title: Neuropeptide and sigma receptors as novel therapeutic targets for the pharmacotherapy of depression.
abstract: Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.
authors.affiliation: Laboratory of Pharmacology, School of Medicine, Democritus University of Thrace (DUTH), Alexandroupolis 68100, Thrace, Greece.
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Paschos
authors.forename: Stavroula
authors.initials: S
authors.lastname: Veletza
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Chatzaki
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018013:Receptors, Neuropeptide / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D018013:Receptors, Neuropeptide; D017480:Receptors, sigma
references.citation: Neuropeptides. 2005 Jun;39(3):143-6
references.pmid: 15944002
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10470-5
references.pmid: 15240875
references.citation: Curr Top Med Chem. 2008;8(6):506-20
references.pmid: 18397172
references.citation: Neuropharmacology. 2002 Dec;43(7):1165-72
references.pmid: 12504923
references.citation: Mol Pharmacol. 1992 Sep;42(3):458-63
references.pmid: 1383685
references.citation: Eur Neuropsychopharmacol. 2007 Jan;17(1):64-9
references.pmid: 16624535
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):6079-84
references.pmid: 10823952
references.citation: Cell Mol Life Sci. 2008 Jun;65(12):1854-63
references.pmid: 18500640
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Dec;26(7-8):1333-8
references.pmid: 12502022
references.citation: Neuropharmacology. 1995 Dec;34(12):1697-9
references.pmid: 8788968
references.citation: Biol Psychiatry. 2006 Apr 1;59(7):594-602
references.pmid: 16197926
references.citation: Neurosci Res. 2000 Aug;37(4):307-14
references.pmid: 10958979
references.citation: Curr Pharm Des. 2005;11(12):1549-59
references.pmid: 15892661
references.citation: Eur J Pharmacol. 2004 Sep 19;499(1-2):135-46
references.pmid: 15363960
references.citation: Neurosci Biobehav Rev. 2002 May;26(3):259-83
references.pmid: 12034130
references.citation: Neuropsychopharmacology. 2002 Aug;27(2):194-202
references.pmid: 12093593
references.citation: Life Sci. 2006 Jan 25;78(9):909-19
references.pmid: 16122764
references.citation: Neuropsychopharmacology. 2004 Jan;29(1):1-14
references.pmid: 12942143
references.citation: J Clin Psychiatry. 2000;61 Suppl 6:4-6
references.pmid: 10775017
references.citation: Genes Brain Behav. 2008 Jul;7(5):532-42
references.pmid: 18221379
references.citation: Neuropeptides. 2005 Jun;39(3):293-8
references.pmid: 15944025
references.citation: J Psychiatr Res. 2003 Nov-Dec;37(6):525-33
references.pmid: 14563384
references.citation: Trends Neurosci. 1999 Jan;22(1):25-30
references.pmid: 10088996
references.citation: J Pharmacol Exp Ther. 1976 Jun;197(3):517-32
references.pmid: 945347
references.citation: Amino Acids. 2006 Oct;31(3):251-72
references.pmid: 16820980
references.citation: Pharmacol Rev. 1998 Mar;50(1):143-50
references.pmid: 9549761
references.citation: J Psychiatr Res. 2004 Mar-Apr;38(2):113-21
references.pmid: 14757324
references.citation: Neuropharmacology. 2001 Jul;41(1):138-49
references.pmid: 11445194
references.citation: J Biol Chem. 1985 Feb 10;260(3):1501-7
references.pmid: 2578461
references.citation: Peptides. 2007 Feb;28(2):326-33
references.pmid: 17196302
references.citation: Acta Neurochir Suppl (Wien). 1990;47:86-9
references.pmid: 2407060
references.citation: Pol J Pharmacol. 2002 Nov-Dec;54(6):699-702
references.pmid: 12866727
references.citation: Psychopharmacology (Berl). 2005 Mar;178(2-3):276-85
references.pmid: 15365683
