory receptors.NMDA receptor includes calcium channel, which is opened in response to receptor activation. NMDA receptors require the binding of two molecules of glutamate or aspartate and two of glycine. Allosteric sites that would cause inhibition of the receptor are not occupied on the figure.
241. Receptors with Internal Ion Channel acetylcholinemembranereceptorNicotinic acetylcholine receptor is made of 5 subunits, 2 of which (shown in orange) bind acetylcholine (red).Nicotinic acetylcholine receptor is made of 5 subunits, 2 of which (shown in orange) bind acetylcholine (red).
251. Receptors with internal ion channel GABAA receptor, nicotonic acetylcholine receptors, ionotropic glutamate receptors, etc.Receptor for gama-amino butyric acid includes chlorine (Cl-) channel, which is opened in response to binding of GABA. Chlorine inputs into cell and hyperpolarization of membrane occurs; so it is inhibitory receptor. There are many modulation sites on GABAA receptor, for example benzodiazepines, barbiturates or ethanol positively modulate activity of this receptor.
262. Receptors Associated with G Proteins adenylyl cyclase systemphosphoinositide systemarachidonic acid systemIt is assumed that signal transduction mediated by receptors associated with G proteins and 2nd messenger systems are altered at mental disorders and during treatment with psychotropic drugs. Scheme for hypothesis of second messengers in signal transduction is on Figure.After activation of receptor by first messenger G proteins are activated and activated G proteins activate effectors enzymes, such as adenylyl cyclase or phospholipase C, and second messengers are produced. Second messenger activate protein kinase of type A, C or calmoduline dependent, which catalyses phosphorylation of cellular proteins and physiological response to receptor activation arises.2nd messengers generated by enzymes activated by G proteins include cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), inositoltriphosphate (IP3), diacylglycerol (DG), calcium (Ca2+), metabolites of arachidonic acid and nitric oxide.Transcription factors can be phosphorylated too, and phosphorylated transcription factors serve as third messengers, which activate gene expression.According to type of 2nd messenger used there are three main pathways of signal transduction studied in biological psychiatry:adenylyl cyclase system;phosphoinositide system;arachidonic acid system.
27Receptors Associated with G Proteins SYSTEMAdenylyl cyclase systemPhosphoinositide systemArachidonic acid systemNEURO-TRANSMITTERNE, 5-HT, DA, AchHistamineTRANSDUCERGs, GiGpUnknown G-proteinPRIMARY EFFECTORAdenylyl cyclasePhospholipase CPhospholipase ASECONDARY MESSENGERcAMPIP3, DAG, Ca++Arachidonic acidSECONDARY EFFECTORProtein kinase ACalcium and calmoduline dependent protein kinasesProtein kinase C5-Lipoxygenase12-LipoxygenaseCycloxygenaseThe secondary messenger is cAMP, IP3, DAG, calcium or arachidonic acid metabolites.Basic properties of several secondary messenger systems are summarized in the Table: adenylyl cyclase system, phosphoinositide system, and arachidonic acid system. They all are quite similar in overall mechanism.Adenylyl cyclase produces cAMP, which activates protein kinase type A.The enzyme phospholipase C produces diacylglycerol and inositol triphosphate; inositol triphosphate increases intracellular calcium levels. Diacylglycerol activates protein kinase C, calcium and calmoduline activates other protein kinases.Proteinkinases phosphorylate cellular proteins, including transcription factors, which lead to physiological effects of receptor activation.
28Types of Receptors System Type acetylcholinergic acetylcholine nicotinic receptorsacetylcholine muscarinic receptorsmonoaminergic1-adrenoceptors2-adrenoceptors-adrenoceptorsdopamine receptorsserotonin receptoraminoacidergicGABA receptorsglutamate ionotropic receptorsglutamate metabotropic receptorsglycine receptorshistamine receptorspeptidergicopioid receptorsother peptide receptorspurinergicadenosine receptors (P1 purinoceptors)P2 purinoceptorsReceptors are pharmacologically classified according to neurotransmitter whereby they are activated. Primary types and selected subtypes of receptors, according to the international agreement, are summarized in following Tables. There are two primary acetylcholine receptor types – nicotinic and muscarinic, and three basic types of norepinephrine receptors – alpha1, alpha2 and beta. Glutamate receptors are divided into ionotropic and metabotropic receptors; ionotropic receptors include internal ion channel, metabotropic receptors are coupled with G proteins.It seems that monoaminergic receptors are the most important in pathophysiology of mental disorders; however, aminoacidergic receptors play important role also.Each type of receptors consists of several subtypes. Subtypes of monoaminergic receptors are summarized in following Tables.
