Neurotransmission, Neuropsychiatry, and Neuropharmacology 2013


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Neurotransmission, Neuropsychiatry, and Neuropharmacology 2013 Postgraduate Course at Aarhus University includes historical information on Masters of Neuropsychopharmacology

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Neurotransmission, Neuropsychiatry, and Neuropharmacology 2013

  1. 1. NEUROTRANSMISSION, PSYCHIATRY AND NEUROPHARMACOLOGY 2013 CFIN Course Donald F. Smith, BSc, MA, PhD, MMSc, DMSc. Center for Psychiatric Research Psychiatric Hospital of Aarhus University 8240 Risskov
  2. 2. Basic Monoaminergic Mechanisms     Who were the founders? What did they do? What impact has it had? How does neurotransmission translate into behavior?
  3. 3. 13 7 2 4 3 10 9 11 8 5 12 1 6
  4. 4. Names in mixed-up order Lewis Seiden Bernard Brodie Linda Buck Otto Loewi John Eccles John Harvey Joseph Schildkraut Seymour Kety Edith Piaf Henry Dale Julius Axelrod Arvid Carlsson Mogens Schou
  5. 5. tch?v=Kya3c4WJZAk
  6. 6. The Nobel Prize in Physiology or Medicine 1936 shared with Sir Henry Dale …for chemical transmission of nerve impulses. In 1921 Loewi discovered the chemical transmission of nerve impulses the research of which was greatly developed by him and his co-workers in the years following, culminating ultimately in his demonstation that the parasympathetic substance («Vagusstoff») is acetylcholine and that a substance closely related to adrenaline played a corresponding role at the sympathetic nerve endings. It was for these researches that he received the Nobel Prize in 1936, jointly with Sir Henry Dale. This and other discoveries in the fields of chemistry, physics, and pharmacology have since then led to a complete renewal of the concepts of the sympathetic nervous system. Otto Loewi
  7. 7. What type of experiment would prove the existence of chemical transmission? Think about this question. Suggest experimental set-ups. What did Loewi do?
  8. 8.     Autonomic influences on the heart have been recognized for many centuries. It was not until 1921, however, that a German physiologist named Otto Loewi stimulated a frog's vagus nerve, collected the released substance, and applied it to a second, different frog heart to demonstrate its effects. For his discovery of this "vagusstuff" (subsequently shown to be acetylcholine), Loewi shared the 1936 Nobel Prize in Physiology or Medicine. We now know that acetylcholine released by the vagus nerve is the predominant parasympathetic influence on the heart while epinephrine and norepinephrine mediate the principal cardiac sympathetic effects. From Maisel, W.H. J Am Coll Cardiol, 2003; 42:1269-1270
  9. 9. Henry Hallett Dale, 1875–1968 Introduced the terminology of cholinergic and adrenergic nerve supply. Barger, G. and Dale, H.H., Chemical structure and sympathomimetic action of amines. J. Physiol. 41: 19-59, 1910 Sir Henry Dale, Transmission of nervous effects by acetylcholine. Harvey Lectures, 32: 229-245, 1937
  10. 10. Action Potential Movie video – type in Google: Hodgkin and Huxley giant squid experiment and then select see Bio330 o330/squid.html
  11. 11. Sir John Carew Eccles Australian research physiologist who received (with Alan Hodgkin and Andrew Huxley) the 1963 Nobel Prize for Physiology or Medicine for his discovery of the chemical means by which impulses are communicated or repressed by nerve cells (neurons).
  12. 12.  Figure 1. Dendrites and cell bodies of schematic neurons connected by dendriticdendritic gap junctions form a laterally connected input layer (“dendritic web”) within a neurocomputational architecture. Dendritic web dynamics are temporally coupled to gamma synchrony EEG, and correspond with integration phases of “integrate and fire” cycles. Axonal firings provide input to, and output from, integration phases (only one input, and three output axons are shown). Cell bodies/soma contain nuclei shown as black circles; microtubule networks pervade the cytoplasm. … gamma EEGsynchronized integration phases include quantum computations in microtubule networks which culminate with conscious moments. Insert closeup shows a gap junction through which microtubule quantum states entangle among different neurons, enabling macroscopic quantum states in dendritic webs extending throughout cortex and other brain regions.
