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Galanin Receptor Antagonists

A Potential Novel Pharmacological Treatment for Mood Disorders

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Abstract

The pathophysiology of mood disorders involves several genetic and social predisposing factors, as well as a dysregulated response to chronic stress. Accumulated evidence during the last two decades has implicated disturbances in brain serotonin and/or noradrenaline (norepinephrine) neurotransmission in the aetiology of depression. In fact, current pharmacological treatment for mood disorders is based on the use of drugs that act mainly by enhancing brain serotonin and noradrenaline neurotransmission by blockade of the active reuptake mechanism for these neurotransmitters. However, current antidepressant drugs have a delayed onset of therapeutic action, and a substantial number of patients do not respond adequately to them. In addition, these drugs have a number of adverse effects that limit patient compliance. In view of this, there is an intense search to identify novel (receptor) targets for antidepressant therapy.

Recent studies have indicated that several neuropeptides and their receptors are potential candidates for the development of novel antidepressant treatment. In this context, galanin is of particular interest, since it is co-localised with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus, nuclei known to play a major role in affective disorders and in the action of antidepressant drugs. The actions of galanin are mediated by three receptor subtypes (GAL1, GAL2 and GAL3), which are coupled to different intracellular effector systems.

Studies in rats have shown that galanin administered intracerebroventricularly is a potent inhibitor of mesencephalic serotonergic neurotransmission, as indicated by a long-lasting reduction in the release of serotonin in the hippocampus. This inhibitory effect is related to activation of the galanin receptors located on the dorsal raphe neurons. Moreover, intracerebroventricular galanin alters the gene expression of serotonin 5-HT1A autoreceptors in the dorsal raphe and also changes their functional activity. In addition, galanin produces a functional blockade of postsynaptic 5-HT1A receptor-mediated responses.

Both pharmacological and genetic studies suggest a role for galanin in depression-like behaviour in rodent models. Transgenic mice overexpressing galanin under the control of the platelet-derived growth factor-β promoter display increased immobility in the forced swim test. Intracerebroventricular administration of galanin in the rat increases depression-like behaviour, and this is fully blocked by the nonselective peptide galanin receptor antagonist M35. Importantly, M35 alone administered intracerebroventricularly produces an antidepressant-like effect. Recently, newly developed receptor-specific nonpeptidergic galanin GAL3 receptor antagonists (SNAP-37889 and SNAP-398299), which cross the blood-brain barrier after systemic administration, have shown antidepressant-like activity in several animal models. On the other hand, stimulation of the GAL2 receptor at the raphe level by local application of the GAL2 receptor agonist galanin (2–11) has been shown to increase serotonin levels in the hippocampus and dorsal raphe. These results indicate an important (mainly inhibitory) role of galanin as a regulator of brain serotonin and 5-HT1A receptor-mediated transmission, which may be of potential importance for understanding mood disorders and for the development of antidepressant drugs.

Taken together, the present evidence suggests that antidepressant efficacy may be associated with compounds acting as antagonists at the GAL3 and/or possibly GAL1 receptors, and/or agonists at the GAL2 receptor.

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References

  1. Akiskal HS. Mood disorders: introduction and overview. In: Sadock BJ, Sadock VA, editors. Comprehensive textbook of psychiatry. New York: Lippincott Williams & Wilkins, 2000: 1284–98

    Google Scholar 

  2. Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe: a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005; 15: 357–76

    Article  PubMed  CAS  Google Scholar 

  3. Murray CJL, Lopez AD, editors. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Boston (MA): The Harvard School of Public Health on behalf of The World Health Organization, 1996

    Google Scholar 

  4. Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001; 11: 240–9

    Article  PubMed  CAS  Google Scholar 

  5. Lesch KP. Gene-environment interaction and the genetics of depression. J Psychiatry Neurosci 2004; 29: 174–84

    PubMed  Google Scholar 

  6. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiatry 1997; 54: 597–606

    Article  PubMed  CAS  Google Scholar 

  7. Fava M, Kendler KS. Major depressive disorder. Neuron 2000; 28: 335–41

    Article  PubMed  CAS  Google Scholar 

  8. Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry 1999; 156: 837–41

    PubMed  CAS  Google Scholar 

  9. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001; 62: 77–91

    Article  PubMed  CAS  Google Scholar 

  10. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001; 7: 541–7

    Article  PubMed  CAS  Google Scholar 

  11. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996; 29: 2–11

    Article  PubMed  CAS  Google Scholar 

  12. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet 1997; 349: 915–9

    Article  PubMed  CAS  Google Scholar 

  13. Frazer A. Pharmacology of antidepressants. J Clin Psychopharmacol 1997; 17Suppl. 1: 2–18S

    Article  Google Scholar 

  14. Millan MJ. The role of monoamines in the actions of established and “novel” antidepressant agents: a critical review. Eur J Pharmacol 2004; 500: 371–84