29Subtypes of Norepinephrine Receptors TransducerStructure (aa/TM)1-adrenoceptors1AGq/11IP3/DAG466/71B519/71D572/72-adrenoceptors2AGi/ocAMP450/72B2C461/72D-adrenoceptors1GscAMP477/72413/73Gs, Gi/o408/7There are three subtypes of alpha1 adrenoceptors, four subtypes of alpha2 adrenoceptors and three subtypes of beta adrenoceptors. All are connected with G proteins.
30Subtypes of Dopamine Receptors TransducerStructure (aa/TM)dopamineD1GscAMP446/7D2GiGq/11cAMPIP3/DAG, K+, Ca2+443/7D3400/7D4cAMP, K+386/7D5477/7There are five subtypes of dopamine receptors.
31Subtypes of Serotonin Receptors TransducerStructure5-HT(5-hydroxytryptamine)5-HT1AGi/ocAMP421/75-HT1B390/75-HT1D377/75-ht1E365/75-ht1F366/75-HT2AGq/11IP3/DAG471/75-HT2B481/75-HT2C458/75-HT3internal cationic channel4785-HT4GscAMP387/75-ht5A?357/75-ht6440/75-HT7445/7There are 13 subtypes of serotonin receptors. All monoaminergic receptors are connected with G proteins except for serotonin 3 subtype, which include ion channel.To understand mechanism of action of psychotropic drugs it is necessary to know transduction mechanism of receptor system which is affected by the drug. E.g., some drug which operates as antagonist of presynaptic alpha2-receptors on serotonergic synapse induces increased serotonergic transmission, because alpha2-adrenoceptors are connected with inhibitory Gi proteins.
32Feedback to Transmitter-Releasing There are many neurotransmitters, many receptors, less G proteins and a few effector systems. But there are many feedbacks at the cellular level and many cross-reactions at the intracellular level. That results in divergence or convergence of signals.Example of negative feedback in synapse is on Figure: Norepinephrine released from noradrenergic synapse can diffuse to adjacent acetylcholinergic synapse and can activate presynaptic alpha2 receptors. Because alpha2 receptors are inhibitory receptors, activation of noradrenergic synapse can cause inhibition of acetylcholinergic synapse. There is great number of similar feedbacks.
33Crossconnection of Transducing Systems on Postreceptor Level AR – adrenoceptorG – G proteinPI-PLC – phosphoinositide specific phospholipase CIP3 – inositoltriphosphateDG – diacylglycerolCaM – calmodulinAC – adenylyl cyclasePKC – protein kinase CExample of intracellular cross connection is on Figure: Activation of serotonin 2 receptor leads to production of diacylglycerol (DAG) as 2nd messenger and DAG activates protein kinase C (PKC). Protein kinase C can phosphorylate adenylyl cyclase and positive regulation of transduction system connected with adrenoreceptors occurs. Protein kinase C can affect noradrenergic signal transduction through direct phosphorylation of receptors, or G proteins also. So, final effect is depended both on differences between subtypes of G proteins and on relative abundance of protein kinase C.
34Psychotropic DrugsBiochemical hypotheses of mental disorders are based on the study of mechanisms of action of psychotropic drugs at the level of:chemical synapseintracellular processes connected with signal transductionBiochemical hypotheses of mental disorders are based on the study of mechanisms of action of psychotropic drugs at the level of chemical synapse, or intracellular processes connected with signal transduction. So, study of mechanisms of action of psychotropic drugs is essential in understanding of etiology of mental disorders.
35Classification of Psychotropics parametereffectgroupwatchfulness (vigility)positivepsychostimulant drugsnegativehypnotic drugsaffectivityantidepressantsanxiolyticsdysphoric drugspsychic integrationsneuroleptics, atypical antipsychoticshallucinogenic agentsmemorynootropicsamnestic drugsClassification psychotropic drugs according to effects on mental functions is shown in Table. They are divided according to effects on watchfulness, affectivity, psychic integration or memory. The effect of the drug can be either positive, or negative. E.g. hallucinogens take negative effects and antipsychotics take positive effects on psychic integrations.