  13. 13.  Eccles demonstrated that one nerve cell communicates with a neighbouring cell by releasing chemicals into the synapse (the narrow cleft, or gap, between the two cells). He showed that the excitement of a nerve cell by an impulse causes one kind of synapse to release into the neighbouring cell a substance (probably acetylcholine) that expands the pores in nerve membranes. The expanded pores then allow free passage of sodium ions into the neighbouring nerve cell and reverse the polarity of electric charge. This wave of electric charge, which constitutes the nerve impulse, is conducted from one cell to another. In the same way, Eccles found, an excited nerve cell induces another type of synapse to release into the neighbouring cell a substance that promotes outward passage of positively charged potassium ions across the membrane, reinforcing the existing polarity and inhibiting the transmission of an impulse. (See also action potential.)
  14. 14.  Eccles's research, which was based largely on the findings of Hodgkin and Huxley, settled a longstanding controversy over whether nerve cells communicate with each other by chemical or by electric means. His work had a profound influence on the medical treatment of nervous diseases and research on kidney, heart, and brain function.
  15. 15. Julius Axelrod (May 30, 1912 – December 29 2004) was an influential American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler. The Nobel Committee honored him for his work on the release and reuptake of catecholamine neurotransmitters, a class of chemicals in the brain that include epinephrine, norepinephrine, and, as was later discovered, dopamine. Axelrod also made major contributions to the understanding of the pineal gland and how it regulates the sleep-wake cycle.
  16. 16.     Early studies of possible relationships between biochemistry and emotions. Not possible to examine the living brain. Focus on the autonomic nervous system. Comparisons between adrenaline and noradrenaline
  17. 17. Adrenaline with R = CH3 
  18. 18. Adrenaline (Epinephrine) and Noradrenaline (Norepinephrine)        Adrenaline and noradrenaline are hormones Adrenaline is synthesized in the adrenal medulla and is released into the bloodstream Noradrenaline is synthesized in nerves of the sympathetic branch of the autonomic nervous system (also called the peripheral sympathetic nervous system) and is released into the synapse. Adrenaline is primarily in the bloodstream Noradrenaline is primarily in the brain Adrenaline and noradrenaline affect alpha- and betaadrenergic receptors Alpha- and beta-adrenergic receptors are, for example, involved in responses of blood vessels and heart.
  19. 19. Physiologic actions of adrenaline   When in the bloodstream, it rapidly prepares the body for action in emergency situations. The hormone boosts the supply of oxygen and glucose to the brain and muscles, while suppressing other non-emergency bodily processes (digestion in particular). It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gastrointestinal tract while dilating arterioles in skeletal muscles. It elevates the blood sugar level by increasing catabolism of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in fat cells. Like some other stress hormones, epinephrine has a suppressive effect on the immune system.[5]
  20. 20.  Norepinephrine is released in the brain by activation of an area of the brain stem called the locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a neurotransmitter system.
  21. 21. Noradrenergic Neuropathways (from Lundbeck Image Website)
  22. 22. Physiologic actions of noradrenaline  Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. Unlike epinephrine, which activates all adrenergic receptors (α1 α2 β1 β2), norepinephrine activates all but β2 receptors. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has different actions on different cell types.
  23. 23. Ax and Funkenstein      Describe some of the experimental set-ups Physiologic response of anger & aggression linked with noradrenaline Physiologic response of fear & anxiety linked with adrenaline Higher excretion of noradrenaline in aggression Higher excretion of epinephrine in anxiety
  24. 24.   8HCM3Z5Ic Mouse in maze
  25. 25.   Empathy in rats – short version
  26. 26.   9XHHxwTxU Operant behavior
  27. 27. Lewis Seiden Operant schedules of reinforcement
  28. 28.     Behavior maintained under a differential-reinforcement-oflow-rate (DRL) 72-s operant schedule, which reinforces responses with interresponse times greater than 72 s, exhibits a rather unique sensitivity to antidepressant drugs. Antidepressants from a number of pharmacological classes, including tricyclic antidepressants, selective serotonin or norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, as well as a number of atypical antidepressants and putative antidepressants, reduce response rate and increase reinforcement rate of rats under this schedule. Consistent with clinical data, it appears that activation of noradrenergic or serotonergic systems provides for parallel means of producing antidepressant-like effects on DRL behavior. The results of studies using DRL behavior highlight important roles for central beta-1 adrenergic receptors, as well as 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors, in the mediation of antidepressant-like behavioral effects.
