Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections

Abstract

Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatinactivated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated.

Excitatory Hindbrain–Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss

“…The current study investigated the neurochemical phenotype and functional significance of hindbrain-forebrain neuronal populations mediating cisplatin-induced anorexia and weight loss in an experimental rat model. Building upon previous findings suggesting that glutamate receptor signaling from CeA-projecting lPBN CGRP neurons triggers anorexia (Carter et al, 2013;Alhadeff et al, 2015), we demonstrate that lPBN¡CeA neurons expressing CGRP are glutamatergic and play a role in mediating cisplatin-induced anorexia. Chemogenetic inhibition of this excitatory projection attenuated cisplatin-induced anorexia and Table of Pearson's and Mander's correlation coefficients for colocalization of CGRP and VGLUT2.…”

“…We reported recently that cisplatin activates lPBN CGRP neurons that project to the CeA and that glutamate receptor signaling within the CeA is required for cisplatininduced malaise and energy balance dysregulation (Alhadeff et al, 2015). It has been suggested that glutamate signaling mediates the anorexia resulting from activation of CGRP neurons within the lPBN (Carter et al, 2013).…”

“…To examine the necessity of lPBN¡CeA or NTS¡lPBN projections in cisplatin-induced anorexia and body weight loss, rats with inhibitory DREADD expression (n ϭ 11 and n ϭ 13 for lPBN¡CeA or NTS¡lPBN projection, respectively) or rats expressing the control virus (n ϭ 10 and n ϭ 9 for lPBN¡CeA or NTS¡lPBN projection, respectively) received intraperitoneal CNO or saline in a pseudo-counterbalanced manner as described previously (Alhadeff et al, 2015) immediately before and 24 h after intraperitoneal saline injection. The dose of CNO (1 mg/kg) was taken from the literature (Carter et al, 2013;Boender et al, 2014) and our preliminary studies (data not shown) indicating no independent effect of this CNO dose on food intake or body weight.…”

“…At least 72 h later, the same rats were injected with CNO or saline immediately before and 24 h after intraperitoneal cisplatin injection. The dose of cisplatin (6 mg/kg) was chosen based on its ability to reduce food intake and body weight (De Jonghe and Horn, 2008;Alhadeff et al, 2015). Again, food intake and body weight were recorded at 24 and 48 h after injection.…”

“…Building upon studies demonstrating that cisplatin activates neurons in the nucleus tractus solitarius (NTS), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) (Horn et al, 2007;De Jonghe and Horn, 2009;Horn, 2009;Alhadeff et al, 2015), our recent work suggests that projections between these regions may mediate cisplatin-induced anorexia and body weight loss, likely via CGRP/glutamatergic signaling (Alhadeff et al, 2015). However, the direct functional role of these projections in cisplatin-induced anorexia and body weight loss remained to be determined.…”