depts.washington/stellalb/nbio.shtml

1. http://depts.washington.edu/stellalb/nbio.shtml

2. Neurobiology 404 Depression, mood disorders Schizophrenia

3. Emotion/feelings Two components: peripheral/physical central/mental Moods - sustained/emotional/feeling states Affect - momentary/emotional/feeling states

4. Disorders of Mood exaggerated or maladaptive emotions Unipolar depression Dysthymia Bipolar disorder

5. Depression

6. Andrew Solomon Anatomy of Melancholy

7. Demographics Depression is present in all cultures 10-20% of the population will experience at least one episode - really 50%? 1.5 - 2X more common in women Increasing occurrence since 1940 Decreasing age of onset since 1940 First episode often preceded by life stress

8. Genetics Occurrence of depression is higher among people with primary relatives who have been depressed. 40-60% concordance in identical twins 10% concordance in dizygotic twins Bipolar disorder vs. unipolar depression 80% concordance in identical twins

9. Drug effects on mood provided the first indication that depression is a disorder of nervous system functioning. Reserpine - produced depression Iproniazid - improved mood Tricyclics (imipramine) alleviated depression

10. Antidepressants alter amine neurotransmitter levels Biogenic amines - neuromodulators

11. Serotonin Affect/Mood Sleep Appetite Sexual behavior Endocrine function Synthesized from tryptophan Precursor of melatonin - sleep rhythms

12. Serotonergic projections

13. Norepinephrine (Noradrenaline) Affect Attention Reward Endocrine function Synthesized from the amino acid tyrosine

14. Noradrenergic projections

16. Antidepressants act at three locations in amine synapses MAO inhibitors Tricyclics SSRIs NSRIs Atypicals

18. Amine transmitter degradation Monoamine oxidase Amine transmitter concentrations NOT SPECIFIC

19. Reuptake inhibitors Amine reuptake Amine in synapse

20. The re-uptake transporters for NE, 5HT and DA comprise a gene family of similar molecules. *12 TM domains *Conserved residues

21. Reuptake transporters are specific to a single neurotransmitter Serotonin Norepinephrine Dopamine

23. NE transport activity

24. NE 5HT DA

25. Selective reuptake inhibitors SSRIs

26. NSRI - Reboxetine

27. Summary Depression is a common disorder that affects multiple neural and endocrine pathways. Drugs that alter amine neurotransmission alleviate the symptoms of depression Amines act largely as neuromodulators. They are released by a Small subset of neurons that have broad projections. Drugs that inhibit the transport of transmitter back into the presynaptic terminal are the most commonly used anti-depressants. Clinical use of antidepressants is tailored to the individual.

28. Amine hypothesis of depression Depression is due to a depletion of amine neurotransmitter. But drug effects on transporters are almost immediate yet anti-depressant action is not noticeable for several weeks.

29. Long term tricyclic administration leads to decreased receptor response to neurotransmitter.

30. Receptor desensitization Chronic receptor activation leads to decreased response to neurotransmitter Receptor internalization Chronic receptor activation leads to internalization of receptors or changes in receptor expression.

31. Amine transmitters activate G-protein-coupled receptors Effector e.g. cyclase Receptor R E a b g GDP Ion channel Trimeric G protein

32. Effector e.g. cyclase Receptor R E a b g Ion channel GTP GDP Trimeric G protein

33. b g Effector e.g. cyclase R E a Receptor GTP Ion channel opened or closed Generation of 2nd messengers e.g. cAMP

34. P b g Activation of receptors reveals a site that is phosphorylated by G Receptor Kinases (GRKs) Effector e.g. cyclase Receptor R E GRK a kinase GTP Ion channel opened or closed Generation of 2nd messengers e.g. cAMP

35. P Phosphorylation of receptors by G Receptor Kinase (GRK) leads to uncoupling from the G protein and recruitment of the protein arrestin effector Receptor a b arrestin g GDP Ion channel Trimeric G protein

36. P Arrestin promotes receptor internalization effector a b g GDP endosome Ion channel Trimeric G protein Receptor arrestin

37. P P Two effects of receptor occupation effector desensitization Receptor a b g A Ion channel G protein effector internalization a b g endosome G protein Ion channel Receptor A

38. Mammalian CNS contains over 10 different serotonin receptors which demonstrate differential expression and cellular localization

41. Revised Amine Hypothesis of Depression Changes in amine levels lead to structural changes that bias the neural/endocrine system towards normalcy or depression.

42. Antidepressants increase synthesis of neurotrophic factors in the hippocampus.

43. Infusion of BDNF into the dentate gyrus of the hippocampus produces similar behavioral effects to antidepressants. J. Neurosci. 22:3251

44. Reduced hippocampal volume in depressed individuals PNAS, 93:3908, 1996

46. Volume is inversely correlated with length of depression J. Neurosci. 19:5034, 1999

47. Fluoxitine increases neuronal proliferation in the hippocampus. Science, 301:805

48. Trophic factor hypothesis of antidepressant action

49. Summary Antidepressants alter levels of neuronal trophic factors. Neuronal survival and proliferation are associated with the behavioral effects of antidepressants.

50. (-) Corticotropin-release factor (CRF) (+) (-) Pituitary Adrenocorticotropin hormone (ACTH) (+) Adrenals Cortisol Corticosterone (+) Cortisol Corticosterone Liver, fat, muscle, lymphycytes, etc The HPA Stress Axis Stressors Hypothalamus