Kappa Opioid Receptors Reduce Serotonin Uptake and Escitalopram Efficacy in the Mouse Substantia Nigra Pars Reticulata.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Receptors, Opioid, kappa*/metabolism ; Pars Reticulata*/metabolism; Mice ; Animals ; Serotonin/metabolism ; Escitalopram ; Selective Serotonin Reuptake Inhibitors/pharmacology ; Substantia Nigra/metabolism

The serotonin and kappa opioid receptor (KOR) systems are strongly implicated in disorders of negative affect, such as anxiety and depression. KORs expressed on axon terminals inhibit the release of neurotransmitters, including serotonin. The substantia nigra pars reticulata (SNr) is involved in regulating affective behaviors. It receives the densest serotonergic innervation in the brain and has high KOR expression; however, the influence of KORs on serotonin transmission in this region is yet to be explored. Here, we used ex vivo fast-scan cyclic voltammetry (FSCV) to investigate the effects of a KOR agonist, U50, 488 (U50), and a selective serotonin reuptake inhibitor, escitalopram, on serotonin release and reuptake in the SNr. U50 alone reduced serotonin release and uptake, and escitalopram alone augmented serotonin release and slowed reuptake, while pretreatment with U50 blunted both the release and uptake effects of escitalopram. Here, we show that the KOR influences serotonin signaling in the SNr in multiple ways and short-term activation of the KOR alters serotonin responses to escitalopram. These interactions between KORs and serotonin may contribute to the complexity in the responses to treatments for disorders of negative affect. Ultimately, the KOR system may prove to be a promising pharmacological target, alongside traditional antidepressant treatments.

