Abstract
Galanin (GAL) is an estrogen-inducible neuropeptide, highly expressed in brain regions reported to be involved in regulation of mood and anxiety. GAL possibly has a direct modulatory effect on hypothalamic–pituitary–adrenal (HPA)-axis regulation. Recent data from pharmacological and genetic studies indicate a significant function of GAL in stress-related disorders. By using a tag SNP approach covering the locus encoding preprogalanin (PPGAL), earlier findings of female-specific associations of polymorphisms in this locus with panic disorder were expanded to a larger sample of 268 outpatients with anxiety disorders (ADs). Within a larger sample of 541 inpatients with major depressive disorder (MDD), we then tested associations of one PPGAL tag SNP with specific depression symptom clusters and HPA-axis activity assessed by the combined dexamethasone-suppression/CRH-stimulation test both at inpatient admission and discharge (n=298). Gender specificity as well as dependence of the association on levels of circulating estrogens was analyzed. Genotyping revealed high linkage disequilibrium in the promoter area of the PPGAL gene, which includes several estrogen-response elements. Confirming earlier results, rs948854, tagging this promoter region, was associated with more severe anxiety pathology in female AD patients, but not in males. In premenopausal female MDD patients, the same allele of rs948854 was associated with more severe vegetative but not cognitive depressive symptoms at discharge and worse treatment response on antidepressant medication. Furthermore, this allele was associated with higher HPA-axis activity at admission. No significant case–control associations could be observed. However, because of power limitations of both patient samples, small effects cannot be excluded. The reported associations in independent samples of AD and MDD support an estrogen-dependent function of GAL in pathophysiology of anxiety and depression, affecting response to antidepressant treatment.
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References
Arvat E, Gianotti L, Ramunni J, Grottoli S, Brossa PC, Bertagna A et al (1995). Effect of galanin on basal and stimulated secretion of prolactin, gonadotropins, thyrotropin, adrenocorticotropin and cortisol in humans. Eur J Endocrinol 133: 300–304.
Bandelow B (1995). Assessing the efficacy of treatments for panic disorder and agoraphobia. II. The Panic and Agoraphobia Scale. Int Clin Psychopharmacol 10: 73–81.
Bardeleben U, Holsboer F (1989). Cortisol response to a combined dexamethasone-human corticotrophin-releasing hormone challenge in patients with depression. J Neuroendocrinol 1: 485–488.
Barrett JC, Fry B, Maller J, Daly MJ (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
Bartfai T, Lu X, Badie-Mahdavi H, Barr AM, Mazarati A, Hua XY et al (2004). Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests. Proc Natl Acad Sci USA 101: 10470–10475.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961). An inventory for measuring depression. Arch Gen Psychiatry 4: 561–571.
Belfer I, Hipp H, Bollettino A, McKnight C, Evans C, Virkkunen M et al (2007). Alcoholism is associated with GALR3 but not two other galanin receptor genes. Genes Brain Behav 6: 473–481.
Belfer I, Hipp H, McKnight C, Evans C, Buzas B, Bollettino A et al (2006). Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Mol Psychiatry 11: 301–311.
Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al (2004). Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36: 1319–1325.
Bland JM, Altman DG (1995). Multiple significance tests: the Bonferroni method. BMJ 310: 170.
Brann DW, Chorich LP, Mahesh VB (1993). Effect of progesterone on galanin mRNA levels in the hypothalamus and the pituitary: correlation with the gonadotropin surge. Neuroendocrinology 58: 531–538.
Britton KT, Lee G, Dana R, Risch SC, Koob GF (1986). Activating and ‘anxiogenic’ effects of corticotropin releasing factor are not inhibited by blockade of the pituitary-adrenal system with dexamethasone. Life Sci 39: 1281–1286.
Brogan RS, Coney LK, Wehrenberg WB, Beretta G, Giustina A (1999). Short-term glucocorticoid administration decreases both hypothalamic and pituitary galanin synthesis in the adult male rat. Metabolism 48: 792–796.
