Behavioural and hypothalamic molecular effects of the anti-cancer agent cisplatin in the rat: A model of chemotherapy-related malaise?

Many cancer patients receiving chemotherapy experience fatigue, disturbed circadian rhythms, anorexia and a variety of dyspeptic symptoms including nausea. There is no animal model for this 'chemotherapy-related malaise' so we investigated the behavioural and molecular effects of a potent chemotherapeutic agent, cisplatin (CP, 6 mg/kg, i.p.) in rats. Dark-phase horizontal locomotor activity declined post-CP reaching a nadir on day 3 (P<0.001), before recovering after 7 days. CP's effect was most marked in the late part (05.00-07.00) of the dark-phase. Food intake reached a nadir (P>0.001) at 2 days, coincident with an increase in gastric contents (cisplatin 9.04 +/- 0.8 vs. saline 2.32 +/- 0.3 g; P<0.001). No changes occurred in hypothalamic mRNA expression for AGRP, NPY, HCRT, CRH, IL-I, IL-6, TNF alpha, ABCG1, SLC6A4, PPIA and HPRT mRNA but tryptophan hydroxylase (TPH) mRNA was decreased (47%, P < 0.05) at day 21 post-CP. This shows that despite marked behavioural effects of cisplatin, only a discrete change (TPH) was found in hypothalamic mRNA expression and that occurred when the animals' behaviour had recovered. Findings are discussed in relation to the neuropharmacology of chemotherapy-induced malaise. (C) 2005 Elsevier Inc. All rights reserved.