PMID- 29486768 OWN - NLM STAT- MEDLINE DCOM- 20190409 LR - 20200225 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 15 IP - 1 DP - 2018 Feb 27 TI - Cellular and behavioral effects of lipopolysaccharide treatment are dependent upon neurokinin-1 receptor activation. PG - 60 LID - 10.1186/s12974-018-1098-4 [doi] LID - 60 AB - BACKGROUND: Several psychiatric conditions are affected by neuroinflammation and neuroimmune activation. The transcription factor nuclear factor kappa light-chain-enhancer of activated B cells (NFkB) plays a major role in inflammation and innate immunity. The neurokinin-1 receptor (NK1R) is the primary endogenous target of the neuroactive peptide substance P, and some data suggests that NK1R stimulation may influence NFkB activity. Both NK1R and NFkB have been shown to play a functional role in complex behaviors including stress responsivity, depression, and addiction. In this study, we test whether NFkB activity in the brain (stimulated by lipopolysaccharide administration) is dependent upon the NK1R. METHODS: Adult male Wistar rats were treated systemically with the NK1R antagonist L822429 followed by administration of systemic lipopolysaccharide (LPS, a strong activator of NFkB). Hippocampal extracts were used to assess expression of proinflammatory cytokines and NFkB-DNA-binding potential. For behavioral studies, rats were trained to consume 1% (w/v) sucrose solution in a continuous access two-bottle choice model. After establishment of baseline, animals were treated with L822429 and LPS and sucrose preference was measured 12 h post-treatment. RESULTS: Systemic LPS treatment causes a significant increase in proinflammatory cytokine expression and NFkB-DNA-binding activity within the hippocampus. These increases are attenuated by systemic pretreatment with the NK1R antagonist L822429. Systemic LPS treatment also led to the development of anhedonic-like behavior, evidenced by decreased sucrose intake in the sucrose preference test. This behavior was significantly attenuated by systemic pretreatment with the NK1R antagonist L822429. CONCLUSIONS: Systemic LPS treatment induced significant increases in NFkB activity, evidenced by increased NFkB-DNA binding and by increased proinflammatory cytokine expression in the hippocampus. LPS also induced anhedonic-like behavior. Both the molecular and behavioral effects of LPS treatment were significantly attenuated by systemic NK1R antagonism, suggesting that NK1R stimulation lies upstream of NFkB activation following systemic LPS administration and is at least in part responsible for NFkB activation. FAU - Fulenwider, Hannah D AU - Fulenwider HD AD - Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA. FAU - Smith, Britessia M AU - Smith BM AD - Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA. FAU - Nichenko, Anna S AU - Nichenko AS AD - Department of Kinesiology, University of Georgia, 115 Ramsey Center, 330 River Road, Athens, GA, 30602, USA. FAU - Carpenter, Jessica M AU - Carpenter JM AD - Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA. FAU - Nennig, Sadie E AU - Nennig SE AD - Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA. FAU - Cheng, Kejun AU - Cheng K AD - NIDA and NIAAA IRP, 9800 Medical Center Drive, Rm 228A MSC-3373, Bethesda, MD, 20892, USA. AD - Present Address: Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. FAU - Rice, Kenner C AU - Rice KC AD - NIDA and NIAAA IRP, 9800 Medical Center Drive, Rm 228A MSC-3373, Bethesda, MD, 20892, USA. FAU - Schank, Jesse R AU - Schank JR AD - Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA, 30602, USA. jschank@uga.edu. LA - eng GR - R00 AA021805/AA/NIAAA NIH HHS/United States GR - AA021805/National Institute on Alcohol Abuse and Alcoholism/ PT - Journal Article DEP - 20180227 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Lipopolysaccharides) RN - 0 (N-((2-cyclopropoxy-5-(5-trifluomethyl)tetrazol-1-yl)benzyl)-2-phenylpiperidin-3-amine) RN - 0 (NF-kappa B) RN - 0 (Neurokinin-1 Receptor Antagonists) RN - 0 (Piperidines) RN - 0 (Receptors, Neurokinin-1) SB - IM MH - Anhedonia/*drug effects/physiology MH - Animals MH - Hippocampus/*drug effects/*metabolism/pathology MH - Lipopolysaccharides/*toxicity MH - Male MH - NF-kappa B/metabolism MH - Neurokinin-1 Receptor Antagonists/*pharmacology MH - Piperidines/pharmacology MH - Rats MH - Rats, Wistar MH - Receptors, Neurokinin-1/*metabolism PMC - PMC6389133 OTO - NOTNLM OT - Anhedonia OT - Cytokines OT - Depression OT - Inflammation OT - Lipopolysaccharide OT - Neuroimmune system OT - Neurokinin-1 receptor OT - Nuclear factor kappa B COIS- ETHICS APPROVAL: Not applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/03/01 06:00 MHDA- 2019/04/10 06:00 PMCR- 2018/02/27 CRDT- 2018/03/01 06:00 PHST- 2017/12/18 00:00 [received] PHST- 2018/02/19 00:00 [accepted] PHST- 2018/03/01 06:00 [entrez] PHST- 2018/03/01 06:00 [pubmed] PHST- 2019/04/10 06:00 [medline] PHST- 2018/02/27 00:00 [pmc-release] AID - 10.1186/s12974-018-1098-4 [pii] AID - 1098 [pii] AID - 10.1186/s12974-018-1098-4 [doi] PST - epublish SO - J Neuroinflammation. 2018 Feb 27;15(1):60. doi: 10.1186/s12974-018-1098-4.