The Influence of the Estrous Cycle on Neuropeptide S Receptor-Mediated Behaviors

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2024 Oct 23

PMID 39443144

Authors

Paula Carvalho Costa

Brisa Salinas

Alaina Wojciechowski

Susan K Wood

Scott Runyon

Stewart D Clark

Affiliations

Soon will be listed here.

Abstract

The neuropeptide S receptor (NPSR) has been identified as a potential therapeutic target for anxiety and post-traumatic stress disorder. Central administration of neuropeptide S (NPS) in male mice produces anxiolytic-like effects, hyperlocomotion, and memory enhancement. Currently, the literature is limited in the number of studies investigating the effects of NPS in female test subjects despite females facing a higher prevalence of anxiety-related pathology, as well as greater risk for adverse effects while taking psychoactive drugs. Moreover, no previous studies have considered the influence of estrous cycle on the effects of NPS. The present study investigates whether NPS-mediated behavioral phenotypes seen in males translate to females, and whether they are affected by estrous cycle stage. Female C57BL/6NCr mice were intracerebroventricularly cannulated and underwent behavioral paradigms to test locomotion, anxiety, and memory. Estrous cycle stage was determined through examination of vaginal cytology. Our results provide evidence that NPS-mediated behaviors are influenced by the estrous cycle. Administration of NPS decreased anxiety-like behaviors more robustly when the female mice were in high estrogen stages of the estrous cycle. Therefore, the desired anxiolytic-like effects of targeting the NPSR are intact in female mice. However, these effects may to be influenced by the stage of the estrous cycle. The NPSR remains a strong potential drug target for new anxiolytic compounds and based on our initial observations further studies exploring the interaction of estrous cycle and the NPS system are warranted. SIGNIFICANCE STATEMENT: The neuropeptide S (NPS) receptor has been identified as a potential target for treating anxiety, a condition that is most prevalent in females. Therefore, the potential interaction of estrous cycle with the NPS system described in the present study is an important first step in understanding the function of the NPS system in females.

References

Okamura N, Garau C, Duangdao D, Clark S, Jungling K, Pape H . Neuropeptide S enhances memory during the consolidation phase and interacts with noradrenergic systems in the brain. Neuropsychopharmacology. 2010; 36(4):744-52. PMC: 3037424. DOI: 10.1038/npp.2010.207. View

Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S . Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(7):1444-8. DOI: 10.1016/j.pnpbp.2007.06.026. View

Byers S, Wiles M, Dunn S, Taft R . Mouse estrous cycle identification tool and images. PLoS One. 2012; 7(4):e35538. PMC: 3325956. DOI: 10.1371/journal.pone.0035538. View

Niimi M . Centrally administered neuropeptide S activates orexin-containing neurons in the hypothalamus and stimulates feeding in rats. Endocrine. 2006; 30(1):75-9. DOI: 10.1385/ENDO:30:1:75. View

Nochaiwong S, Ruengorn C, Thavorn K, Hutton B, Awiphan R, Phosuya C . Global prevalence of mental health issues among the general population during the coronavirus disease-2019 pandemic: a systematic review and meta-analysis. Sci Rep. 2021; 11(1):10173. PMC: 8119461. DOI: 10.1038/s41598-021-89700-8. View

Tupak S, Reif A, Pauli P, Dresler T, Herrmann M, Domschke K . Neuropeptide S receptor gene: fear-specific modulations of prefrontal activation. Neuroimage. 2012; 66:353-60. DOI: 10.1016/j.neuroimage.2012.10.033. View

Gottlieb D, OConnor G, Wilk J . Genome-wide association of sleep and circadian phenotypes. BMC Med Genet. 2007; 8 Suppl 1:S9. PMC: 1995620. DOI: 10.1186/1471-2350-8-S1-S9. View

Klauke B, Deckert J, Zwanzger P, Baumann C, Arolt V, Pauli P . Neuropeptide S receptor gene (NPSR) and life events: G × E effects on anxiety sensitivity and its subdimensions. World J Biol Psychiatry. 2012; 15(1):17-25. DOI: 10.3109/15622975.2011.646302. View

Raczka K, Gartmann N, Mechias M, Reif A, Buchel C, Deckert J . A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol Psychiatry. 2010; 15(11):1045, 1067-74. DOI: 10.1038/mp.2010.79. View

10.

Badia-Elder N, Henderson A, Bertholomey M, Dodge N, Stewart R . The effects of neuropeptide S on ethanol drinking and other related behaviors in alcohol-preferring and -nonpreferring rats. Alcohol Clin Exp Res. 2008; 32(8):1380-7. DOI: 10.1111/j.1530-0277.2008.00713.x. View

11.

Vinogradova E, Zhukov D, Batuev A . [Effect of estrous cycle phase on pain threshold in female white rats]. Ross Fiziol Zh Im I M Sechenova. 2002; 87(9):1244-9. View

12.

Xing L, Shi G, Mostovoy Y, Gentry N, Fan Z, McMahon T . Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation. Sci Transl Med. 2019; 11(514). PMC: 7587149. DOI: 10.1126/scitranslmed.aax2014. View

13.

Zhu H, Mingler M, McBride M, Murphy A, Valenzuela D, Yancopoulos G . Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1. Psychoneuroendocrinology. 2010; 35(8):1119-32. PMC: 2888805. DOI: 10.1016/j.psyneuen.2010.01.012. View

14.

Xu Y, Reinscheid R, Huitron-Resendiz S, Clark S, Wang Z, Lin S . Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron. 2004; 43(4):487-97. DOI: 10.1016/j.neuron.2004.08.005. View

15.

Spada J, Sander C, Burkhardt R, Hantzsch M, Mergl R, Scholz M . Genetic association of objective sleep phenotypes with a functional polymorphism in the neuropeptide S receptor gene. PLoS One. 2014; 9(6):e98789. PMC: 4045816. DOI: 10.1371/journal.pone.0098789. View

16.

Leonard S, Dwyer J, Sukoff Rizzo S, Platt B, Logue S, Neal S . Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders. Psychopharmacology (Berl). 2008; 197(4):601-11. DOI: 10.1007/s00213-008-1080-4. View

17.

Streit F, Haddad L, Paul T, Frank J, Schafer A, Nikitopoulos J . A functional variant in the neuropeptide S receptor 1 gene moderates the influence of urban upbringing on stress processing in the amygdala. Stress. 2014; 17(4):352-61. DOI: 10.3109/10253890.2014.921903. View

18.

Cannella N, Kallupi M, Li H, Stopponi S, Cifani C, Ciccocioppo R . Neuropeptide S differently modulates alcohol-related behaviors in alcohol-preferring and non-preferring rats. Psychopharmacology (Berl). 2016; 233(15-16):2915-24. PMC: 4935615. DOI: 10.1007/s00213-016-4333-7. View

19.

Salari N, Hosseinian-Far A, Jalali R, Vaisi-Raygani A, Rasoulpoor S, Mohammadi M . Prevalence of stress, anxiety, depression among the general population during the COVID-19 pandemic: a systematic review and meta-analysis. Global Health. 2020; 16(1):57. PMC: 7338126. DOI: 10.1186/s12992-020-00589-w. View

20.

Lennertz L, Quednow B, Schuhmacher A, Petrovsky N, Frommann I, Schulze-Rauschenbach S . The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response. Int J Neuropsychopharmacol. 2011; 15(9):1205-15. DOI: 10.1017/S1461145711001623. View