Biochemistry and Biological Psychiatry

ass. prof. Zdenk Fiar, CSc. Department of Psychiatry 1st Faculty of Medicine Charles University, Prague Head: prof. MUDr. Ji Raboch, DrSc.

Biochemistry 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)

Biological Psychiatry: Web Pages

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

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

Neurons Action potentials Synapses

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

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

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 rapid-onset and rapidly reversible responses in the target cell 5. Existence of specific receptor
There are two main groups of neurotransmitters: classical neurotransmitters neuropeptides

Selected Classical Neurotransmitters

System Transmitter

Cholinergic Aminoacidergic
Monoaminergic Catecholamines Indolamines

acetylcholine GABA, aspartic acid, glutamic acid, glycine, homocysteine

dopamine, norepinephrine, epinephrine tryptamine, serotonin

Others, related to aa Purinergic

histamine, taurine
adenosine, ADP, AMP, ATP nitric oxide

Catecholamine Biosynthesis

Serotonin Biosynthesis

Reuptake and Metabolism of Monoamine Neurotransmitters

Reuptake Monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT)

Selected Bioactive Peptides

Peptide Group
substance P, substance K (tachykinins), neurotensin, brain and cholecystokinin (CCK), gastrin, bombesin gastrointestinal peptides 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) pituitary hormones hypothalamic releasing factors

neuronal

oxytocin, vasopressin
atrial natriuretic peptide (ANF), vasoactive intestinal peptide (VIP) enkephalines (met-, leu-), dynorphin, -endorphin

neurohypophyseal peptides
neuronal and endocrine opiate peptides

Growth Factors in the Nervous System

Neurotrophins Nerve growth factor (NGF) Brain-derived neurotrophic factor (BDNF) Neurotrophin 3 (NT3) Neurotrophin 4/5 (NT4/5) Ciliary neurotrophic factor (CNTF) Leukemia inhibitory factor (LIF) Interleukin 6 (IL-6) Cardiotrophin 1 (CT-1)
FGF-1 FGF-2 Transforming growth factors (TGF) Bone morphogenetic factors (BMPs) Glial-derived neurotrophic factor (GDNF) Neurturin Epidermal growth factor (EGF) Transforming growth factor (TGF) Neuregilins

Neurokines

Fibroblast growth factors Transforming growth factor superfamily Epidermal growth factor superfamily

Other growth factors

Platelet-derived growth factor (PDGF) Insulin-like growth factor I (IGF-I)

Membrane Receptors

Receptor is macromolecule specialized on transmission of information.

Receptor complex includes:
1. Specific binding site 2. Internal ion channel or transduction element 3. Effector system (ion channels or system of 2nd messengers)

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

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

1. Receptors with Internal Ion Channel

1. Receptors with Internal Ion Channel

acetylcholine membrane

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

receptor

acetylcholine

1. Receptors with internal ion channel

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

2. Receptors Associated with G Proteins

1. adenylyl cyclase system 2. phosphoinositide system 3. arachidonic acid system

Receptors Associated with G Proteins

SYSTEM Adenylyl cyclase system Phosphoinositide Arachidonic acid system system NE, 5-HT, DA, Ach Gp Phospholipase C IP3, DAG, Ca++ Histamine Unknown Gprotein Phospholipase A Arachidonic acid 5-Lipoxygenase 12-Lipoxygenase Cycloxygenase NEURONE, 5-HT, DA, TRANSMITTER Ach TRANSDUCER Gs, Gi

PRIMARY EFFECTOR
SECONDARY MESSENGER SECONDARY EFFECTOR

Adenylyl cyclase cAMP

Calcium and calmoduline Protein kinase A dependent protein kinases Protein kinase C

Types of Receptors
System acetylcholinergic Type acetylcholine nicotinic receptors

acetylcholine muscarinic receptors

monoaminergic 1-adrenoceptors 2-adrenoceptors -adrenoceptors

dopamine receptors
serotonin receptor aminoacidergic GABA receptors glutamate ionotropic receptors

glutamate metabotropic receptors

glycine receptors histamine receptors peptidergic purinergic opioid receptors

other peptide receptors

adenosine receptors (P1 purinoceptors) P2 purinoceptors

Subtypes of Norepinephrine Receptors

RECEPTORS 1-adrenoceptors Subtype 1A 1B 1D 2-adrenoceptors 2A 2B Gq/11 Gq/11 Gq/11 Gi/o Gi/o Transducer IP3/DAG IP3/DAG IP3/DAG cAMP cAMP Structure (aa/TM) 466/7 519/7 572/7 450/7 450/7

2C
2D -adrenoceptors 1 2

Gi/o
Gi/o Gs Gs

cAMP
cAMP cAMP cAMP

461/7
450/7 477/7 413/7

Gs, Gi/o cAMP

408/7

Subtypes of Dopamine Receptors

RECEPTORS dopamine Subtype D1 D2 Gs Gi Gq/11 Gi Gi Gs Transducer cAMP cAMP IP3/DAG, K+, Ca2+ cAMP cAMP, K+ cAMP Structure (aa/TM) 446/7 443/7

D3 D4 D5

400/7 386/7 477/7

Subtypes of Serotonin Receptors

RECEPTORS 5-HT
(5-hydroxytryptamine)