36Main Psychotropic Drugs AntipsychoticsAntidepressantsAnxiolyticsHypnoticsCognitivesPsychostimulantsHallucinogensMain psychopharmacological drugs are:AntipsychoticsAntidepressantsAnxiolyticsHypnoticsCognitivesPsychostimulantsHallucinogensLecture of prof. Faltus „Psychopharmacology“ occupies itself by these drugs in details. I will talk about biochemical mechanisms of action of antipsychotics and antidepressants only, because they are the most frequently used drugs in psychiatry.
37Potential 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 expressionCentral nervous system drugs act primary as agonists or antagonists of neurotransmitter receptors, inhibitors of regulatory enzymes, and blockers or stimulators of neurotransmitter transporters.Potential action of psychotropic drugs is summarized in the Table. Affected are: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
38Classification of Antipsychotics GroupExamplesConventional antipsychotics(classical neuroleptics)chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazinedroperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazineAtypical antipsychotics(antipsychotics of 2nd generation)amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazoleAntipsychotics are divided into two groups:Conventional antipsychoticsAtypical antipsychoticsConventional antipsychotics can be divided on basal and incisive; however, this division is obsolete and it is not used already.
39Mechanisms of Action of Antipsychotics Conventional antipsychoticsD2 receptor blockade of postsynaptic in the mesolimbic pathwayAtypical antipsychoticsD2 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 schizophreniaAll conventional antipsychotics have affinity to dopamine 2 receptors and act as their blockators. They affect positive symptoms of schizophrenia mainly (hallucinations, delusions, bizarre behaviour, positive formal thought disorder). They bring about anticholinergic, antihistaminic, cardiovascular side effect, and extrapyramidal symptoms (EPS).Atypical antipsychotics (serotonin-dopamine antagonists) are antagonists of dopamine 2 and serotonin 2A receptors, but they can affect many other types of receptors. They are much more efficient in treatment of negative symptoms of schizophrenia (alogia, affective flattening, avolition-apathy, anhedonia-asociality, attentional deficit) in comparison with conventional antipsychotics. Atypical antipsychotics have lower side effects - lower extrapyramidal symptoms or tardive dyskinesis.
40Receptor Systems Affected by Atypical Antipsychotics risperidoneD2, 5-HT2A, 5-HT7, 1, 2sertindoleD2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1ziprasidoneD2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, 1, NRI, SRIloxapineD2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, M1, H1, NRIzotepineD2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, 1, H1, NRIclozapineD2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1olanzapineD2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, 1, M1-5, H1quetiapineD2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1aripiprazoleD2, 5-HT2A, 5-HT1A, 1, 2, H1Receptor systems affected by atypical antipsychotics are summarized in the Table. All atypical antipsychotics are inhibitors of dopamine 2 and serotonin 2A receptors. But they affect many other receptor types or transporters; these effects could be related to their positive effects on affective symptoms. So, atypical antipsychotics are effective in the treatment of schizoaffective disorder, and some atypical antipsychotics are used in treatment of bipolar affective disorder also.
41Classification of Antidepressants (based on acute pharmacological actions) Inhibitors of neurotransmitter catabolismmonoamine oxidase inhibitors (IMAO)Reuptake inhibitorsserotonin 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 receptors5-HT1AAntagonists of receptors2-AR5-HT2Inhibitors or stimulators of other components of signal transductionExamples, clinical use and division of antidepressants is included in the lecture of prof. Faltus (Psychopharmacology). So, I mention biochemical mechanisms of their action only.Molecular mechanisms of action of antidepressants are much more diverse than that of antipsychotics.Classification of antidepressants based on their acute pharmacological actions is shown in the Table.The most of antidepressants takes effect as inhibitors of neurotransmitter catabolism or reuptake inhibitors. Some antidepressants are agonists or antagonists of receptors and some affect intracellular components of signal transduction.