  29. 29.   Do class exercise with DRL-schedules Pairwise for the students. Each student decides how long each interval should be and then reinforces the other student with candy (M&Ms) each time the correct response is made.
  30. 30. Joseph Schildkraut was the founding director of the Neuropsychopharmacology/Psychiatric Chemistry Laboratory at the Massachusetts Mental Health Center. Joseph Schildkraut Schildkraut received his AB from Harvard College in 1955, followed by his MD from HMS in 1959. He completed his residency at MMHC and spent four years at the National Institute of Mental Health. He rejoined the HMS community in 1967 and began a career at MMHC that would span nearly four decades, first as an assistant professor of psychiatry, becoming full professor in 1974, and retiring as emeritus in 2004. Former editor in chief of the Journal of Psychiatric Research, Schildkraut was the author of more than 200 scientific publications. His seminal paper, “The Catecholamine Hypothesis of Affective Disorders,” published in 1965, set the agenda for biological research on depression for the next 25 years. This paper was recognized in 1997 as the most cited of all articles ever published in the American Journal of Psychiatry and one of the most cited papers in the history of psychiatry.
  31. 31. Seymour Kety In 1951, Kety became the first scientific director of the National Institute of Mental Health (NIMH). He established a broad program of fundamental research representing all of the disciplines concerned with the brain and behavior. That program has nurtured one Nobel Prize-winning scientist and four recipients of Lasker awards. Kety not only recruited distinguished scholars to NIMH, but also conceived and established the research agenda that put psychiatry and psychology on a rigorous scientific footing. It has been described as a "research program of unprecedented breadth," that included laboratories in each of the pertinent biological as well as behavioral disciplines. As a consequence, Kety is credited by the Lasker Foundation with "shepherding psychiatry into a new scientific era."
  32. 32. The Central Dogma 1. Synthesis 2. Storage 3. Release 4. Metabolism 5. Reuptake 6. Receptor From Lundbeck Image Bank Note Fusion of a synaptic vesicle with the pre-synaptic membrane
  33. 33. As head of the Laboratory for Clinical Pharmacology at NIH after the war, Dr. Brodie worked with and trained a group of scientists who would become the leaders in the science of neuroscience and drug metabolism. Their work was accompanied by increased research into instrumentation Bernard B. Brodie and technology, including the spectrophotofluorometer. Dr. Brodie won the Lasker Award, often considered the American Nobel Prize, in 1967. The award cited his "extraordinary contributions to biochemical pharmacology." Imipramine
  34. 34. ”Fortunately, we had inbuilt in our programme a serendipity factor, an ingredient that I recommend with some reservations to the streamlined pharmaceutical laboratories of today – an animal caretaker who on occasion mixes the animals up a bit. One day he sent us rats that unbeknown to us had been receiving daily doses of imipramine for quite another kind of experiment. As a matter of fact, they were not even our rats – they belonged to Dr. Gillette and I can sympathize with his annoyance when he discovered that his animals had disappeared. Since we had no idea that the rats had been treated with imipramine, you may imagine our surprise when on administration of reserpine the animals almost literally climbed the walls” Bernard B. Brodie, Some ideas on the mode of action of imipraminetype antidepressants, 1965
  35. 35. Bernard B. Brodie; Alfred Pletscher; Parkhurst A. Shore, Science, New Series, Vol. 122, No. 3177. (Nov. 18, 1955), p. 968.
  36. 36. Arvid Carlsson shared the Nobel Prize in Physiology or Medicine of 2000 with Richard Kandel and Paul Greenberg for their discoveries concerning signal transduction in the nervous system. Arvid Carlsson
  37. 37. Nortriptyline Imipramine Molecular Structures Pharmacological Profiles of NETs and SERTs SERTs and NETs are the pharmacological targets for a variety of therapeutic antidepressants and abused substances. Tricyclic antidepressant sensitivity is shared by NETs and SERTs, but not by DA transporters. Tertiary amine tricyclics (imipramine, amitriptyline) are more potent at SERTs as compared to the NET-preferring secondary amine tricyclics desipramine and nortriptyline. The steric interactions by which the addition of a single methyl group increases potency of the tertiary amines for SERT are not known; however, mutagenesis of the SERT protein should prove useful in identifying residues important in this effect and allow predictions concerning binding of ligands to the transporter.