    Article  PubMed  CAS  Google Scholar 

  15. Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron 2002; 34: 13–25

    Article  PubMed  CAS  Google Scholar 

  16. Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry 2000; 61: 712–21

    Article  PubMed  CAS  Google Scholar 

  17. Ogren S, Fuxe K. Effects of antidepressant drugs on serotonin receptor mechanisms. In: Green A, editor. Neuropharmacolo-gy of serotonin. Oxford: Oxford University Press, 1985: 131–80

    Google Scholar 

  18. Sulser F. New perspectives on the molecular pharmacology of affective disorders. Eur Arch Psychiatry Neurol Sci 1989; 238: 231–9

    Article  PubMed  CAS  Google Scholar 

  19. Vetulani J, Sulser F. Action of various antidepressant treatments reduces reactivity of noradrenergic cyclic AMP-generating system in limbic forebrain. Nature 1975; 257: 495–6

    Article  PubMed  CAS  Google Scholar 

  20. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 1996; 16: 2365–72

    PubMed  CAS  Google Scholar 

  21. Lemonde S, Turecki G, Bakish D, et al. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003; 23: 8788–99

    PubMed  CAS  Google Scholar 

  22. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–9

    Article  PubMed  CAS  Google Scholar 

  23. Heilig M. The NPY system in stress, anxiety and depression. Neuropeptides 2004; 38: 213–24

    Article  PubMed  CAS  Google Scholar 

  24. Lu X, Barr AM, Kinney JW, et al. A role for galanin in antidepressant actions with a focus on the dorsal raphe nucleus. Proc Natl Acad Sci U S A 2005; 102: 874–9

    Article  PubMed  CAS  Google Scholar 

  25. Nikisch G, Agren H, Eap CB, et al. Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram. Int J Neuropsy-chopharmacol 2005; 8: 403–10

    Article  CAS  Google Scholar 

  26. Khan A, Warner HA, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 2000; 57: 311–7

    Article  PubMed  CAS  Google Scholar 

  27. Quitkin FM, McGrath PJ, Stewart JW, et al. Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients. J Clin Psychiatry 2005; 66: 670–6

    Article  PubMed  Google Scholar 

  28. Pinder RM. On the feasibility of designing new antidepressants. Hum Psychopharmacol 2001; 16: 53–9

    Article  PubMed  CAS  Google Scholar 

  29. Tamminga CA, Nemeroff CB, Blakely RD, et al. Developing novel treatments for mood disorders: accelerating discovery. Biol Psychiatry 2002; 52: 589–609

    Article  PubMed  Google Scholar 

  30. Rupniak NM, Carlson EJ, Webb JK, et al. Comparison of the phenotype of NK1R-/-mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 2001; 12: 497–508

    Article  PubMed  CAS  Google Scholar 

  31. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640–5

    Article  PubMed  CAS  Google Scholar 

  32. Timpl P, Spanagel R, Sillaber I, et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 1998; 19: 162–6

    Article  PubMed  CAS  Google Scholar 

  33. Nielsen DM, Carey GJ, Gold LH. Antidepressant-like activity of corticotropin-releasing factor type-1 receptor antagonists in mice. Eur J Pharmacol 2004; 499: 135–46

    Article  PubMed  CAS  Google Scholar 

  34. Heinrichs SC, De Souza EB, Schulteis G, et al. Brain pene-trance, receptor occupancy and antistress in vivo efficacy of a small molecule corticotropin releasing factor type I receptor selective antagonist. Neuropsychopharmacology 2002; 27: 194–202

    Article  PubMed  CAS  Google Scholar 

  35. Chaki S, Nakazato A, Kennis L, et al. Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450. Eur J Pharmacol 2004; 485: 145–58

    Article  PubMed  CAS  Google Scholar 

  36. Redrobe JP, Dumont Y, Fournier A, et al. The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test. Neuropsychopharmacology 2002; 26: 615–24

    Article  PubMed  CAS  Google Scholar 

  37. Swanson CJ, Blackburn TP, Zhang X, et al. Anxiolytic- and antidepressant-like profiles of the galanin-3 receptor (Gal3) antagonists SNAP 37889 and SNAP 398299. Proc Natl Acad Sci U S A 2005; 102: 17489–94

    Article  PubMed  CAS  Google Scholar 

  38. Kuteeva E, Hökfelt T, Ögren SO. Behavioural characterisation of young adult transgenic mice overexpressing galanin under the PDGF-B promoter. Regul Pept 2005; 125: 67–78