42Action of SSRISelective serotonin reuptake inhibitors (SSRI) are the most frequently used antidepressants. Their receptor mechanism of action on serotonergic neuron in a depressed patient is shown on Figure.Before treatment (A):There is relative deficiency of serotonin in a depressed patient.Number of serotonin receptors is up-regulated, including presynaptic autoreceptors as well as postsynaptic receptors.Releasing of serotonin from synaptic knob can be affected: 1. positively by activity of serotonin transporter (SERT), or by tryptophan (serotonin precursor) availability; 2. negatively by activation both presynaptic inhibitory receptors - serotonin 1B or noradrenergic alpha2 receptor, and somatodendritic receptors - serotonin 1A receptors decrease firing rate of action potentials.After acute administration of SSRI (B):A considerable part of serotonin transporters is blocked and serotonin remains for a longer time in extracellular space. This induce the increase of serotonin in the somatodendritic area mainly.Negative feedback mediated by inhibitory presynaptic and somatodendritic receptors is increased and both frequency of firing of action potentials and amount of serotonin released from presynaptic button is decreased.After chronic treatment by SSRI (C):The increased serotonin at the inhibitory somatodendritic serotonin 1A receptors causes them to down-regulate and/or desensitise. It results in increase of frequency of firing of action potentials and in increase of the amount of serotonin released to synaptic cleft. The marked increase of serotonin release in the axon terminal is delayed as compared with the processes after acute administration of SSRI. This delay may explain why therapeutic action of antidepressants is not immediate.The increased serotonin at the axon terminal causes down-regulation and/or desensitization of postsynaptic and presynaptic receptors. This desensitization may mediate the reduction of side effects of SSRI.
43Biological Hypotheses of Mental Disorders SchizophreniaAffective disordersAt the end of my lecture I introduce some biological hypotheses of schizophrenia or affective disorders.
44SchizophreniaBiological models of schizophrenia can be divided into four related classes:Environmental modelsGenetic modelsNeurodevelopmental modelsDopamine hypothesisSchizophrenia is specific human disease.Biological models of schizophrenia can be divided into four related classes:Environmental modelsGenetic modelsNeurodevelopmental modelsDopamine hypothesisEnvironmental models suppose that either stress or physical factors are the main evoking phenomenon in schizophrenia.Evidence for a genetic contribution to schizophrenia comes from twin and familiar studies mainly.The leading hypothesis for the aetiology of schizophrenia is related to disturbance in normal brain development.From the biochemical point of view, dopamine hypothesis is the most important
45Schizophrenia - Genetic Models Multifactorial-polygenic 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.Genetic data support multifactorial-polygenic threshold model. According to this model schizophrenia is the result of a combined effects 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.However, specific genes responsible for schizophrenia are not known.
46Schizophrenia - 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.The principal assumption of neurodevelopmental models is that normal brain development is disrupted in specific ways at critical periods of lifetime. Resulting lesions and damages produce the symptoms of schizophrenia only through interaction with the normal maturation processes in the brain, which occur in late adolescence or early adulthood.Neurodevelopmental hypothesis states that 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.The neurodevelopmental model therefore directs attention to both genetic and no genetic risk factors that may have impacted on the developing brain during prenatal and perinatal life.Genetic contribution to schizophrenia development consists in wrong genetic program for the normal formation of synapses and migration of neurons in the developing brain.No genetic contribution to schizophrenia consists in effects of pregnancy and birth complications (PBCs), such as viral infections in utero, gluten sensitivity, brain malformations, and obstetric complications.
47Basis of Classical Dopamine Hypothesis of Schizophrenia Dopamine-releasing 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.The biochemical hypotheses of schizophrenia are orientated towards the role of neurotransmitters and their receptors - dopamine, serotonin, glutamate, GABA and norepinephrine mainly.Dopamine plays a key role in biochemical hypotheses of schizophrenia. Dopamine hypothesis of schizophrenia was formulated almost 40 years ago and plays a prominent role in schizophrenia research.Basis of classical dopamine hypothesis of schizophrenia are summarized on the slide:Dopamine-releasing drugs, such as amphetamine, mescaline, LSD (diethyl amide of lysergic acid) 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 as a result of blockade of postsynaptic dopamine receptors or as a result of desensitisation of inhibitory dopamine autoreceptors localized on cell bodies.
48Classical 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.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 2 receptors. This increased activity can be localized in specific brain regions.