  38. 38. Tricyclic Actions From Lundbeck Image Bank
  39. 39.  Show Forced-Swim Test dyNILb5U&NR=1&feature=endscreen
  40. 40. Serotonin and Avoidance Behavior Prof. John Harvey
  41. 41. Normal ”Monkey Business”
  42. 42. Serotonin and Behavior   xKBiidbeo Altering Serotonin Levels Changes Monkey Behavior and Status
  43. 43. That’s probably enough for today
  44. 44. Low SelfEsteem Sexual Disturbance Thought Disorders Eating Disorders Noradrenaline & Serotonin Neurotransmission Sleep Disturbance Psychomotor Disturbance Memory Disturbance Psychosomatic Suicidal Disorders Tendency
  45. 45. The Central Dogma 1. Synthesis 2. Storage 3. Release 4. Metabolism 5. Reuptake 6. Receptor From Lundbeck Image Bank Note Fusion of a synaptic vesicle with the pre-synaptic membrane
  46. 46. Mechanism of action of noradrenaline re-uptake transporters The action of noradrenaline at the synapse is terminated by its re-uptake across the pre-synaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and cotransport of sodium and chloride ions and noradrenaline from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The noradrenaline re-uptake transporter is then available to bind another noradrenaline molecule for re-uptake. From Lundbeck Image Bank
  47. 47. Mechanism of action of 5-HT re-uptake transporters The action of 5-HT at the synapse is terminated by its re-uptake across the presynaptic membrane. This is an energy dependent process. Sodium/potassium ATPases use energy from ATP hydrolysis to create a concentration gradient of ions across the pre-synaptic membrane that drives the opening of the transporter and co-transport of sodium and chloride ions and 5-HT from the synaptic cleft. Potassium ions binding to the transporter enable it to return to the outward position. Release of the potassium ions into the synaptic cleft equilibrates the ionic gradient across the pre-synaptic membrane. The 5-HT re-uptake transporter is then available to bind another 5-HT molecule for re-uptake.
  48. 48.  Mention that molecular ”tools” can be purchased for testing hypotheses about the role of each receptor in neurotransmission and behavioral tasks.
  49. 49. Key compounds for The Catecholamine (and Serotonin) Hypothesis of Affective Disorders       Reserpine Tetrabenazine Amphetamine Monoamine oxidase inhibitors Imipramine Dehydroxyphenylalanine (DOPA)
  50. 50. From website of Journal of Affective Disorders, March, 2009
  51. 51. Low SelfEsteem Sexual Disturbance Thought Disorders Eating Disorders Depressive Disorders Sleep Disturbance Psychomotor Disturbance Memory Disturbance Psychosomatic Suicidal Disorders Tendency
  52. 52. Antidepressants (clinical and preclinical) that have been tested as PET radioligands          Paroxetine Citalopram Fluoxetine Venlafaxine Clomipramine Nefopam Mianserin NS2381 & NS2456 McN5652
  53. 53. Harry F. Harlow, “Love in Infant Monkeys,” 1959 An infant monkey clinging to its terry cloth “mother.”
  54. 54. I don’t understand this information! Can someone explain it to me?