    Article  PubMed  CAS  Google Scholar 

  39. Weiss JM, Boss-Williams KA, Moore JP, et al. Testing the hypothesis that locus coeruleus hyperactivity produces depression-related changes via galanin. Neuropeptides 2005; 39: 281–7

    Article  PubMed  CAS  Google Scholar 

  40. Kuteeva E, Wardi T, Hökfelt T, et al. Galanin enhances and a galanin antagonist attenuates depression-like behaviour in the rat. Eur Neuropsychopharmacol. Epub 2006 Apr 17

  41. Gavioli EC, Marzola G, Guerrini R, et al. Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. Eur J Neurosci 2003; 17: 1987–90

    Article  PubMed  CAS  Google Scholar 

  42. Trapella C, Guerrini R, Piccagli L, et al. Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist. Bioorg Med Chem 2006; 14: 692–704

    Article  PubMed  CAS  Google Scholar 

  43. Hökfelt T, Broberger C, Xu ZQ, et al. Neuropeptides: an overview. Neuropharmacology 2000; 39: 1337–56

    Article  PubMed  Google Scholar 

  44. Juaneda C, Dumont Y, Quirion R. The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sei 2000; 21: 432–8

    Article  CAS  Google Scholar 

  45. Hökfelt T, Bartfai T, Bloom F. Neuropeptides: opportunities for drug discovery. Lancet Neurol 2003; 2: 463–72

    Article  PubMed  Google Scholar 

  46. Lundberg JM, Hökfelt T. Multiple co-existence of peptides and classical transmitters in peripheral autonomic and sensory neurons: functional and pharmacological implications. Prog Brain Res 1986; 68: 241–62

    Article  PubMed  CAS  Google Scholar 

  47. Brodin E, Rosen A, Schött E, et al. Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions. Neuropeptides 1994; 26: 253–60

    Article  PubMed  CAS  Google Scholar 

  48. Redrobe JP, Dumont Y, Quirion R. Neuropeptide Y (NPY) and depression: from animal studies to the human condition. Life Sci 2002; 71: 2921–37

    Article  PubMed  CAS  Google Scholar 

  49. Holmes A, Heilig M, Rupniak NM, et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci 2003; 24: 580–8

    Article  PubMed  CAS  Google Scholar 

  50. Holsboer F. Corticotropin-releasing hormone modulators and depression. Curr Opin Investig Drugs 2003; 4: 46–50

    PubMed  CAS  Google Scholar 

  51. Keller M, Montgomery S, Ball W, et al. Lack of efficacy of the substance p (neurokininl receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry 2006; 59: 216–23

    Article  PubMed  CAS  Google Scholar 

  52. Tatemoto K, Rökaeus A, Jörnvall H, et al. Galanin: a novel biologically active peptide from porcine intestine. FEBS Lett 1983; 164: 124–8

    Article  PubMed  CAS  Google Scholar 

  53. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and suicidal behavior. Neuropsychopharma-cology 1999; 21: 99–105S

    Google Scholar 

  54. Aghajanian GK, Sprouse JS, Sheldon P, et al. Electrophysiology of the central serotonin system: receptor subtypes and transducer mechanisms. Ann N Y Acad Sci 1990; 600: 93–103

    Article  PubMed  CAS  Google Scholar 

  55. Azmitia EC, Gannon PJ, Kheck NM, et al. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology 1996; 14: 35–46

    Article  PubMed  CAS  Google Scholar 

  56. Lesch KP. The ipsapirone/5-HT1 A receptor challenge in anxiety disorders and depression. In: Stahl S, Hesselink J, Gastpar M, et al., editors. Serotonin 1A receptors in depression and anxiety. New York: Raven Press, 1992: 135–62

    Google Scholar 

  57. Stockmeier CA, Shapiro LA, Dilley GE, et al. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 1998; 18: 7394–401

    PubMed  CAS  Google Scholar 

  58. Lopez JF, Chalmers DT, Little KY, et al. Regulation of serotoninl A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998; 43: 547–73

    Article  PubMed  CAS  Google Scholar 

  59. Drevets WC, Frank E, Price JC, et al. Serotonin type-1A receptor imaging in depression. Nucl Med Biol 2000; 27: 499–507

    Article  PubMed  CAS  Google Scholar 

  60. Bhagwagar Z, Rabiner EA, Sargent PA, et al. Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11QWAY-100635. Mol Psychiatry 2004; 9: 386–92

