1. Biochemistry and Biological Psychiatry ass. prof. Zdeněk Fišar, CSc. Department of Psychiatry 1st Faculty of Medicine Charles University, Prague Head: prof. MUDr. Jiří Raboch, DrSc.

2. 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)

3. 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)

4. 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.

5. Cellular Neurochemistry • Neurons • Action potentials • Synapses

6. 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.

7. 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.

8. Morphology of Chemical Synapse

9. Chemical Synapse - Signal Transduction

10. Model of Plasma Membrane

11. Membrane Transporters

12. Intercellular and Intracellular Signalling • Neurotransmitters • Growth factors • Receptors • G proteins • Effectorsystems (2nd messengers, proteinkinases, transcription factors)

13. Criteria to Identify Neurotransmitters • There are two main groups of neurotransmitters: • classical neurotransmitters • neuropeptides

14. Selected Classical Neurotransmitters nitric oxide

15. Catecholamine Biosynthesis

16. Serotonin Biosynthesis

17. Reuptake and Metabolism of Monoamine Neurotransmitters • Reuptake • Monoamine oxidase (MAO) • Catechol-O-methyltransferase (COMT)

18. Selected Bioactive Peptides

19. Growth Factors in the Nervous System

20. Membrane Receptors • Receptor is macromolecule specialized on transmission of information. • Receptor complex includes: • Specific binding site • Internal ion channel or transduction element • Effector system (ion channels or system of 2nd messengers)

21. Regulation of receptors • Density of receptors (down-regulation, up-regulation) • Properties of receptors (desensitisation, hypersensitivity)

22. 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

23. 1. Receptors with Internal Ion Channel

24. acetylcholine membrane receptor acetylcholine 1. Receptors with Internal Ion Channel Nicotinic acetylcholine receptor is made of 5 subunits, 2 of which (shown in orange) bind acetylcholine (red).

25. 1. Receptors with internal ion channel GABAA receptor, nicotonic acetylcholine receptors, ionotropic glutamate receptors, etc.

26. 2. Receptors Associated with G Proteins • adenylyl cyclase system • phosphoinositide system • arachidonic acid system

27. Receptors Associated with G Proteins

28. Types of Receptors

29. Subtypes of Norepinephrine Receptors

30. Subtypes of Dopamine Receptors

31. Subtypes of Serotonin Receptors

32. Feedback to Transmitter-Releasing

33. 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

34. 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

35. Classification of Psychotropics

36. Main Psychotropic Drugs • Antipsychotics • Antidepressants • Anxiolytics • Hypnotics • Cognitives • Psychostimulants • Hallucinogens

37. Potential Action of Psychotropics

38. Classification of Antipsychotics

39. Mechanisms of Action of Antipsychotics

40. Receptor Systems Affected by Atypical Antipsychotics

41. Classification of Antidepressants(based on acute pharmacological actions)

42. Action of SSRI

43. Biological Hypotheses of Mental Disorders • Schizophrenia • Affective disorders

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

45. 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.

46. 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.

47. Basis 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.

48. 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.

49. Biological Psychiatry and Affective Disorders

50. Data for Neurotransmitter Hypothesis