  55. 55. From Science, 301: 16033-16038, 2003
  56. 56. From Science, 301: 16033-16038, 2003
  57. 57.   ”Although the impact of neurogenetics on social sciences has long been anticipated and represents an inevitable – albeit welcome – development, the transition from complicated correlations to useful predictions will be a challenge.” Klaus-Peter Lesch, Embo reports, 2007
  58. 58. Families of Serotonergic Receptors
  59. 59. Serotonergic Neuropathways (from Lundbeck Image Website)
  60. 60. From Lundbeck Image Bank
  61. 61.     5-HT receptor subtypes The actions of 5-HT are mediated by a range of different 5-HT receptors. The 5-HT receptors are classified into seven main receptor subtypes, 5-HT1–7. Six of the seven subtypes are G-protein-coupled receptors; 5-HT3 is a ligand-gated cation channel. 5-HT1 receptors occur primarily in the brain and cerebral blood vessels (5-HT1D only), where they mediate neural inhibition and vasoconstriction. They function mainly as inhibitory presynaptic receptors, linked to inhibition of adenylate cyclase. Specific agonists at 5-HT1 receptors include sumatriptan (used in migraine therapy) and buspirone (used in the treatment of anxiety). Spiperone and methiothepin are specific antagonists of 5-HT1 receptors. 5-HT2 receptors are found in the CNS and in many peripheral sites. They act through phospholisae C to produce excitatory neuronal and smooth muscle effects. Specific ligands at 5-HT sites include LSD – acting as an agonist in the CNS and as an antagonist in the periphery – and ketanserin and methysergide (both antagonists).
  62. 62.    5-HT3 receptors occur mainly in the peripheral nervous system, particularly on nociceptive afferent neurones and on autonomic and enteric neurones. The effects of these receptors are excitatory, mediated by receptor-coupled ion channels. 5-HT3 antagonists (eg ondansetron, tropisetron) are used predominantly as anti-emetic drugs. 5-HT4 receptors are found in the brain, as well as peripheral organs like the heart, bladder and gastrointestinal (GI) tract. Within the GI tract they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis. A specific 5-HT4 agonist is metoclopramide used for treating gastrointestinal disorders. Little is known about the function and pharmacology of 5-HT5, 5-HT6 and 5HT7 receptors.
  63. 63. 5-HT receptors – 7-transmembrane spanning, G-protein coupled receptors There are four broad ‘superfamilies’ of receptor: (1) the channel-linked (ionotropic) receptors; (2) the G-protein coupled (metabotropic) receptors; (3) the kinase-linked receptors; and (4) receptors that regulate gene transcription. The 5-HT1, 2, 4, 5, 6 and 7 receptors belong to the G-protein coupled superfamily. They are membrane receptors that have 7 transmembrane spanning a-helices. 5-HT binding to the ‘binding groove’ on the extracellular portion of the receptor activates the G-proteins, which initiate secondary messenger signalling pathways. The downstream effect is either inhibitory or stimulatory, depending on the type of G-protein linked to the receptor – 5HT1 receptors are linked to inhibitory G-proteins, whereas 5-HT2, 4, 6 and 7 are linked to stimulatory G-proteins.
  64. 64. From Lundbeck Image Bank Distribution of 5-HT1A receptors in the normal brain There are seven sub-types of 5-HT receptor and the 1A subtype is widely expressed throughout the brain. The highest levels of this subtype are found in the hippocampus and medial temporal cortex, with slightly lower levels in the pre-frontal cortex. Low levels of 5-HT1A are found in the basal ganglia.
  65. 65. Distribution of 5-HT1A receptors in depression In depression the density of 5-HT1A receptors is altered compared with the normal brain. The 5-HT1A receptor density is increased in the hippocampus and medial temporal cortex, while the density of these receptors is reduced compared with normal in the cerebellum, basal ganglia and prefrontal cortex. From Lundbeck Image Bank
  66. 66. From Lundbeck Image Bank Distribution of 5-HT2 receptors in the normal brain There are seven main types of serotonin receptors in the brain. The 5HT2 receptors (A, B and C subtypes) are widely distributed throughout the brain. Briefly, these receptors can be found in the cerebral cortex, amygdala, hypothalamus, hippocampus, substantia nigra, choroid plexus, substantia innominata and some components of the basal ganglia.
  67. 67. Distribution of 5-HT2 receptors in the brain of those affected by depression In depression the distribution of 5-HT2 receptors is altered compared with the normal brain. The 5-HT2 receptor density is decreased in the frontal, temporal, parietal and occipital cortical regions compared with normal. 5-HT2 expression in the hippocampus, basal ganglia, substantia nigra, hypothalamus, choroid plexus and substantia innominata remains unaffected by depression. From Lundbeck Image Bank
  68. 68. Distribution of 5-HT3 receptors in the brain From Lundbeck Image Bank The 5-HT3 receptor subtype is a ligand-gated ion channel that controls dopamine release. It is a common target of antiemetic therapy, as well as other psychoactive drugs. A high density of 5-HT3 receptors has been identified in the human brainstem, particularly in the area postrema (the putative vomiting center of the brain) and the nucleus tractus solitarius. Lower levels of expression of the 5-HT3 receptor have been shown in the limbic system, hippocampus and the cerebral cortex.