    Article  PubMed  CAS  Google Scholar 

  61. Albert PR, Lemonde S. 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist 2004; 10: 575–93

    Article  PubMed  CAS  Google Scholar 

  62. Pineyro G, Blier P. Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 1999; 51: 533–91

    PubMed  CAS  Google Scholar 

  63. Albert PR, Lembo P, Starring JM, et al. The 5-HT1A receptor: signaling, desensitization, and gene transcription. Neuropsychopharmacology 1996; 14: 19–25

    Article  PubMed  CAS  Google Scholar 

  64. Artigas F, Bel N, Casanovas JM, et al. Adaptative changes of the serotonergic system after antidepressant treatments. Adv Exp Med Biol 1996; 398: 51–9

    Article  PubMed  CAS  Google Scholar 

  65. Rueter LE, De Montigny C, Blier P. Electrophysiological characterization of the effect of long-term duloxetine administration on the rat serotonergic and noradrenergic systems. J Pharmacol Exp Ther 1998; 285: 404–12

    PubMed  CAS  Google Scholar 

  66. Rökaeus A, Carlquist M. Nucleotide sequence analysis of cDNAs encoding a bovine galanin precursor protein in the adrenal medulla and chemical isolation of bovine gut galanin. FEBS Lett 1988; 234: 400–6

    Article  PubMed  Google Scholar 

  67. Rökaeus A, Melander T, Hökfelt T, et al. A galanin-like peptide in the central nervous system and intestine of the rat. Neurosci Lett 1984; 47: 161–6

    Article  PubMed  Google Scholar 

  68. Skofitsch G, Jacobowitz DM. Immunohistochemical mapping of galanin-like neurons in the rat central nervous system. Peptides 1985; 6: 509–46

    Article  PubMed  CAS  Google Scholar 

  69. Melander T, Hökfelt T, Rökaeus A. Distribution of galanin-like immunoreactivity in the rat central nervous system. J Comp Neurol 1986; 248: 475–517

    Article  PubMed  CAS  Google Scholar 

  70. Perez SE, Wynick D, Steiner RA, et al. Distribution of galaninergic immunoreactivity in the brain of the mouse. J Comp Neurol 2001; 434: 158–85

    Article  PubMed  CAS  Google Scholar 

  71. Kordower JH, Le HK, Mufson EJ. Galanin immunoreactivity in the primate central nervous system. J Comp Neurol 1992; 319: 479–500

    Article  PubMed  CAS  Google Scholar 

  72. Melander T, Hökfelt T, Rökaeus A, et al. Coexistence of galanin-like immunoreactivity with catecholamines, 5-hydroxytryptamine, GABA and neuropeptides in the rat CNS. J Neurosci 1986; 6: 3640–54

    PubMed  CAS  Google Scholar 

  73. Xu ZQ, Hökfelt T. Expression of galanin and nitric oxide synthase in subpopulations of serotonin neurons of the rat dorsal raphe nucleus. J Chem Neuroanat 1997; 13: 169–87

    Article  PubMed  CAS  Google Scholar 

  74. Xu ZQ, Shi TJ, Hökfelt T. Galanin/GMAP- and NPY-like immunoreactivities in locus coeruleus and noradrenergic nerve terminals in the hippocampal formation and cortex with notes on the galanin-R1 and -R2 receptors. J Comp Neurol 1998; 392: 227–51

    Article  PubMed  CAS  Google Scholar 

  75. Hökfelt T, Xu ZQ, Shi TJ, et al. Galanin in ascending systems: focus on coexistence with 5-hydroxytryptamine and noradrenaline. Ann N Y Acad Sci 1998; 863: 252–63

    Article  PubMed  Google Scholar 

  76. Hökfelt T, Millhorn D, Seroogy K, et al. Coexistence of peptides with classical neurotransmitters. Experientia 1987; 43: 768–80

    Article  PubMed  Google Scholar 

  77. Holets VR, Hökfelt T, Rökaeus A, et al. Locus coeruleus neurons in the rat containing neuropeptide Y, tyrosine hydroxylase or galanin and their efferent projections to the spinal cord, cerebral cortex and hypothalamus. Neuroscience 1988; 24: 893–906

    Article  PubMed  CAS  Google Scholar 

  78. Dahlström A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system: I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 1964; 62Suppl. 232: 1–55

    Google Scholar 

  79. Ungerstedt U. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta Physiol Scand Suppl 1971; 367: 1–48

    CAS  Google Scholar 

  80. Melander T, Bartfai T, Brynne N, et al. Galanin in the cholinergic basal forebrain: histochemical, autoradiographic and in vivo studies. Prog Brain Res 1989; 79: 85–91

