Effects of chemotherapy on operant responding for palatable food in male and female mice

Abstract

Patients treated with cancer chemotherapeutics frequently report chemotherapy-induced peripheral neuropathy (CIPN), changes in mood (depression and anxiety) and functional impairments. Rodent models of CIPN elicit limited alterations in functional behaviors, which pose challenges in developing preclinical models of chemotherapy-induced behavioral depression. The study examined the consequences of chemotherapy-induced mechanical hypersensitivity (paclitaxel: 32 or 64 mg/kg, cumulative; oxaliplatin: 30 mg/kg, cumulative) on behavioral depression, as measured with operant responding for palatable food during periods of food restriction and ad libitum chow, consumption of noncontingently available palatable food in the presence of ad libitum chow, and voluntary wheel running. The study employed two inbred mouse strains (C57BL/6J and Balb/cJ) and examined potential sex differences. All chemotherapeutic regimens caused profound mechanical hypersensitivity for the duration of the observation periods (up to 7 months), but no treatments changed voluntary wheel running or consumption of noncontingent palatable food. The high dose of paclitaxel temporarily reduced operant responding for palatable food in male C57BL/6J mice undergoing food restriction or maintained on ad libitum chow. However, paclitaxel failed to decrease operant responding for palatable food in free-feeding female C57BL/6J mice or Balb/cJ mice of either sex. Moreover, oxaliplatin did not significantly alter operant responding for palatable food in male or female C57BL/6J mice maintained on ad libitum chow. These findings demonstrate a dissociation between chemotherapy-induced mechanical hypersensitivity and behavioral depression. The transient effects of paclitaxel on operant responding in male C57BL/6J mice may represent a fleeting behavioral correlate of chemotherapy-associated pain-like behaviors.

Impact of Dose, Sex, and Strain on Oxaliplatin-Induced Peripheral Neuropathy in Mice

“…Male C57BL/6J mice showed an increase in response to acetone after the 1st week of high-dose oxaliplatin treatment that persisted for at least 1 week after cessation of the treatment regimen. Similarly, Meade et al ( 44 ) demonstrated that oxaliplatin causes cold hypersensitivity in male and female C57BL/6J mice. Administration of cumulative 3 mg/kg of oxaliplatin spread over 15 days resulted in cold hypersensitivity that lasted for 1 week after last injection.…”

“…Another explanation for changes in sucrose preference is gustatory alteration induced by oxaliplatin. However, in our recent study, C57BL/6J and BALB/cJ mice subjected to the same high-dose oxaliplatin schedule consumed similarly number of sucrose pellets as the vehicle control group ( 44 ).…”

Neuropathic injury drives a generalized negative affective state in mice

“…Many groups have used traditional, 'Skinner box'-based operant tasks to determine whether pain models affect learning and motivated responding. Depending on the type and duration of injury, the operant task tested, and the species or strain used, these models have produced mixed results [6,29,56,57,60,64,65,69]. Here we report that, in male and female C57BL/6J mice, SNI reduces operant responding for sugar pellets in a novel overnight, homecage fixed-ratio 3 and progressive ratio tasks.…”

“…Preclinical models of pain-induced negative affect, however, have unique reproducibility and translational challenges [17,44,65,74,82]. Differential reproducibility of pain-induced negative affect between labs appears to largely arise from a variety of critical factors including behavioral assay protocols, animal subject environment prior to experimental testing, species, strain, sex, breeding strategies, and sex of the experimenter [17,24,44,52,60,77,83]. Here we aimed to clearly document pain-induced negative affect arising from one particular neuropathic injury (i.e., SNI) in one particular mouse strain (i.e., C57BL/6J) by assessing multiple behavioral outputs per animal and attempting to identify relationships between these behaviors that have not been previously tested.…”

“…Importantly, rodents used in this study were all male and female C57BL/6J mice. This point is critical to the overall interpretation of the experiments because sex and strain differences in neuropathic pain-induced negative affect are well known across species in the literature [24,60,82]. For example, one study found Balb/c mice increased exploration of the center zone in the OFT, a proxy for decreased anxiety-like behavior, one month of spared nerve injury.…”