  69. 69. From Lundbeck Image Bank The 5-HT3 receptor The 5-HT3 receptor is distinct from the other 5-HT receptor subtypes, in that it is a ligand-gated ion channel that is permeable to sodium and potassium. The 5-HT3 receptor is structurally similar to the nicotinic acetylcholine receptor and is composed of 5 subunits. Two subunits have been cloned, 5-HT3A and 5-HT3B, and homomeric (5-HT3A) and heteromeric (5-HT3A/5-HT3B) forms of the receptor have both been characterised
  70. 70. Mechanism of action of a 5-HT3 antagonist Binding of an agonist at the 5-HT binding site causes a conformational change and activation of the 5-HT3 receptor. As a ligand gated ion channel this permits the movement of positively charged ions from the synaptic cleft into the cytoplasm. Binding of an antagonist at the 5-HT binding site prevents this activation and cell depolarisation is inhibited. From Lundbeck Image Bank
  71. 71. From Lundbeck Image Bank Distribution of 5-HT4 receptors in the brain The 5-HT4 receptor subtype is coupled to a G-protein that stimulates the intracellular messenger adenylate cyclase that, in turn, regulates neurotransmission. In the human brain, a high density of 5-HT4 receptors has been identified in the striato-nigral system, notably in the caudate nucleus, lenticular nucleus (putamen and globus pallidus) and the substantia nigra. Lower levels of expression of the 5-HT4 receptor have been shown in the hippocampus and the frontal cortex.
  72. 72. From Lundbeck Image Bank Distribution of 5-HT6 and 5-HT7 receptors in the brain The 5-HT6 and 5-HT7 subtypes of serotonin receptor are coupled to a G-protein that stimulates the intracellular messenger adenylate cyclase that, in turn, regulates neurotransmission. In the human brain, a high density of 5-HT6 receptors has been identified in the olfactory tubercle, corpus striatum, nucleus accumbens, dentate gyrus and hippocampus. Lower levels of expression of the 5-HT6 receptor have been shown in the cerebellum and amygdala. Studies in the rat suggest the 5-HT7 receptor is widely distributed in the brain; examination of human brain tissue has shown expression in the thalamus.
  73. 73. The Problem that needs Solving! Noone knows the neurobiological basis of depression. The long-term aim is to invent procedures for early diagnosis of treatment-resistant depression and for guiding its evidence-based treatment.
  74. 74. Location of Serotonin Transporter Autoradiographic studies using [3H]citalopram and [3H]imipramine identify the amygdala, thalamus, hypothalamus, CA3 region of the hippocampus, substantia nigra, locus coeruleus, and the raphe nuclei of the midbrain as the brain regions with the highest level of 5HT uptake sites.
  75. 75. Brief Account of Background • The neurotransmitter serotonin is allegedly involved in therapeutic actions of most antidepressant drugs. • Clomipramine is an ”old-style” antidepressant drug. It acts primarily on serotonergic mechanisms, particularly when it is given intravenously. • Citalopram is a ”new-style” antidepressant drug. It shows remarkable selectively on serotonergic mechanisms
  76. 76. Some evidence for a role of the mediodorsal nucleus of the thalamus (MDT) in depressive disorders.      PET radioligands of antidepressant drugs accumulate in the MDT There is a relatively high density of serotonin uptake sites in the MDT Neuronal damage of the MDT is associated with symptoms of depressive disorder Limbic regions are reciprocally innervated by the MDT Clomipramine, an antidepressant drug, alters the relative rate of blood flow in the MDT
  77. 77. Aim: to determine whether an intravenous infusion of clomipramine or citalopram affects the relative rate of blood flow in the mediodorsal nucleus of the thalamus of healthy humans.