Ceccatelli S, Eriksson M, Hokfelt T (1989). Distribution and coexistence of corticotropin-releasing factor-, neurotensin-, enkephalin-, cholecystokinin-, galanin- and vasoactive intestinal polypeptide/peptide histidine isoleucine-like peptides in the parvocellular part of the paraventricular nucleus. Neuroendocrinology 49: 309–323.
Consortium TIH (2003). The International HapMap project. Nature 426: 789–796.
Evans HF, Shine J (1991). Human galanin: molecular cloning reveals a unique structure. Endocrinology 129: 1682–1684.
Fava M, Hwang I, Rush AJ, Sampson N, Walters EE, Kessler RC (2009). The importance of irritability as a symptom of major depressive disorder: results from the national comorbidity survey replication. Mol Psychiatry (originally published online 10 March 2009; doi:10.1038/MP.2009.20).
Fuxe K, Jansson A, Diaz-Cabiale Z, Andersson A, Tinner B, Finnman UB et al (1998). Galanin modulates 5-hydroxytryptamine functions. Focus on galanin and galanin fragment/5-hydroxytryptamine1A receptor interactions in the brain. Ann N Y Acad Sci 863: 274–290.
Gentleman SM, Falkai P, Bogerts B, Herrero MT, Polak JM, Roberts GW (1989). Distribution of galanin-like immunoreactivity in the human brain. Brain Res 505: 311–315.
Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62.
Hemmer A, Hyde JF (1992). Regulation of galanin secretion from pituitary cells in vitro by estradiol and GHRH. Peptides 13: 1201–1206.
Hennings JM, Owashi T, Binder EB, Horstmann S, Menke A, Kloiber S et al (2009). Clinical characteristics and treatment outcome in a representative sample of depressed inpatients—findings from the Munich Antidepressant Response Signature (MARS) project. J Psychiatr Res 43: 215–229.
Heuser I, Yassouridis A, Holsboer F (1994). The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. J Psychiatr Res 28: 341–356.
Holmes PV, Blanchard DC, Blanchard RJ, Brady LS, Crawley JN (1995). Chronic social stress increases levels of preprogalanin mRNA in the rat locus coeruleus. Pharmacol Biochem Behav 50: 655–660.
Holsboer F (2000). The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23: 477–501.
Hooi SC, Maiter DM, Martin JB, Koenig JI (1990). Galaninergic mechanisms are involved in the regulation of corticotropin and thyrotropin secretion in the rat. Endocrinology 127: 2281–2289.
Howard G, Peng L, Hyde JF (1997). An estrogen receptor binding site within the human galanin gene. Endocrinology 138: 4649–4656.
Ising M, Lucae S, Binder EB, Bettecken T, Uhr M, Ripke S et al (2009). A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression. Arch Gen Psychiatry 66: 966–975.
Kaplan LM, Gabriel SM, Koenig JI, Sunday ME, Spindel ER, Martin JB et al (1988). Galanin is an estrogen-inducible, secretory product of the rat anterior pituitary. Proc Natl Acad Sci USA 85: 7408–7412.
Keck ME, Wigger A, Welt T, Muller MB, Gesing A, Reul JM et al (2002). Vasopressin mediates the response of the combined dexamethasone/CRH test in hyper-anxious rats: implications for pathogenesis of affective disorders. Neuropsychopharmacology 26: 94–105.
Kehr J, Yoshitake T, Wang FH, Razani H, Gimenez-Llort L, Jansson A et al (2002). Galanin is a potent in vivo modulator of mesencephalic serotonergic neurotransmission. Neuropsychopharmacology 27: 341–356.
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62: 617–627.
Khoshbouei H, Cecchi M, Dove S, Javors M, Morilak DA (2002a). Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav 71: 407–417.
Khoshbouei H, Cecchi M, Morilak DA (2002b). Modulatory effects of galanin in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuropsychopharmacology 27: 25–34.
Kofler B, Evans HF, Liu ML, Falls V, Iismaa TP, Shine J et al (1995). Characterization of the 5′-flanking region of the human preprogalanin gene. DNA Cell Biol 14: 321–329.