    Article  PubMed  CAS  Google Scholar 

  81. Senut MC, Menetrey D, Lamour Y. Cholinergic and peptidergic projections from the medial septum and the nucleus of the diagonal band of Broca to dorsal hippocampus, cingulate cortex and olfactory bulb: a combined wheatgerm agglutinin-apohorseradish peroxidase-gold immunohistochemical study. Neuroscience 1989; 30: 385–403

    Article  PubMed  CAS  Google Scholar 

  82. Bartfai T, Hökfelt T, Langel U. Galanin: a neuroendocrine peptide. Crit Rev Neurobiol 1993; 7: 229–74

    PubMed  CAS  Google Scholar 

  83. Crawley JN. Minireview: galanin-acetylcholine interactions: relevance to memory and Alzheimer’s disease. Life Sci 1996; 58: 2185–99

    Article  PubMed  CAS  Google Scholar 

  84. Ögren SO, Schött PA, Kehr J, et al. Modulation of acetylcholine and serotonin transmission by galanin: relationship to spatial and aversive learning. Ann N Y Acad Sci 1998; 863: 342–63

    Article  PubMed  Google Scholar 

  85. Hökfelt T. Galanin and its receptors: introduction to the Third International Symposium, San Diego, California, USA, 21-22 Oct 2004. Neuropeptides 2005; 39: 125–42

    Article  PubMed  CAS  Google Scholar 

  86. Branchek TA, Smith KE, Gerald C, et al. Galanin receptor subtypes. Trends Pharmacol Sci 2000; 21: 109–17

    Article  PubMed  CAS  Google Scholar 

  87. Iismaa TP, Shine J. Galanin and galanin receptors. Results Probl Cell Differ 1999; 26: 257–91

    PubMed  CAS  Google Scholar 

  88. Fathi Z, Cunningham AM, Iben LG, et al. Cloning, pharmacological characterization and distribution of a novel galanin receptor. Brain Res Mol Brain Res 1997; 51: 49–59

    Article  PubMed  CAS  Google Scholar 

  89. Kolakowski Jr LF, O’Neill GP, Howard AD, et al. Molecular characterization and expression of cloned human galanin receptors GALR2 and GALR3. J Neurochem 1998; 71: 2239–51

    Article  PubMed  CAS  Google Scholar 

  90. Parker EM, Izzarelli DG, Nowak HP, et al. Cloning and characterization of the rat GALR1 galanin receptor from Rinl4B insulinoma cells. Brain Res Mol Brain Res 1995; 34: 179–89

    Article  PubMed  CAS  Google Scholar 

  91. Smith KE, Walker MW, Artymyshyn R, et al. Cloned human and rat galanin GALR3 receptors: pharmacology and activation of G-protein inwardly rectifying K+ channels. J Biol Chem 1998; 273: 23321–6

    Article  PubMed  CAS  Google Scholar 

  92. Wang S, He C, Maguire MT, et al. Genomic organization and functional characterization of the mouse GalR1 galanin receptor. FEBS Lett 1997; 411: 225–30

    Article  PubMed  CAS  Google Scholar 

  93. Skofitsch G, Sills MA, Jacobowitz DM. Autoradiographic distribution of 125I-galanin binding sites in the rat central nervous system. Peptides 1986; 7: 1029–42

    Article  PubMed  CAS  Google Scholar 

  94. Melander T, Köhler C, Nilsson S, et al. Autoradiographic quantitation and anatomical mapping of 1251-galanin binding sites in the rat central nervous system. J Chem Neuroanat 1988; 1: 213–33

    PubMed  CAS  Google Scholar 

  95. Hedlund PB, Yanaihara N, Fuxe K. Evidence for specific N-terminal galanin fragment binding sites in the rat brain. Eur J Pharmacol 1992; 224: 203–5

    Article  PubMed  CAS  Google Scholar 

  96. O’Donnell D, Ahmad S, Wahlestedt C, et al. Expression of the novel galanin receptor subtype GALR2 in the adult rat CNS: distinct distribution from GALR1. J Comp Neurol 1999; 409: 469–81

    Article  PubMed  Google Scholar 

  97. O’Donnell D, Menniken F, Hoffert C, et al. Localization of galanin receptor subtypes in the rat CNS. In: Quirion RBA, Hökfelt T, editors. Handbook of chemical neuroanatomy. Amsterdam: Elsevier, 2003: 195–244

    Google Scholar 

  98. Mennicken F, Hoffert C, Pelletier M, et al. Restricted distribution of galanin receptor 3 (GalR3) mRNA in the adult rat central nervous system. J Chem Neuroanat 2002; 24: 257–68