references.citation: Behav Brain Res. 2003 May 15;141(2):251-5
references.pmid: 12742262
references.citation: J Psychiatr Res. 2000 May-Jun;34(3):171-81
references.pmid: 10867111
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6370-5
references.pmid: 11959912
references.citation: Neuropsychopharmacology. 2002 Sep;27(3):371-9
references.pmid: 12225694
references.citation: Br J Psychiatry. 1991 Jan;158:59-63
references.pmid: 1673078
references.citation: Int J Clin Pract. 2007 Dec;61(12):2030-40
references.pmid: 17944926
references.citation: Peptides. 2001 May;22(5):835-44
references.pmid: 11337098
references.citation: Pharmacol Rev. 1994 Dec;46(4):551-99
references.pmid: 7534932
references.citation: Can J Psychiatry. 1997 May;42(4):367-77
references.pmid: 9161761
references.citation: J Clin Psychiatry. 2004 Apr;65(4):492-9
references.pmid: 15119911
references.citation: Circ Res. 1988 Oct;63(4):812-20
references.pmid: 2458861
references.citation: Pharmacol Rep. 2006 Jul-Aug;58(4):493-500
references.pmid: 16963794
references.citation: J Pharmacol Exp Ther. 2001 Sep;298(3):1269-79
references.pmid: 11504830
references.citation: Biol Psychiatry. 1989 Feb 1;25(3):355-9
references.pmid: 2536563
references.citation: Am J Psychiatry. 1987 Jul;144(7):873-7
references.pmid: 3496802
references.citation: Exp Neurol. 2008 Mar;210(1):128-36
references.pmid: 18035354
references.citation: Neuropsychopharmacology. 2002 May;26(5):615-24
references.pmid: 11927186
references.citation: Nature. 1999 Aug 19;400(6746):766-8
references.pmid: 10466725
references.citation: Science. 1984 Dec 14;226(4680):1342-4
references.pmid: 6334362
references.citation: Eur J Neurosci. 2003 Jul;18(1):143-8
references.pmid: 12859347
references.citation: J Pharmacol Sci. 2005 Mar;97(3):317-36
references.pmid: 15750289
references.citation: J Biol Chem. 1998 Sep 4;273(36):23321-6
references.pmid: 9722565
references.citation: Eur J Pharmacol. 1993 Nov 30;250(1):R5-6
references.pmid: 8119305
references.citation: J Med Chem. 2000 Jan 27;43(2):177-89
references.pmid: 10649973
references.citation: Neuropsychopharmacology. 2003 Jan;28(1):140-7
references.pmid: 12496950
references.citation: Therapie. 2004 Jan-Feb;59(1):5-12
references.pmid: 15199661
references.citation: Eur J Pharmacol. 2000 Jun 16;398(2):239-46
references.pmid: 10854835
references.citation: Pharmacol Biochem Behav. 2006 Apr;83(4):533-9
references.pmid: 16624395
references.citation: Biol Psychiatry. 2006 Oct 15;60(8):892-5
references.pmid: 16499879
references.citation: Trends Pharmacol Sci. 2000 Mar;21(3):109-17
references.pmid: 10689365
references.citation: Biochem Biophys Res Commun. 1987 Nov 13;148(3):1208-14
references.pmid: 3318828
references.citation: J Comp Neurol. 2001 May 28;434(2):158-85
references.pmid: 11331523
references.citation: Am J Psychiatry. 2006 Apr;163(4):637-43
references.pmid: 16585438
references.citation: Biol Psychiatry. 2005 Jul 15;58(2):132-42
references.pmid: 16038684
references.citation: J Comp Neurol. 1992 May 22;319(4):479-500
references.pmid: 1377713
references.citation: Baillieres Clin Endocrinol Metab. 1996 Jan;10(1):75-96
references.pmid: 8734452
references.citation: Neuropsychopharmacology. 2004 Apr;29(4):777-84
references.pmid: 14702025
references.citation: N Engl J Med. 2008 Jan 3;358(1):55-68
references.pmid: 18172175
references.citation: Pharmacol Biochem Behav. 2005 Sep;82(1):223-7
references.pmid: 16181667
references.citation: Mol Psychiatry. 2001 Sep;6(5):540-6
references.pmid: 11526468
references.citation: Trends Pharmacol Sci. 1992 Mar;13(3):85-6
references.pmid: 1315463
