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Biochemistry and Biological Psychiatry. Department of Psychiatry 1 st Faculty of Medicine Charles University, Prague Head: Prof. MUDr. Jiří Raboch, DrSc. Introduction.
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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.
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.
Criteria to Identify Neurotransmitters • There are two main groups of neurotransmitters: • classical neurotransmitters • neuropeptides
Membrane Receptors • Receptor is macromolecule specialized on transmission of information. • Receptor complex includes: • Specific binding site • Transduction element • Effector system (2nd messengers) • Regulation of receptors: • Number of receptors (down-regulation, up-regulation) • Properties of receptors (desensitisation, hypersensitivity)
Receptor Classification • Receptor coupled directly to the ion channel • Receptor associated with G proteins • Receptor with intrinsic guanylyl cyclase activity • Receptor with intrinsic tyrosine kinase activity
Receptors Associated with G Proteins • adenylyl cyclase system • phosphoinositide system
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
Classification of Antidepressants(based on acute pharmacological actions)
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 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.
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.
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 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.
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