    Article  PubMed  CAS  Google Scholar 

  99. Hawes JJ, Picciotto MR. Characterization of GalR1, GalR2, and GalR3 immunoreactivity in catecholaminergic nuclei of the mouse brain. J Comp Neurol 2004; 479: 410–23

    Article  PubMed  Google Scholar 

  100. Karelson E, Langel U. Galaninergic signalling and adenylate cyclase. Neuropeptides 1998; 32: 197–210

    Article  PubMed  CAS  Google Scholar 

  101. Bartfai T, Fisone G, Langel U. Galanin and galanin antagonists: molecular and biochemical perspectives. Trends Pharmacol Sci 1992; 13: 312–7

    Article  PubMed  CAS  Google Scholar 

  102. Liu HX, Brumovsky P, Schmidt R, et al. Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors. Proc Natl Acad Sci U S A 2001; 98: 9960–4

    Article  PubMed  CAS  Google Scholar 

  103. Lu X, Lundström L, Bartfai T. Galanin (2–11) binds to GalR3 in transfected cell lines: limitations for pharmacological definition of receptor subtypes. Neuropeptides 2005; 39: 165–7

    Article  PubMed  CAS  Google Scholar 

  104. Jacoby AS, Hort YJ, Constantinescu G, et al. Critical role for GALRl galanin receptor in galanin regulation of neuroendocrine function and seizure activity. Brain Res Mol Brain Res 2002; 107: 195–200

    Article  PubMed  CAS  Google Scholar 

  105. Holmes A, Kinney JW, Wrenn CC, et al. Galanin GAL-R1 receptor null mutant mice display increased anxiety-like behavior specific to the elevated plus-maze. Neuropsychophar-macology 2003; 28: 1031–44

    CAS  Google Scholar 

  106. Xu ZQ, Zhang X, Pieribone VA, et al. Galanin-5-hydroxy-tryptamine interactions: electrophysiological, immunohistochemical and in situ hybridization studies on rat dorsal raphe neurons with a note on galanin R1 and R2 receptors. Neuroscience 1998; 87: 79–94

    Article  PubMed  CAS  Google Scholar 

  107. Larm JA, Shen PJ, Gundlach AL. Differential galanin receptor-1 and galanin expression by 5-HT neurons in dorsal raphe nucleus of rat and mouse: evidence for species-dependent modulation of serotonin transmission. Eur J Neurosci 2003; 17: 481–93

    Article  PubMed  Google Scholar 

  108. Kehr J, Yoshitake T, Wang FH, et al. Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission. Neuropsychopharmacology 2002; 27: 341–56

    Article  PubMed  CAS  Google Scholar 

  109. Yoshitake T, Reenila I, Ögren SO, et al. Galanin attenuates basal and antidepressant drug-induced increase of extracellular serotonin and noradrenaline levels in the rat hippocampus. Neurosci Lett 2003; 339: 239–42

    Article  PubMed  CAS  Google Scholar 

  110. Yoshitake T, Yoshitake S, Yamaguchi M, et al. Activation of 5-HT(1A) autoreceptors enhances the inhibitory effect of galanin on hippocampal 5-HT release in vivo. Neuropharmacology 2003; 44: 206–13

    Article  PubMed  CAS  Google Scholar 

  111. Razani H, Diaz-Cabiale Z, Fuxe K, et al. Intraventricular galanin produces a time-dependent modulation of 5-HT1A receptors in the dorsal raphe of the rat. Neuroreport 2000; 11: 3943–8

    Article  PubMed  CAS  Google Scholar 

  112. Razani H, Diaz-Cabiale Z, Misane I, et al. Prolonged effects of intraventricular galanin on a 5-hydroxytryptamine(1A) receptor mediated function in the rat. Neurosci Lett 2001; 299: 145–9

    Article  PubMed  CAS  Google Scholar 

  113. Hedlund PB, Fuxe K. Galanin and 5-HT1A receptor interactions as an integrative mechanism in 5-HT neurotransmission in the brain. Ann N Y Acad Sci 1996; 780: 193–212

    Article  PubMed  CAS  Google Scholar 

  114. Fuxe K, Jansson A, Diaz-Cabiale Z, et al. Galanin modulates 5-hydroxytryptamine functions: focus on galanin and galanin fragment/5-hydroxytryptamine1A receptor interactions in the brain. Ann N Y Acad Sci 1998; 863: 274–90

    Article  PubMed  CAS  Google Scholar 

  115. Hjorth S, Sharp T. Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis. Life Sci 1991; 48: 1779–86

    Article  PubMed  CAS  Google Scholar 

  116. Invernizzi R, Carli M, Di Clemente A, et al. Administration of 8-hydroxy-2-(Di-n-propylamino)tetralin in raphe nuclei dorsalis and medianus reduces serotonin synthesis in the rat brain: differences in potency and regional sensitivity. J Neurochem 1991; 56: 243–7