references.citation: Neuropsychopharmacology. 2007 Sep;32(9):1941-9
references.pmid: 17287823
references.citation: J Clin Psychiatry. 2005;66 Suppl 7:5-13
references.pmid: 16124836
references.citation: Trends Pharmacol Sci. 2003 Nov;24(11):580-8
references.pmid: 14607081
references.citation: Eur J Pharmacol. 1996 Sep 5;311(1):7-14
references.pmid: 8884230
references.citation: Nature. 1995 Nov 16;378(6554):287-92
references.pmid: 7477349
references.citation: Eur J Pharmacol. 2008 Apr 7;583(2-3):340-9
references.pmid: 18255056
references.citation: Curr Pharm Des. 2005;11(2):205-25
references.pmid: 15638758
references.citation: Nat Rev Neurosci. 2005 Jun;6(6):463-75
references.pmid: 15891777
references.citation: Am J Obstet Gynecol. 2006 Jul;195(1):288-95
references.pmid: 16626608
references.citation: Neurosci Biobehav Rev. 2007;31(1):89-102
references.pmid: 16934871
references.citation: Nat Genet. 2000 Apr;24(4):410-4
references.pmid: 10742108
references.citation: Paediatr Perinat Epidemiol. 2001 Jul;15 Suppl 2:124-35
references.pmid: 11520405
references.citation: Neurosci Lett. 2000 Apr 21;284(1-2):89-92
references.pmid: 10771169
references.citation: J Comp Neurol. 2001 Sep 3;437(4):496-504
references.pmid: 11503148
references.citation: J Pharmacol Exp Ther. 2001 Nov;299(2):449-58
references.pmid: 11602654
references.citation: Neuropeptides. 1993 Jun;24(6):317-9
references.pmid: 7688872
references.citation: J Neurosci. 1995 Jun;15(6):4250-8
references.pmid: 7790909
references.citation: Life Sci. 1997;60(18):1523-33
references.pmid: 9126874
references.citation: Neurosci Bull. 2008 Jun;24(3):155-9
references.pmid: 18500388
references.citation: Mol Psychiatry. 2004 Mar;9(3):287-92
references.pmid: 15094789
references.citation: J Neurol Neurosurg Psychiatry. 1985 Jan;48(1):50-7
references.pmid: 3973621
references.citation: Behav Pharmacol. 2001 Nov;12(6-7):497-508
references.pmid: 11742144
references.citation: Curr Med Chem. 2006;13(23):2751-60
references.pmid: 17073626
references.citation: Can J Physiol Pharmacol. 2002 May;80(5):489-94
references.pmid: 12056558
references.citation: Mol Pharmacol. 2002 Dec;62(6):1314-20
references.pmid: 12435798
references.citation: Br J Pharmacol. 2007 Jul;151(6):737-48
references.pmid: 17471183
references.citation: Neuroreport. 2002 Jul 2;13(9):1223-7
references.pmid: 12151774
references.citation: Peptides. 1999;20(3):367-72
references.pmid: 10447095
references.citation: Brain Res. 2001 Oct 12;915(2):170-5
references.pmid: 11595206
references.citation: Eur J Neurosci. 1998 Jul;10(7):2337-45
references.pmid: 9749762
references.citation: J Manag Care Pharm. 2007 Jul;13(6 Suppl A):S2-7
references.pmid: 17672818
references.citation: Neurosci Lett. 2006 Sep 11;405(1-2):111-5
references.pmid: 16854525
references.citation: Pharmacol Biochem Behav. 2002 Mar;71(3):419-23
references.pmid: 11830176
references.citation: Gynecol Endocrinol. 2001 Apr;15(2):98-102
references.pmid: 11379015
references.citation: Mol Psychiatry. 2004 Mar;9(3):278-86, 224
references.pmid: 14699428
references.citation: Pharmacol Biochem Behav. 1998 Nov;61(3):247-52
references.pmid: 9768559
references.citation: Pharmacol Rev. 1990 Dec;42(4):355-402
references.pmid: 1964225
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7570-5
references.pmid: 11416224
references.citation: Eur Neuropsychopharmacol. 1999 Mar;9(3):205-11
references.pmid: 10208289
references.citation: Arch Gen Psychiatry. 2008 Feb;65(2):190-200
references.pmid: 18250257
references.citation: J Neurosci. 1995 Oct;15(10):6340-50
references.pmid: 7472399
references.citation: J Pharmacol Exp Ther. 2004 Nov;311(2):427-40