  78. 78. Time Line of PET scanning for Project 90 H215O H215O Volunteer arrives Place in Scanner Install Venflon H215O H215O H215O H215O i.v. infusion (30 min) Double-blind Placebo, Clomipramine or Citalopram Debriefing
  79. 79.      18 healthy volunteers based on interview, MMSI, depression rating, blood data, EKG, and MR. 3 scans with [15O]H2O (preinfusion condition) 30 min intravenous infusion of isotonic saline (placebo), clomipramine or citalopram (randomized, double-blind) 3 scans with [15O]H2O (postinfusion condition) Data analysis by random effects model using SPM99
  80. 80. Neocortex ACh ACh Glutamate Striatum Amygdala Hippocampus Glutamate Glutamate GABA GABA Dorsomedial Thalamus GABA Pallidum ACh GABA DA Hypothalamus NA ACh 5-HT Substantia Locus Parabrachial Dorsal Nigra Ceruleus Nucleus Raphé
  81. 81. Blier, P. European Neuropsychopharmacology, 13: 57-66, 2003.
  82. 82. Noradrenaline (NA) exerts a tonic, inhibitory action on serotonin (5-HT) release via α2-heteroceptors, so antagonism of α2-heteroceptors enhances 5-HT release. NA NA NA 5-HT 5-HT NA binding at α2-autoreceptors reduces NA release, so antagonism of α2-autoreceptors enhances NA release. NA NA NA NA NA = NA neuron = α2-autoreceptor = 5-HT neuron = α2-heteroceptor
  83. 83. Noradrenaline a2 adrenergic receptor There are two different types of adrenoreceptor – the α and β receptors. The α receptors are further classified into α1 and α2 subtypes and the β receptors are further classified into β1, β2 and β3 subtypes. The α2 adrenoreceptors are widely distributed throughout the body and are found in adrenergic neurones, blood vessels, the pancreas and in smooth muscle. Coupled to inhibitory G-proteins,α2 adrenoreceptors have an inhibitory effect on neurotransmission when bound by an agonist. From Lundbeck Image Bank
  84. 84. From Lundbeck Image Bank Mechanism of action of an a2 adrenergic receptor antagonist An α2 adrenergic receptor antagonist prevents the activation of the α2 adrenergic receptor. The α2 receptor is coupled to inhibitory Gproteins, which dissociate from the receptor following agonist binding, and inhibit both secondary messenger signaling mechanisms and cell depolarisation. Antagonist binding to the α2 adrenergic receptor prevents secondary messenger inhibition and allows cell depolarisation to occur.
  85. 85. 12 Cerebellum Amygdala Frontal cortex Thalamus Striatum Hippocampus Radioactivity (kBq/cc) 10 8 6 4 2 0 0 10 20 30 40 50 60 Time (min) Time-course of radioactivity derived from [N-methyl-11C]mirtazapine in selected regions of human brain.
  86. 86. Parametric map of the binding potential of [11C]mirtazapine in 17 healthy human volunteers. 1.5 1.0 0.5
  87. 87. Emotional Memory Amygdalothalamocortical Pathway Unconditioned Responses Corticothalamic Pathway Cortical Limbic Pathway Conditioned Responses Visceral Limbic Pathway Corticocortico Pathway Sense of Danger Corticostriato- thalamic Pathway Symptoms of Depression ACh 5-HT Sleep Disorders ACh GABA Cognitive Disorders 5-HT NA Eating Disorders
  88. 88. Who’s Who in Psychopharmacology              1) Otto Loewi 2) Henry Dale 3) Julius Axelrod 4) Joseph Schildkraut 5) Seymour Kety 6) Bernard Brodie 7) Arvid Carlsson 8) Mogens Schou 9) Edith Piaf 10) John Harvey 11) Lewis Seiden 12) Linda Buck 13) John Eccles
  89. 89. Drugs affecting NETs and SERTs  Other potent NET antagonists include nomifensine, mazindol, and nisoxetine. Highly selective antagonists for SERTs such as paroxetine and fluoxetine have been developed whose chemical structures differ from the tricyclic nucleus, but which are effective antidepressants supporting alterations in serotonin neurons as targets in affective disorders (22). Cocaine is a nonselective, competitive antagonist of NE, 5HT, and DA transport. The addictive potential of cocaine is though to be a consequence of actions on CNS DATs, whereas the life-threatening cardiovascular effects of cocaine may involve blockade of NETs at sympathetic and CNS autonomic synapses. Some other drugs of abuse including p-chloroamphetamine, fenfluramine, and (3,4-methylenedioxy) methamphetamine (MDMA, "ecstasy") also are inhibitors of 5HT uptake. Interestingly, MDMA and the other amphetamines are neurotoxic substrates for SERTs and additionally cause efflux of 5HT by a transported-mediated exchange process (59).