Kunzel HE, Binder EB, Nickel T, Ising M, Fuchs B, Majer M et al (2003). Pharmacological and nonpharmacological factors influencing hypothalamic-pituitary-adrenocortical axis reactivity in acutely depressed psychiatric in-patients, measured by the Dex-CRH test. Neuropsychopharmacology 28: 2169–2178.
Kuteeva E, Hokfelt T, Wardi T, Ogren SO (2008). Galanin, galanin receptor subtypes and depression-like behaviour. Cell Mol Life Sci 65: 1854–1863.
Landgraf R (2006). The involvement of the vasopressin system in stress-related disorders. CNS Neurol Disord Drug Targets 5: 167–179.
Leibowitz SF (1998). Differential functions of hypothalamic galanin cell grows in the regulation of eating and body weight. Ann N Y Acad Sci 863: 206–220.
Levran O, Londono D, O’Hara K, Nielsen DA, Peles E, Rotrosen J et al (2008). Genetic susceptibility to heroin addiction; a candidate-gene association study. Genes Brain Behav 7: 720–729.
Lopez FJ, Merchenthaler I, Ching M, Wisniewski MG, Negro-Vilar A (1991). Galanin: a hypothalamic-hypophysiotropic hormone modulating reproductive functions. Proc Natl Acad Sci USA 88: 4508–4512.
Ma X, Tong YG, Schmidt R, Brown W, Payza K, Hodzic L et al (2001). Effects of galanin receptor agonists on locus coeruleus neurons. Brain Res 919: 169–174.
Malendowicz LK, Nussdorfer GG, Nowak KW, Mazzocchi G (1994). The possible involvement of galanin in the modulation of the function of rat pituitary-adrenocortical axis under basal and stressful conditions. Endocr Res 20: 307–317.
Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR (1989). Menopause and risk factors for coronary heart disease. N Engl J Med 321: 641–646.
Mazzocchi G, Malendowicz LK, Rebuffat P, Nussdorfer GG (1992). Effects of galanin on the secretory activity of the rat adrenal cortex: in vivo and in vitro studies. Res Exp Med (Berl) 192: 373–381.
Mechenthaler I (2008). Galanin and the neuroendocrine axes. Cell Mol Life Sci 65: 1826–1835.
Meczekalski B, Slopien R, Warenik-Szymankiewicz A (2001). The concentration of galanin in postmenopausal women before and after application of hormone replacement therapy compared to women of reproductive age. Med Sci Monit 7: 928–932.
Michener SR, Aimone LD, Yaksh TL, Go VL (1990). Distribution of galanin-like immunoreactivity in the pig, rat and human central nervous system. Peptides 11: 1217–1223.
Mitsukawa K, Lu X, Bartfai T (2008). Galanin, galanin receptors and drug targets. Cell Mol Life Sci 65: 1796–1805.
Murck H, Held K, Ziegenbein M, Kunzel H, Holsboer F, Steiger A (2004). Intravenous administration of the neuropeptide galanin has fast antidepressant efficacy and affects the sleep EEG. Psychoneuroendocrinology 29: 1205–1211.
Nemeroff CB, Owens MJ (2002). Treatment of mood disorders. Nat Neurosci 5 (Suppl): 1068–1070.
O’Neal HA, Van Hoomissen JD, Holmes PV, Dishman RK (2001). Prepro-galanin messenger RNA levels are increased in rat locus coeruleus after treadmill exercise training. Neurosci Lett 299: 69–72.
Oquendo MA, Barrera A, Ellis SP, Li S, Burke AK, Grunebaum M et al (2004). Instability of symptoms in recurrent major depression: a prospective study. Am J Psychiatry 161: 255–261.
Ottlecz A, Snyder GD, McCann SM (1988). Regulatory role of galanin in control of hypothalamic-anterior pituitary function. Proc Natl Acad Sci USA 85: 9861–9865.
Pepin MC, Pothier F, Barden N (1992). Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene. Nature 355: 725–728.
Picciotto MR (2008). Galanin and addiction. Cell Mol Life Sci 65: 1872–1879.
Rhoades HM, Overall JE (1983). The Hamilton Depression Scale: factor scoring and profile classification. Psychopharmacol Bull 19: 91–96.