references.pmid: 15297468
references.citation: Psychopharmacol Bull. 2002 Summer;36 Suppl 2:6-23
references.pmid: 12490820
references.citation: Endocrinology. 2003 Jun;144(6):2580-7
references.pmid: 12746321
references.citation: Biol Psychiatry. 2006 Feb 1;59(3):216-23
references.pmid: 16248986
references.citation: J Neurochem. 2004 Apr;89(1):54-63
references.pmid: 15030389
references.citation: Braz J Psychiatry. 2003 Oct;25(4):231-8
references.pmid: 15328550
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2001 Jan;25(1):283-99
references.pmid: 11263757
references.citation: Pharmacopsychiatry. 2004 Nov;37 Suppl 3:S214-20
references.pmid: 15547788
references.citation: Schizophr Bull. 2003;29(4):671-92
references.pmid: 14989406
references.citation: Biol Psychiatry. 2005 Apr 15;57(8):935-7
references.pmid: 15820716
references.citation: Curr Drug Targets CNS Neurol Disord. 2003 Jun;2(3):191-200
references.pmid: 12769799
references.citation: Neuropeptides. 2000 Oct;34(5):255
references.pmid: 11049729
references.citation: Curr Pharm Des. 2006;12(30):3857-76
references.pmid: 17073684
references.citation: Cell Mol Biol (Noisy-le-grand). 1999 Nov;45(7):1083-92
references.pmid: 10644013
references.citation: J Psychiatr Res. 2005 Mar;39(2):173-7
references.pmid: 15589565
references.citation: Endocrinology. 1994 Oct;135(4):1511-28
references.pmid: 7925112
references.citation: Neuropsychopharmacology. 2005 Sep;30(9):1589-97
references.pmid: 15770236
references.citation: Psychol Med. 2000 Jan;30(1):219-23
references.pmid: 10722192
references.citation: Neuropeptides. 2007 Oct;41(5):307-20
references.pmid: 17637475
references.citation: Neuropsychopharmacology. 2004 Feb;29(2):385-92
references.pmid: 14666114
references.citation: Neuropeptides. 2001 Apr;35(2):82-91
references.pmid: 11384203
references.citation: Neuropsychopharmacology. 1997 Oct;17(4):284-92
references.pmid: 9326754
references.citation: Mol Cell Endocrinol. 1999 Dec 20;158(1-2):55-63
references.pmid: 10630405
references.citation: J Psychiatr Res. 2007 Oct;41(7):553-60
references.pmid: 17023001
references.citation: Life Sci. 2002 Nov 8;71(25):2921-37
references.pmid: 12384178
references.citation: Behav Brain Res. 2008 May 16;189(1):9-16
references.pmid: 18258314
references.citation: Behav Brain Res. 1994 Jul 29;63(1):81-8
references.pmid: 7524534
references.citation: Neuroscience. 1998 Nov;87(1):79-94
references.pmid: 9722143
references.citation: Biol Psychiatry. 1997 Oct 15;42(8):744-7
references.pmid: 9325570
references.citation: Dev Psychopathol. 2001 Summer;13(3):419-49
references.pmid: 11523842
references.citation: J Neurochem. 1999 Aug;73(2):641-6
references.pmid: 10428060
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2843-8
references.pmid: 11226328
references.citation: Arch Gen Psychiatry. 2001 Jul;58(7):655-62
references.pmid: 11448372
references.citation: Pharmacol Ther. 1999 Apr;82(1):1-61
references.pmid: 10341356
references.citation: Eur Neuropsychopharmacol. 2002 Oct;12(5):489-94
references.pmid: 12208567
references.citation: Neurosci Biobehav Rev. 2001 Dec;25(7-8):619-26
references.pmid: 11801287
references.citation: J Clin Endocrinol Metab. 1995 Jan;80(1):185-9
references.pmid: 7829610
references.citation: J Pharmacol Exp Ther. 2003 Feb;304(2):874-80
references.pmid: 12538845
references.citation: Health Qual Life Outcomes. 2006 Jan 18;4:2
references.pmid: 16420706
references.citation: J Clin Endocrinol Metab. 2002 Apr;87(4):1646-53
references.pmid: 11932296
references.citation: Science. 1998 Sep 11;281(5383):1640-5
references.pmid: 9733503
