title: Cisplatin induces neuronal activation and increases central AMPA and NMDA receptor subunit gene expression in mice.
abstract: Although rats and mice do not vomit, these species are widely studied as models of energy balance and sickness behavior. Previous work has shown that rats exhibit similar neuroanatomical activation of brain and visceral afferent pathways following cisplatin chemotherapy compared to vomiting species. However, the neural response to cisplatin in mice is understudied. Here, food intake, body weight, and central c-Fos immunofluorescence were analyzed in the hindbrains of male C57BL/6 mice following IP saline or cisplatin (5mg/kg, and 20mg/kg doses). As glutamate receptor signaling is classically linked to inhibitory feeding pathways in the rodent, gene expression of selected α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor subunits were assessed in the dorsal vagal complex (DVC), parabrachial nucleus (PBN), amygdala, and bed nucleus of the stria terminalis (BNST). Our results show dose-dependent reductions in food intake and body weight following cisplatin treatment, as well as increases in cisplatin-induced c-Fos in the PBN and throughout the DVC. Quantitative PCR analysis shows cisplatin-induced increases in NMDA receptor subunit expression, particularly NR2B, in the DVC, PBN, BNST, and amygdala. In addition, upregulation of AMPA receptor subunits (GluA1 and/or GluA2) were observed in all regions examined except the amygdala. Taken together, these results suggest similar neural pathways mediating cisplatin effects in mice compared to other well-studied species, which are likely mediated by central upregulation of AMPA and NMDA receptors.
authors.affiliation: Dept. of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, United States.
authors.forename: Ruby A
authors.initials: RA
authors.lastname: Holland
authors.affiliation: Dept. of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Leonard
authors.affiliation: Dept. of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kensey
authors.affiliation: Dept. of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, United States.
authors.forename: Paavali A
authors.initials: PA
authors.lastname: Hannikainen
authors.affiliation: Dept. of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, United States. Electronic address: ebartd@nursing.upenn.edu.
authors.forename: Bart C
authors.initials: BC
authors.lastname: De Jonghe
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D002945:Cisplatin; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPA; Cisplatin; NMDA; NR2B; Nausea; c-Fos