Biochemistry and Biological Psychiatry
Department of Psychiatry 1st Faculty of Medicine Charles University, Prague Head: Prof. MUDr. Jiří Raboch, DrSc.
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.
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.
Model of Plasma Membrane
Synapse
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.
Morphology of Chemical Synapse
Synapses
Chemical Synapse Signal Transduction
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 Cholinergic Aminoacidergic
Monoaminergic
Transmitter acetylcholine GABA, aspartic acid, glutamic acid, glycine, homocysteine dopamine, norepinephrine, epinephrine tryptamine, serotonin histamine, taurine adenosine, ADP, AMP, ATP
• Catecholamines
• Indolamines
• Others, related to aa Purinergic
Catecholamine Biosynthesis
Serotonin Biosynthesis
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) hypothalamic releasing factors
neuronal
growth hormone (GH), prolactin (PRL), lutenizing hormone (LH), thyrotropin (TSH) oxytocin, vasopressin atrial natriuretic peptide (ANF), vasoactive intestinal peptide (VIP) enkephalines (met-, leu-), dynorphin, -endorphin
pituitary hormones neurohypophyseal peptides neuronal and endocrine opiate peptides
Membrane Transporters
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
Neurokines
Fibroblast growth factors
Transforming growth factor superfamily
Epidermal growth factor superfamily Other growth factors
Transforming growth factors (TGF) Bone morphogenetic factors (BMPs) Glial-derived neurotrophic factor (GDNF) Neurturin
Epidermal growth factor (EGF) Transforming growth factor (TGF) Neuregilins 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. Transduction element 3. Effector system (2nd messengers)
Regulation of receptors:
1. Number of receptors (down-regulation, upregulation) 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
GABAA Receptor
Receptors Associated with G Proteins
• adenylyl cyclase system • phosphoinositide system
Types of Receptors
System
acetylcholinergic monoaminergic
Type
acetylcholine nicotinic receptors acetylcholine muscarinic receptors 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 Gq/11 Gq/11 Gq/11 Gi/o Transducer IP3/DAG IP3/DAG IP3/DAG cAMP Structure (aa/TM) 466/7 519/7 572/7 450/7
2B
2C
Gi/o
Gi/o
cAMP
cAMP
450/7
461/7
2D
-adrenoceptors 1 2 3
Gi/o
Gs Gs
cAMP
cAMP cAMP
450/7
477/7 413/7 408/7
Gs, Gi/o cAMP
Subtypes of Dopamine Receptors
RECEPTORS dopamine Subtype D1 Gs Transducer cAMP Structure (aa/TM) 446/7
D2
Gi Gq/11
Gi
cAMP IP3/DAG, K+, Ca2+
cAMP
443/7
D3
400/7
D4
D5
Gi
Gs
cAMP, K+
cAMP
386/7
477/7
Subtypes of Serotonin Receptors
RECEPTORS 5-HT
(5-hydroxytryptamine)
Subtype 5-HT1A 5-HT1B Gi/o Gi/o
Transducer cAMP cAMP
Structure 421/7 390/7
5-HT1D
5-ht1E
Gi/o
Gi/o
cAMP
cAMP
377/7
365/7
5-ht1F
5-HT2A 5-HT2B 5-HT2C 5-HT3
Gi/o
Gq/11 Gq/11 Gq/11
cAMP
IP3/DAG IP3/DAG IP3/DAG
366/7
471/7 481/7 458/7
internal cationic channel 478
5-HT4
5-ht5A
Gs
?
cAMP
387/7
357/7
5-ht5B
5-ht6 5-HT7
?
Gs Gs cAMP cAMP
370/7
440/7 445/7
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
Interaction of Amphiphilic Drugs with Membrane
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
Classification of Psychotropics
parameter effect group
watchfulnes (vigility)
affectivity
positive
negative positive
psychostimulant drugs
hypnotic drugs antidepressants anxiolytics
negative
psychic integrations memory positive
dysphoric drugs
neuroleptics, atypical antipsychotics
negative
positive
hallucinogenic agents
nootropics
negative
amnestic drugs
Classification of Antipsychotics
group 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
conventional antipsychotics (classical neuroleptics) incisive antipsychotics
basal (sedative) antipsychotics
atypical antipsychotics (antipsychotics of 2nd generation)
Mechanisms of Action of Antipsychotics
D2 receptor blockade of postsynaptic in conventional the mesolimbic pathway antipsychotics D2 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 schizophrenia
atypical antipsychotics
Receptor Systems Affected by Atypical Antipsychotics
risperidone D2, 5-HT2A, 5-HT7, 1, 2
sertindole D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1 ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI loxapine D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1, 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
Classification of Antidepressants
(based on acute pharmacological actions)
inhibitors of monoamine oxidase inhibitors (IMAO) neurotransmitter catabolism
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-HT2A antagonist/reuptake inhibitors (SARI)
5-HT1A 2-AR, 5-HT2
agonists of receptors antagonists of receptors
inhibitors or stimulators of other components of signal transduction
Action of SSRI
Schizophrenia
Biological models of schizophrenia can be divided into three related classes: Environmental models Genetic models Neurodevelopmental models
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 noninherited 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. 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 utero gluten sensitivity brain malformations obstetric complications
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. 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.
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.
Biological Psychiatry and Affective Disorders
BIOLOGY genetics stress chronobiology NEUROCHEMISTRY
vulnerability to mental disorders increased sensitivity desynchronisation of biological rhythms number, affinity, sensitivity G proteins, 2nd messengers, phosphorylation, transcription increased activity during depression
neurotransmitters availability, metabolism receptors postreceptor processes
IMMUNONEUROENDOCRINOLOGY
HPA (hypothalamicpituitaryadrenocortical)
system
immune function
different changes during depression
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
Neurotransmitter Hypothesis of Affective Disorders
catecholamine hypothesis indolamine hypothesis cholinergic-adrenergic balance hypothesis „permissive“ hypothesis dopamine hypothesis
hypothesis of biogenic amine monoamine hypothesis
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.
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.
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.
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 (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.
Postreceptor Hypotheses
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.
Antidepressant Treatments
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
serum cholesterol (3,7-6,5 mmol/l) and lipemia (5-8 g/l)
Indication
brain disease at atherosclerosis thyroid disorder, hyperparathyreosis or hypothyroidism can be an undesirable side effect of Li-therapy before pharmacotherapy and in alcoholics diabetes mellitus during pharmacotherapy
cholesterolemia, TSH, T3, T4, blood pressure, mineralogram (calcemia, phosphatemia)
hepatic tests: bilirubin (total < 17mmol/l), cholesterol, aminotranspherase (AST, ALT, TZR, TVR), alkaline phosphatase glycaemia blood picture
determination of metabolites of psychotropics in urine or in blood
lithemia (0,4-1,2 mmol/l), function of thyroid and kidney (serum creatinine, urea), pH of urine, molality, clearance, serum mineralogram (Na, K)
control or toxicology
during lithiotherapy
Classic and Special Biochemical Tests
Test
determination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, DA metabolite), hydroxyindolacetic acid (HIAA, 5research HT metabolite), methoxyhydroxyphenylglycole (MHPG, NE metabolite)
Indication
neurotransmitter receptors and transporters
cerebrospinal fluid: pH, tension, elements, abundance of globulins (by electrophoresis)
research
diagnosis of progressive paralysis, …
neuroendocrinne stimulative or suppressive tests: dexamethasone suppressive test (DST), depressive disorders TRH test, fenfluramine test
prolactin determination
increased during treatment with neuroleptics