references.citation: Neuropsychopharmacology. 2005 Jan;30(1):35-42
references.pmid: 15367924
references.citation: Neuromolecular Med. 2005;7(1-2):157-80
references.pmid: 16052044
references.citation: Neuropeptides. 2004 Aug;38(4):189-200
references.pmid: 15337371
references.citation: J Psychiatr Res. 2004 Mar-Apr;38(2):129-36
references.pmid: 14757326
references.citation: Neuropeptides. 1999 Apr;33(2):181-8
references.pmid: 10657489
references.citation: Life Sci. 1992;50(15):PL101-6
references.pmid: 1313515
references.citation: Ann N Y Acad Sci. 1988;537:273-91
references.pmid: 3059929
references.citation: Neuroendocrinology. 1990 Mar;51(3):328-36
references.pmid: 2157997
references.citation: Pharmacol Biochem Behav. 2008 Sep;90(3):463-9
references.pmid: 18495229
references.citation: Recent Pat CNS Drug Discov. 2008 Jun;3(2):77-93
references.pmid: 18537767
references.citation: Am J Psychiatry. 2002 Oct;159(10):1675-81
references.pmid: 12359672
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17489-94
references.pmid: 16287967
references.citation: Neuropharmacology. 2003 Feb;44(2):206-13
references.pmid: 12623219
references.citation: Life Sci. 2001 Jun 1;69(2):133-42
references.pmid: 11441903
references.citation: Therapie. 2002 Jul-Aug;57(4):385-96
references.pmid: 12422559
references.citation: Clin Pharmacol Ther. 2003 Mar;73(3):170-7
references.pmid: 12621382
references.citation: Eur J Pharmacol. 2005 Jan 10;507(1-3):99-105
references.pmid: 15659299
references.citation: Amino Acids. 2006 Oct;31(3):215-30
references.pmid: 16738800
references.citation: Eur Neuropsychopharmacol. 2008 Oct;18(10):729-50
references.pmid: 18657401
references.citation: J Psychiatr Res. 1999 Sep-Oct;33(5):363-70
references.pmid: 10504004
references.citation: Neuropeptides. 2008 Aug;42(4):387-97
references.pmid: 18554714
references.citation: Eur J Endocrinol. 2003 Aug;149(2):79-90
references.pmid: 12887283
references.citation: Ann N Y Acad Sci. 1998 Dec 21;863:459-65
references.pmid: 9928199
references.citation: Nat Neurosci. 1998 May;1(1):69-73
references.pmid: 10195112
references.citation: Curr Opin Neurobiol. 2000 Apr;10(2):211-8
references.pmid: 10753802
references.citation: Psychopharmacology (Berl). 2006 Aug;187(2):237-44
references.pmid: 16779555
references.citation: Mol Cell Biol. 2005 Jun;25(11):4804-11
references.pmid: 15899880
references.citation: Curr Drug Targets CNS Neurol Disord. 2004 Apr;3(2):113-21
references.pmid: 15078186
references.citation: Drug News Perspect. 1998 Oct;11(8):458-68
references.pmid: 15616674
references.citation: Front Neuroendocrinol. 2004 Sep-Dec;25(3-4):132-49
references.pmid: 15589266
references.citation: Eur Neuropsychopharmacol. 2007 Nov;17(11):708-16
references.pmid: 17376658
references.citation: Arch Gen Psychiatry. 1996 Feb;53(2):137-43
references.pmid: 8629889
references.citation: Pharmacol Biochem Behav. 2007 Jan;86(1):8-20
references.pmid: 17257664
references.citation: Eur J Pharmacol. 2008 Apr 7;583(2-3):350-7
references.pmid: 18272149
references.citation: Exp Clin Psychopharmacol. 2007 Dec;15(6):519-28
references.pmid: 18179304
references.citation: Trends Neurosci. 2008 Sep;31(9):464-8
references.pmid: 18675469
references.citation: Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9
references.pmid: 8813641
references.citation: Ann N Y Acad Sci. 1998 Dec 21;863:364-82
references.pmid: 9928183
references.citation: J Psychopharmacol. 2008 Aug;22(6):691-6
references.pmid: 18308813
references.citation: Neuropharmacology. 2001 Dec;41(8):976-88
references.pmid: 11747902
references.citation: JAMA. 2003 Jun 18;289(23):3095-105
references.pmid: 12813115