49Biological Psychiatry and Affective Disorders BIOLOGYgeneticsvulnerability to mental disordersstressincreased sensitivitychronobiologydesynchronisation of biological rhythmsNEUROCHEMISTRYneurotransmittersavailability, metabolismreceptorsnumber, affinity, sensitivitypostreceptor processesG proteins, 2nd messengers, phosphorylation, transcriptionIMMUNONEURO-ENDOCRINOLOGYHPA (hypothalamic-pituitary-adrenocortical) systemincreased activity during depressionimmune functiondifferent changes during depressionAffective disorders are characterized by depression, mania, or both.Depression and mania are thought to be heterogeneous illnesses that can result from dysfunction of several neurotransmitter or metabolic systems. Approaches of biological psychiatry to the study of affective disorders are summarized in the Table:they are biological approaches which include genetic effects, effect of stress, effect of disturbed chronobiology;neurochemical approaches include properties of neurotransmitter systems – neurotransmitters, receptors, effector system;immunoneuroendocrinological approaches are based on observation of increased activity hypothalamic-pituitary-adrenocortical (HPA) axis during depression and on changes in immune systemI introduce some neurochemical hypotheses of affective disorders.There are evidences that the monoamine neurotransmitter systems are involved in the treatment of affective disorders. Studies have led to a series of hypotheses concerning the mechanism of the action of antidepressant treatments, as well as pathophysiology of depression, that have focused on alterations in brain levels of serotonin and norepinephrine or their receptors.
50Data for Neurotransmitter Hypothesis Tricyclic antidepressants through blockade of neurotransmitter reuptake increase neurotransmission at noradrenergic and serotonergic synapsesMAOIs increase availability of monoamine neurotransmitters in synaptic cleftDepressive symptoms are observed after treatment by reserpine, which depletes biogenic amines in synapseOriginal biochemical hypotheses of affective disorders were neurotransmitter hypotheses.Discovery of the tricyclic antidepressants implied hypothesis about significant role for the biogenic amine, particularly norepinephrine and serotonin in the ethiopathogenesis of affective disorders.Reduced activity of the serotonergic and noradrenergic systems has been reported in subgroups of patients with major depression, but this has not been observed in all depressed patients.Data for neurotransmitter hypothesis are derived from observations that:tricyclic antidepressants through blockade of neurotransmitter reuptake increase neurotransmission at noradrenergic and serotonergic synapses;inhibitors of monoamine oxidase (MAOIs) increase availability of monoamine neurotransmitters in synaptic cleft;depressive symptoms are observed after treatment by reserpine, which depletes biogenic amines in synapse.
51Monoamine HypothesisDepression 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.The first major theory about the biological ethiology of depression was monoamine hypothesis supposing that depression was due to a deficiency of monoamine neurotransmitters, norepinephrine and serotonin. Inhibitors of monoamine oxidase act as antidepressants by blocking of enzyme which degrade monoamine neurotransmitters, thus allowing presynaptic accumulation of monoamine neurotransmitters. Tricyclic antidepressants act as antidepressants by blocking membrane transporters ensuring reuptake of serotonin or norepinephrine, thus causing increased extracellular neurotransmitter concentrations.According to advanced monoamine theory, serotonin or norepinephrine levels in the brain are regulated by monoamine oxidase type A (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.
52Permissive 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).Permissive biogenic amine hypothesis interconnect serotonergic and noradrenergic systems; this neurotransmitter hypothesis persists as part of more recent hypothesis.The hypothesis states that 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).
53Receptor HypothesesThe 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 common problem of neurotransmitter hypotheses is that they are unable to explain why therapeutic effects of antidepressants become evident after several weeks of pharmacotherapy. This was reason why receptor hypothesis of affective disorders were formulated.The receptor hypothesis posits that disturbance occurs in function of receptors for the key monoamine neurotransmitters. Such wrong receptor function may be caused by depletion of monoamine neurotransmitters, by abnormalities in the receptor, or by problems with signal transduction on postreceptor level.According to 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.
54Receptor Hypotheses 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 -AR in depression. Long-term antidepressant treatment causes down regulation of 1-AR. Transient increase of neurotransmitter availability can cause fault to mania.It was formulated a large amount of receptor hypotheses.Very elegant but not confirmed was receptor catecholamine hypothesis: Supersensitivity of catecholamine receptors in the presence of low levels of serotonin is the biochemical basis of depression.The common result of chronic treatment by majority of antidepressants is the down regulation of beta-adrenergic receptors, which can be modulated by interaction with the serotonin system, dopamine system, neuropeptides and hormones. Classical norepinephrine receptor hypothesis of affective disorders was formulated: There is increased density of postsynaptic beta-adrenoceptors in depression due to decreased norepinephrine release, or disturbed interactions of noradrenergic, serotonergic and dopaminergic systems. Long-term antidepressant treatment causes down regulation of beta-adrenoceptors by inhibition of norepinephrine reuptake, stimulation or blockade of receptors, regulation through serotonergic or dopaminergic systems, etc. Transient increase of neurotransmitter availability can cause fault to mania.