Ripke S (2007). WG-Permer: Rapid Analysis of Large Scale Whole Genome Association Studies. MPI of Psychiatry: Munich. http://www.wg-permer.org.
Rokaeus A, Brownstein MJ (1986). Construction of a porcine adrenal medullary cDNA library and nucleotide sequence analysis of two clones encoding a galanin precursor. Proc Natl Acad Sci USA 83: 6287–6291.
Schmidt WE, Kratzin H, Eckart K, Drevs D, Mundkowski G, Clemens A et al (1991). Isolation and primary structure of pituitary human galanin, a 30-residue nonamidated neuropeptide. Proc Natl Acad Sci USA 88: 11435–11439.
Sharkey LM, Madamba SG, Siggins GR, Bartfai T (2008). Galanin alters GABAergic neurotransmission in the dorsal raphe nucleus. Neurochem Res 33: 285–291.
Stenzel-Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW (1994). Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci 14 (5 Pt 1): 2579–2584.
Strohle A, Poettig M, Barden N, Holsboer F, Montkowski A (1998). Age- and stimulus-dependent changes in anxiety-related behaviour of transgenic mice with GR dysfunction. Neuroreport 9: 2099–2102.
Sweerts BW, Jarrott B, Lawrence AJ (1999). Expression of preprogalanin mRNA following acute and chronic restraint stress in brains of normotensive and hypertensive rats. Brain Res Mol Brain Res 69: 113–123.
Tseng JY, Kolb PE, Raskind MA, Miller MA (1997). Estrogen regulates galanin but not tyrosine hydroxylase gene expression in the rat locus ceruleus. Brain Res Mol Brain Res 50: 100–106.
Tyszkiewicz JP, Fong TM, Dong Y (2008). GABAB receptors are required for galanin modulation of membrane properties of neurons in the arcuate nucleus of rats. Brain Res 1191: 63–68.
Unschuld PG, Ising M, Erhardt A, Lucae S, Kohli M, Kloiber S et al (2008). Polymorphisms in the galanin gene are associated with symptom-severity in female patients suffering from panic disorder. J Affect Disord 105: 177–184.
Vrontakis ME, Peden LM, Duckworth ML, Friesen HG (1987). Isolation and characterization of a complementary DNA (galanin) clone from estrogen-induced pituitary tumor messenger RNA. J Biol Chem 262: 16755–16758.
Westfall PH, Young SS (1993). Resampling-based Multiple Testing: Examples and Methods for p-value Adjustment. Wiley: New York.
Wittchen HU (1999). Screening for mental disorders: performance of the Composite International Diagnostic—Screener (CID–S). Int J Methods Psychiatr Res 8: 59–70.
Wrenn CC, Crawley JN (2001). Pharmacological evidence supporting a role for galanin in cognition and affect. Prog Neuropsychopharmacol Biol Psychiatry 25: 283–299.
Xu ZQ, Zhang X, Pieribone VA, Grillner S, Hokfelt T (1998). Galanin-5-hydroxytryptamine interactions: electrophysiological, immunohistochemical and in situ hybridization studies on rat dorsal raphe neurons with a note on galanin R1 and R2 receptors. Neuroscience 87: 79–94.
Acknowledgements
We thank Sabine Damast, Maik Koedel, and Susann Sauer for excellent technical assistance. This work has been funded by the Bavarian Ministry of Commerce and by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), Förderkennzeichen 01GS0481. We are responsible for the contents of this publication.
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All the authors, except FH and EBB, declare that, except for the income received from our primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interests. FH wishes to declare that he personally received grant support from Bristol Myer Squibb, is founder and share holder of Affectis, and share holder of Corcept and Neurocrine. EBB wishes to declare that she personally received grant support from the National Institute of Mental Health and the Doris Duke Charitable foundation.
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Unschuld, P., Ising, M., Roeske, D. et al. Gender-Specific Association of Galanin Polymorphisms with HPA-Axis Dysregulation, Symptom Severity, and Antidepressant Treatment Response. Neuropsychopharmacol 35, 1583–1592 (2010). https://doi.org/10.1038/npp.2010.30
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DOI: https://doi.org/10.1038/npp.2010.30
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