    Article  PubMed  CAS  Google Scholar 

  117. Fuxe K, von Euler G, Agnati LF, et al. Galanin selectively modulates 5-hydroxytryptamine 1A receptors in the rat ventral limbic cortex. Neurosci Lett 1988; 85: 163–7

    Article  PubMed  CAS  Google Scholar 

  118. Misane I, Razani H, Wang FH, et al. Intraventricular galanin modulates a 5-HT1A receptor-mediated behavioural response in the rat. Eur J Neurosci 1998; 10: 1230–40

    Article  PubMed  CAS  Google Scholar 

  119. Schött PA, Bjelke B, Ögren SO. Distribution and kinetics of galanin infused into the ventral hippocampus of the rat: relationship to spatial learning. Neuroscience 1998; 83: 123–36

    Article  PubMed  Google Scholar 

  120. Pieribone VA, Xu ZQ, Zhang X, et al. Galanin induces a hyperpolarization of norepinephrine-containing locus coeruleus neurons in the brainstem slice. Neuroscience 1995; 64: 861–74

    Article  PubMed  CAS  Google Scholar 

  121. Svensson TH. Stress, central neurotransmitters, and the mechanism of action of alpha 2-adrenoceptor agonists. J Cardiovasc Pharmacol 1987; 10Suppl. 12: S88–92

    Article  PubMed  CAS  Google Scholar 

  122. Seutin V, Verbanck P, Massotte L, et al. Galanin decreases the activity of locus coeruleus neurons in vitro. Eur J Pharmacol 1989; 164: 373–6

    Article  PubMed  CAS  Google Scholar 

  123. Sevcik J, Finta EP, Illes P. Galanin receptors inhibit the spontaneous firing of locus coeruleus neurones and interact with (x-opioid receptors. Eur J Pharmacol 1993; 230: 223–30

    Article  PubMed  CAS  Google Scholar 

  124. Tsuda K, Yokoo H, Goldstein M. Neuropeptide Y and galanin in norepinephrine release in hypothalamic slices. Hypertension 1989; 14: 81–6

    Article  PubMed  CAS  Google Scholar 

  125. Starke K, Gothert M, Kilbinger H. Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 1989; 69: 864–989

    PubMed  CAS  Google Scholar 

  126. Starke K. Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 1977; 77: 1–124

    Article  PubMed  CAS  Google Scholar 

  127. Yoshitake T, Wang FH, Kuteeva E, et al. Enhanced hippocampal noradrenaline and serotonin release in galanin-overexpres-sing mice after repeated forced swimming test. Proc Natl Acad Sci U S A 2004; 101: 354–9

    Article  PubMed  CAS  Google Scholar 

  128. Aston-Jones G, Rajkowski J, Kubiak P, et al. Role of the locus coeruleus in emotional activation. Prog Brain Res 1996; 107: 379–402

    Article  PubMed  CAS  Google Scholar 

  129. Harro J, Oreland L. Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus. Brain Res Brain Res Rev 2001; 38: 79–128

    Article  PubMed  CAS  Google Scholar 

  130. Morilak DA, Barrera G, Echevarria DJ, et al. Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1214–24

    Article  PubMed  CAS  Google Scholar 

  131. Holmes PV, Blanchard DC, Blanchard RJ, et al. Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus. Pharmacol Biochem Behav 1995; 50: 655–60

    Article  PubMed  CAS  Google Scholar 

  132. Khoshbouei H, Cecchi M, Dove S, et al. Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav 2002; 71: 407–17

    Article  PubMed  CAS  Google Scholar 

  133. Khoshbouei H, Cecchi M, Morilak DA. Modulatory effects of galanin in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuropsychopharmacology 2002; 27: 25–34

    Article  PubMed  CAS  Google Scholar 

  134. Bing O, Moller C, Engel JA, et al. Anxiolytic-like action of centrally administered galanin. Neurosci Lett 1993; 164:17–20

    Article  PubMed  CAS  Google Scholar 

  135. Möller C, Sommer W, Thorsell A, et al. Anxiogenic-like action of galanin after intra-amygdala administration in the rat. Neuropsychopharmacology 1999; 21: 507–12

    Article  PubMed  Google Scholar 

  136. Holmes A, Yang RJ, Crawley JN. Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice. J Mol Neurosci 2002; 18: 151–65