Subtype 5-HT1A Gi/o

Transducer cAMP

Structure 421/7

5-HT1B
5-HT1D 5-ht1E 5-ht1F

Gi/o
Gi/o Gi/o Gi/o

cAMP
cAMP cAMP cAMP

390/7
377/7 365/7 366/7

5-HT2A
5-HT2B 5-HT2C 5-HT3 5-HT4 5-ht5A 5-ht6

Gq/11
Gq/11 Gq/11 Gs ? Gs

IP3/DAG
IP3/DAG IP3/DAG cAMP cAMP

471/7
481/7 458/7 387/7 357/7 440/7

internal cationic channel 478

5-HT7

Gs

cAMP

445/7

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
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 positive negative group psychostimulant drugs hypnotic drugs

affectivity

positive

antidepressants
anxiolytics

negative

dysphoric drugs

psychic integrations
memory

positive
negative positive negative

neuroleptics, atypical antipsychotics

hallucinogenic agents nootropics amnestic drugs

Main Psychotropic Drugs

Antipsychotics Antidepressants Anxiolytics Hypnotics Cognitives Psychostimulants Hallucinogens

Potential Action of Psychotropics

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

Classification of Antipsychotics
Group Examples
chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine

Conventional antipsychotics (classical neuroleptics)

droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine
amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazole

Atypical antipsychotics (antipsychotics of 2nd generation)

Mechanisms of Action of Antipsychotics

Conventional D2 receptor blockade of postsynaptic in the mesolimbic pathway antipsychotics
D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms; enhanced dopamine release and 5-HT2A Atypical receptor blockade in the mesocortical pathway to reduce negative symptoms; antipsychotics other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia

Receptor Systems Affected by Atypical Antipsychotics

risperidone D2, 5-HT2A, 5-HT7, 1, 2
D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1 sertindole ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, loxapine M1, H1, NRI zotepine D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1, D3, D4, 1, H1, NRI clozapine D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1 olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1, D3, D4, D5, 1, M1-5, H1 quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1 aripiprazole D2, 5-HT2A, 5-HT1A, 1, 2, H1

Classification of Antidepressants
(based on acute pharmacological actions)
Inhibitors of neurotransmitter monoamine oxidase inhibitors (IMAO) catabolism serotonin reuptake inhibitors (SRI) norepinephrine reuptake inhibitors (NRI) selective SRI (SSRI) selective NRI (SNRI) serotonin/norepinephrine inhibitors (SNRI) norepinephrine and dopamine reuptake inhibitors (NDRI) 5-HT2A antagonist/reuptake inhibitors (SARI)

Reuptake inhibitors

Agonists of receptors
Antagonists of receptors

5-HT1A
2-AR 5-HT2

Inhibitors or stimulators of other components of signal transduction

Action of SSRI

Biological Hypotheses of Mental Disorders

Schizophrenia Affective disorders

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

Schizophrenia - 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.

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.

Basis of Classical Dopamine Hypothesis of Schizophrenia

1.

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.

2.

3.

Antipsychotics raise dopamine turnover.

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.

Biological Psychiatry and Affective Disorders

BIOLOGY genetics
vulnerability to mental disorders

stress
chronobiology

increased sensitivity
desynchronisation of biological rhythms number, affinity, sensitivity G proteins, 2nd messengers, phosphorylation, transcription increased activity during depression

NEUROCHEMISTRY neurotransmitters availability, metabolism receptors postreceptor processes IMMUNONEUROENDOCRINOLOGY HPA

(hypothalamicpituitaryadrenocortical)

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 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.

Permissive Biogenic Amine Hypothesis

A deficit in central serotonergic transmission permits affective disorder, but is insufficient for its cause; changes in central catecholaminergic transmission, when they occur in the context of a deficit in serotonergic transmission, act as a proximate cause for affective disorders and determine their quality (catecholaminergic transmission being elevated in mania and diminished in depression).

Receptor Hypotheses
The common final result of chronic treatment by majority of antidepressants is the downregulation or up-regulation of postsynaptic or presynaptic receptors. The delay of clinical response corresponds with these receptor alterations.

Receptor 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.

Neurotransmitter Regulation of Mood and Behavior

Dopamine
Motivation Alertness Pleasure Attention Energy Interest Reward Mood Anxiety Norepinephrine

Obsession Compulsion Serotonin

Nutt 2008

Postreceptor Hypotheses
Neurotrophic hypothesis (molecular and cellular theory) of depression: Transcription factor, cAMP response elementbinding protein (CREB), is one intracellular target of long-term antidepressant treatment and brain-derived neurotrophic factor (BDNF) is one target gene of CREB. Chronic stress leads to decrease in expression of BDNF in hippocampus. Long-term increase in levels of glucocorticoids, ischemia, neurotoxins, hypoglycaemia etc. decreases neuron survival. Long-term antidepressant treatment leads to increase in expression of BDNF and his receptor trkB through elevated function of serotonin and norepinephrine systems.
Duman et al. 1997

Neurotrophic Effects of Antidepressants

Nestler et al. 2002

Antidepressant Treatments

Thank you for your attention

Web pages: http://connect.lf1.cuni.cz http://portal.lf1.cuni.cz