Handb Exp Pharmacol. 2022;271:97-112. (PMID: 34136961)
J Neurophysiol. 2006 Dec;96(6):3465-73. (PMID: 17005613)
Am J Psychiatry. 1999 Jun;156(6):837-41. (PMID: 10360120)
Acta Psychiatr Scand Suppl. 2000;(406):7-13. (PMID: 11131470)
Psychoneuroendocrinology. 2020 Apr;114:104599. (PMID: 32045797)
J Neurosci. 2016 Oct 5;36(40):10274-10284. (PMID: 27707965)
J Neurosci Methods. 2005 Apr 15;143(1):49-62. (PMID: 15763136)
Psychopharmacology (Berl). 2010 Jun;210(2):121-35. (PMID: 20352414)
J Neurochem. 2020 Apr;153(1):33-50. (PMID: 31419307)
Br J Pharmacol. 2006 Jul;148(6):795-806. (PMID: 16751796)
J Neurosci. 2012 Sep 5;32(36):12325-36. (PMID: 22956823)
Bio Protoc. 2018 Oct 05;8(19):e2473. (PMID: 34532508)
J Neurosci Methods. 2015 Feb 15;241:10-7. (PMID: 25528111)
Brain Res. 2010 Feb 16;1314:44-55. (PMID: 19716811)
Curr Opin Neurobiol. 2013 Aug;23(4):675-83. (PMID: 23374536)
Neurosci Biobehav Rev. 2008 Aug;32(6):1136-51. (PMID: 18468686)
Cell Mol Neurobiol. 2022 Aug;42(6):1671-1692. (PMID: 33651238)
Anal Chem. 1995 Mar 15;67(6):1115-20. (PMID: 7717525)
J Affect Disord. 2002 Feb;68(1):49-57. (PMID: 11869782)
Anal Chem. 2022 Jun 28;94(25):8847-8856. (PMID: 35713335)
Anal Chem. 2009 Nov 15;81(22):9462-71. (PMID: 19827792)
J Neurochem. 1996 Dec;67(6):2434-42. (PMID: 8931476)
Molecules. 2021 Aug 06;26(16):. (PMID: 34443366)
J Neurosci Methods. 2011 Nov 15;202(2):158-64. (PMID: 21392532)
Front Pharmacol. 2014 Nov 17;5:253. (PMID: 25452729)
ACS Med Chem Lett. 2022 Oct 17;13(11):1707-1714. (PMID: 36385929)
Psychopharmacology (Berl). 1995 Jun;119(3):334-41. (PMID: 7675970)
eNeuro. 2020 Jul 23;7(4):. (PMID: 32561573)
J Neurosci. 2019 May 22;39(21):4162-4178. (PMID: 30862664)
Brain Res. 2009 Oct 13;1293:61-75. (PMID: 19332030)
Psychopharmacology (Berl). 2005 Nov;183(1):118-26. (PMID: 16184376)
J Neurosci. 2012 Dec 5;32(49):17582-96. (PMID: 23223282)
J Neurosci. 2008 Jan 9;28(2):407-14. (PMID: 18184783)
Front Psychiatry. 2014 Dec 08;5:170. (PMID: 25538632)
J Neurosci. 2015 Sep 16;35(37):12917-31. (PMID: 26377476)
J Neurosci. 2006 Mar 22;26(12):3206-9. (PMID: 16554471)
ACS Meas Sci Au. 2021 Jun 29;1(1):11-19. (PMID: 36785731)
J Psychosom Res. 2002 Oct;53(4):865-71. (PMID: 12377295)
Psychiatry Clin Neurosci. 2019 Apr;73(4):143-153. (PMID: 30653780)
Psychopharmacology (Berl). 2012 Jan;219(1):1-13. (PMID: 21901317)
ACS Chem Neurosci. 2013 May 15;4(5):715-20. (PMID: 23597074)
J Neurochem. 2014 Aug;130(3):351-9. (PMID: 24702305)
Neuroscience. 1999 Apr;90(1):229-34. (PMID: 10188949)
Braz J Med Biol Res. 2008 Dec;41(12):1037-46. (PMID: 19148364)
Front Pharmacol. 2021 Jun 30;12:705813. (PMID: 34276387)
Prog Neuropsychopharmacol Biol Psychiatry. 2021 Mar 8;105:110135. (PMID: 33058959)
FASEB J. 2008 Jun;22(6):1702-14. (PMID: 18216289)
Neuron. 2011 Aug 11;71(3):498-511. (PMID: 21835346)
Pharmacol Rev. 1996 Dec;48(4):567-92. (PMID: 8981566)
Neuroreport. 1998 Jun 1;9(8):1777-81. (PMID: 9665599)
Front Hum Neurosci. 2017 Jun 20;11:316. (PMID: 28676747)
Neuropsychopharmacology. 1999 Aug;21(2 Suppl):28S-32S. (PMID: 10432486)
Neuropharmacology. 2007 Jun;52(8):1596-605. (PMID: 17459426)
Eur J Pharmacol. 2003 Feb 28;463(1-3):235-72. (PMID: 12600714)
Sci Signal. 2016 Nov 29;9(456):ra117. (PMID: 27899527)
Perspect Psychol Sci. 2016 Jul;11(4):456-63. (PMID: 27474134)
Neuropharmacology. 2017 Feb;113(Pt A):281-292. (PMID: 27743931)
J Pharmacol Exp Ther. 2002 Nov;303(2):549-56. (PMID: 12388635)
Brain Res. 2010 Feb 16;1314:56-73. (PMID: 19782055)
Neurochem Int. 2014 Jul;73:107-12. (PMID: 24462583)
Psychosom Med. 1995 Sep-Oct;57(5):423-6. (PMID: 8552731)
Curr Med Chem. 2006;13(25):3069-81. (PMID: 17073648)
Biochem Pharmacol. 2001 Dec 1;62(11):1481-9. (PMID: 11728384)
Neurosci Biobehav Rev. 2019 Nov;106:245-262. (PMID: 30227143)
J Neurosci. 2010 Jul 21;30(29):9762-70. (PMID: 20660258)
Neuropsychopharmacology. 2018 Jan;43(2):362-372. (PMID: 28649993)

P50 AA026117 United States AA NIAAA NIH HHS; R01DA048490 United States DA NIDA NIH HHS; U01 AA014091 United States AA NIAAA NIH HHS; T32 AA007565 United States AA NIAAA NIH HHS; P50AA026117 United States AA NIAAA NIH HHS; T32AA007565 United States AA NIAAA NIH HHS; U01AA014091 United States AA NIAAA NIH HHS; R01DA054694 United States DA NIDA NIH HHS; R01 DA054694 United States DA NIDA NIH HHS; R01 DA048490 United States DA NIDA NIH HHS

Keywords: 488; U50; antidepressants; escitalopram; fast-scan cyclic voltammetry; kappa opioid receptor; serotonin; serotonin release; serotonin transporter; serotonin uptake; substantia nigra pars reticulata

0 (Receptors, Opioid, kappa)
333DO1RDJY (Serotonin)
4O4S742ANY (Escitalopram)
0 (Selective Serotonin Reuptake Inhibitors)

Date Created: 20230211 Date Completed: 20230214 Latest Revision: 20240912

20240912

PMC9916942

10.3390/ijms24032080

36768403