    Article  PubMed  CAS  Google Scholar 

  137. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977; 266: 730–2

    Article  PubMed  CAS  Google Scholar 

  138. Lucki I, O’Leary OF. Distinguishing roles for norepinephrine and serotonin in the behavioral effects of antidepressant drugs. J Clin Psychiatry 2004; 65Suppl. 4: 11–24

    PubMed  CAS  Google Scholar 

  139. Bellido I, Diaz-Cabiale Z, Jimenez-Vasquez PA, et al. Increased density of galanin binding sites in the dorsal raphe in a genetic rat model of depression. Neurosci Lett 2002; 317: 101–5

    Article  PubMed  CAS  Google Scholar 

  140. Holmes A, Li Q, Koenig EA, et al. Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior. Psychopharmacology (Berl) 2005; 178: 276–85

    Article  CAS  Google Scholar 

  141. Borsini F, Lecci A, Sessarego A, et al. Discovery of antidepressant activity by forced swimming test may depend on preexposure of rats to a stressful situation. Psychopharmacology (Berl) 1989; 97: 183–8

    Article  CAS  Google Scholar 

  142. Cryan JF, Holmes A. The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 2005; 4: 775–90

    Article  PubMed  CAS  Google Scholar 

  143. Petty F, Chae Y, Kramer G, et al. Learned helplessness sensitizes hippocampal norepinephrine to mild stress. Biol Psychiatry 1994; 35: 903–8

    Article  PubMed  CAS  Google Scholar 

  144. Petty F, Kramer G, Wilson L, et al. In vivo serotonin release and learned helplessness. Psychiatry Res 1994; 52: 285–93

    Article  PubMed  CAS  Google Scholar 

  145. Weiss JM, Bonsall RW, Demetrikopoulos MK, et al. Galanin: a significant role in depression? Ann N Y Acad Sei 1998; 863: 364–82

    Article  CAS  Google Scholar 

  146. Bartfai T, Lu X, Badie-Mahdavi H, et al. Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests. Proc Natl Acad Sci U S A 2004; 101: 10470–5

    Article  PubMed  CAS  Google Scholar 

  147. Florén A, Sollenberg U, Lundström L, et al. Multiple interaction sites of galnon trigger its biological effects. Neuropeptides 2005; 39: 547–58

    Article  PubMed  CAS  Google Scholar 

  148. Saar K, Mazarati AM, Mahlapuu R, et al. Anticonvulsant activity of a nonpeptide galanin receptor agonist. Proc Natl Acad Sci U S A 2002; 99: 7136–41

    Article  PubMed  CAS  Google Scholar 

  149. Gottsch ML, Zeng H, Hohmann JG, et al. Phenotypic analysis of mice deficient in the type 2 galanin receptor (GALR2). Mol Cell Biol 2005; 25: 4804–11

    Article  PubMed  CAS  Google Scholar 

  150. Sweerts BW, Jarrott B, Lawrence AJ. Expression of preprogalanin mRNA following acute and chronic restraint stress in brains of normotensive and hypertensive rats. Brain Res Mol Brain Res 1999; 69: 113–23

    Article  PubMed  CAS  Google Scholar 

  151. Morilak DA, Cecchi M, Khoshbouei H. Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress. Life Sci 2003; 73: 715–26

    Article  PubMed  CAS  Google Scholar 

  152. Mazarati AM, Baldwin RA, Shinmei S, et al. In vivo interaction between serotonin and galanin receptors types 1 and 2 in the dorsal raphe: implication for limbic seizures. J Neurochem 2005; 95: 1495-503

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This paper was supported by The Swedish Research Council (grant numbers 04X-11588, 04X-2887), The Marianne and Marcus Wallenberg Foundation, Wallenberg Consortium North, Karolinska Institutet Funds and an EC Grant (NEWMOOD; LHSM-CT-2003-503474). We thank Drs T.P. Iismaa, J. Shine (figure 2) and C.J. Swanson (figure 8) for allowing us to reproduce some of their figures.

Dr Ögren serves as a consultant to AstraZeneca and has a research grant from the company, Dr Hökfelt served as a consultant for Lundbeck America in 2005.

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  1. Department of Neuroscience, Karolinska Institutet, Retzius väg, Stockholm 8, S-171 77, Sweden

    Sven Ove Ögren, Eugenia Kuteeva, Tomas Hökfelt & Jan Kehr

  2. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Jan Kehr

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  1. Sven Ove Ögren
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  2. Eugenia Kuteeva
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Correspondence to Sven Ove Ögren.

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Ögren, S.O., Kuteeva, E., Hökfelt, T. et al. Galanin Receptor Antagonists. CNS Drugs 20, 633–654 (2006). https://doi.org/10.2165/00023210-200620080-00003

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