  90. 90. Distinction between NATs and DATs  Studies demonstrate (a) a high density of [3H]nisoxetine binding sites in rat brain regions containing a high density of noradrenergic soma or terminals, including the locus coeruleus and hypothalamic nuclei, and (b) a low density in regions receiving sparse noradrenergic innervation, such as the striatum (61). A marked loss of [3H]nisoxetine labeled sites occurs following chemical brain lesions with the neurotoxins 6-hydroxydopamine (6-OHDA) and DSP-4, indicating that forebrain labeling is most likely associated with noradrenergic terminals rather than targets or surrounding glia, although a small perisynaptic contribution which disappears with loss of innervation cannot be excluded.
  91. 91. Before 2002 most PET and SPECT studies involving radiolabelled SSRI’s were performed with: S CH3 N Me CO2Me I ß-CIT N H (+)-McN 5652
  92. 92. Today the most promising candidates are based on substituted phenylthiobenzylamine derivatives: CH3 CH3 N NH2 S N NH2 CH3 S NC I ADAM CH3 CH3 N NH2 S H3C DASB MADAM CH3
  93. 93. The Nobel Prize in Physiology or Medicine 2004 shared for discoveries of odorant receptors and the organization of the olfactory system Prof. Linda B. Buck
  94. 94. Mogens Schou Mogens Schou received the Lasker Prize of Clinical Medical Research in 1987 for his contribution to lithium therapy for affective disorders.
  95. 95.  J Physiol (Paris). 1981;77(2-3):455-61. Links – Enhancement of the 5-HT neurotransmission by antidepressant treatments. – De Montigny C. – The hypothesis of an etiopathogenic role of 5-HT and that of a mediation by the 5-HT system in the effect of antidepressant treatments have often been confused. Little unequivocal evidence exists for a 5-HT deficit in depression. However, several recent animal and clinical data suggest that the 5-HT system might contribute to the therapeutic effect of various antidepressant treatments. Long-term administration of tricyclic antidepressant (TCA) drugs induces a sensitization of rat forebrain neurons to iontophoretically-applied 5-HT. Repeated electroconvulsive shocks result also in an increased sensitivity of forebrain 5-HT receptors. However, chronic administration of a new antidepressant drug, zimelidine, a potent and long-lasting 5-HT uptake blocker, fails to modify 5-HT receptor sensitivity. These results suggest that enhancement of 5-HT neurotransmission obtained via either pre- or postsynaptic mechanisms might determine the antidepressant effect of these treatments. In a recent clinical study, we observed that lithium administration to TCA-resistant depressive patients induced a rapid relief of depression. It is possible that the presynaptic enhancing effect of lithium on the 5-HT system might unveil the TCA-induced sensitization of the postsynaptic 5-HT receptors. Most depressed patients exhibit marked diurnal variations of mood. Preliminary experiments in rats revealed that the responsiveness of hippocampal neurons to iontophoretically-applied 5-HT is enhanced in the evening. Similar diurnal variations of 5HT receptor sensitivity might occur in human brain and be related to diurnal variation of mood in depression. Since normal individuals do not show these fluctuations of mood, it is proposed that the "mood regulating system" might become 5-HT dependent in depressed patients.
  96. 96. Who’s Who in Psychopharmacology              1) Otto Loewi 2) Henry Dale 3) Julius Axelrod 4) Joseph Schildkraut 5) Seymour Kety 6) Bernard Brodie 7) Arvid Carlsson 8) Mogens Schou 9) Edith Piaf 10) John Harvey 11) Lewis Seiden 12) Linda Buck 13) John Eccles