55Neurotransmitter Regulation of Mood and Behavior MotivationPleasureRewardAlertnessEnergyDopamineNorepinephrineAttentionInterestObsessionCompulsionMoodAnxietyHowever, common receptor system affected by all antidepressants was not found. Proposed neurotransmitter regulation of mood and behavior is summarized in Figure.Moreover, different neurotransmitters may be responsible for different symptoms of depression, depending on which brain regions are affected.Changes in norepinephrine, dopamine, glutamate, and GABA in cortical regions may contribute to depressed mood, cognitive dysfunction, anhedonia, and apathy.Dysfunctional transmission of dopamine and norepinephrine in the prefrontal cortex can impair concentration and decisiveness.Anxiety, guilt, and negative emotions are influenced by serotonergic activity in the limbic system as well as by lack of glutamate reuptake or metabolism in amygdala, etc.SerotoninNutt 2008
56Postreceptor 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.The introduction of new, more selective antidepressants and unknown mechanisms of action of mood stabilizers (lithium, valproate) led to new reflection upon the mechanism of their action.Most promising are recent investigations of the postreceptor events, i.e. second messenger systems, adenylyl cyclase system, phospholinositide system, G proteins, transcription factors etc.Neurotrophic hypothesis (molecular and cellular theory) of depression was formulated in 1997 and it is leading current neurochemical hypothesis.According to neurotrophic hypothesis the transcription factor CREB (cAMP response element-binding protein) 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
57Neurotrophic Effects of Antidepressants Neurotrophic effects of antidepressants are shown on the picture.On the left you can see hippocampal pyramidal neuron in normal state. Innervations with monoaminergic, glutamanergic neurons and others is indicated. Activity and plasticity of the neuron is regulated by neurotrophin BDNF and by transcription factor CREB.In the middle are imaged changes in the neuron after heavy stress or as a result of increased glucocorticoid levels. Dendritic tree is reduced and density of synaptic spines is decreased, probably in connection with decrease of expression of BDNF.On the right is shown effect of long-term treatment with antidepressants, which induce opposite effects on dendritic tree and synaptic spine density, probably due to increase of expression of neurotrophic factor BDNF.Nestler et al. 2002
58Antidepressant Treatments A model for the molecular mechanism of action of antidepressant treatments is shown on Figure.Antidepressant treatment causes inhibition of serotonin and norepinephrine reuptake or breakdown.Short-term antidepressant treatment increase extracellular levels of serotonin and norepinephrine.Long-term treatment leads to decrease in the function and expression of serotonin and norepinephrine receptors, to increase in the cAMP signal transduction, and to increase in expression of the transcription factor CREB.Increased activity of the cAMP signal transduction cascade indicates that the functional output of serotonin and norepninephrine is up-regulated, even though levels of certain serotonin and norepinephrine receptors are down-regulated.Expression of BDNF and its receptor trkB is also increased by long-term antidepressant treatment, so increased neuronal survival occurs.
59Laboratory Survey in Psychiatry Laboratory survey methods in psychiatry coincide with internal and neurological methods:Classic and special biochemical and neuroendocrine testsImmunological testsElectrocardiography (ECG)Electroencephalography (EEG)Computed tomography (CT)Nuclear magnetic resonance (NMR)Phallopletysmography
60Classic and Special Biochemical Tests Indicationserum cholesterol (3,7-6,5 mmol/l) and lipemia (5-8 g/l)brain disease at atherosclerosischolesterolemia, TSH, T3, T4, blood pressure, mineralogram (calcemia, phosphatemia)thyroid disorder, hyperparathyreosis or hypothyroidism can be an undesirable side effect of Li-therapyhepatic tests: bilirubin (total < 17mmol/l), cholesterol, aminotranspherase (AST, ALT, TZR, TVR), alkaline phosphatasebefore pharmacotherapy and in alcoholicsglycaemiadiabetes mellitusblood pictureduring pharmacotherapydetermination of metabolites of psychotropics in urine or in bloodcontrol or toxicologylithemia (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
61Classic and Special Biochemical Tests Indicationdetermination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, DA metabolite), hydroxyindolacetic acid (HIAA, 5-HT metabolite), methoxyhydroxyphenylglycole (MHPG, NE metabolite)researchneurotransmitter receptors and transporterscerebrospinal 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 testdepressive disordersprolactin determinationincreased during treatment with neuroleptics
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