Effects of Cyclophosphamide on the Kaolin Consumption (Pica Behavior) in Five Strains of Adult Male Rats

Abstract

ABSTRACT. It is known that pica, the consumption of non-nutritive substances such as kaolin, can be induced by administration of toxins or emetic agents in rats. In the present study, we examined the effects of intraperitoneal (i.p.) administration of cyclophosphamide on pica behavior and on the concentration of 5-hydroxyindoleacetic acids (5HIAA) in cerebrospinal fluid (CSF) in the following five strains of adult male rats: Sprague Dawley (SD), Wistar, Fischer 344 (F344), Wistar-Imamichi (WI) and Long Evans (LE). Cyclophosphamide (25 mg or 50 mg/kg) was injected (i.p.) into the rats and kaolin and food intake were measured at 24 hr after injection. The animals were anesthetized with urethane (1 g/kg) at 3 hr after injection of cyclophosphamide, and CSF was collected from the cisterna magna. WI and LE rats clearly showed pica behavior as compared with the other strains. In LE rats, the concentration of 5HIAA in CSF also increased in a dose-dependent manner of cyclophosphamide. The pretreatment with ondansetron (5-HT 3 antagonist) restored both changes (kaolin consumption and 5HIAA levels) induced by cyclophosphamide. These results suggest that the LE rat is sensitive to cyclophosphamide, that pica induced by cyclophosphamide mimics many aspects of emesis including the serotonergic response in the central nervous system and that use of the pica model would be a practical method for evaluating the effects of antiemetic drugs in addition to the mechanism of emesis. Cancer chemotherapy with cyclophosphamide or cisplatin is usually associated with nausea or vomiting in humans [1,2,5,8,16]. These cytotoxic drugs can induce emesis in ferrets [8] and house musk shrews [14,20], and these two animal species have been often used in experiments for emesis. However, studies on the mechanisms of emesis in common laboratory animals such as rats and mice are limited due to the lack of vomiting reflex in rats and mice [8]. Although rats and mice do not vomit, they show pica behavior (the consumption of non-nutritive substances such as kaolin) in response to the various emetic stimuli [7,12,24,[30][31][32]. In rats, pica behavior can be induced by administration of cancer chemotherapy agents [11-13, 18, 22], lithium chloride [18,32], copper sulphate [32] and by motion exposure [7,24]. This behavior is recognized as an index of emesis, and the kaolin ingestion model can be used as a quantifiable behavioral assay of toxins [8,15]. In previous reports, Long Evans (LE) and Wistar rats were mainly used in experiments for pica behavior [11-13, 18, 22], but the reasons why these two strains have been used in this field of study are unclear. There has been no study comparing the expression of pica induced by any emetic stimuli among several strains of rats. In order to choose the best strain of rat for future pica research, we examined the effects of intraperitoneal (i.p.) administration of cyclophosphamide on pica behavior using Sprague Dawley (SD), Wistar, Fischer 344 (F344), Wistar-Imamichi (WI) and LE adult male rats in the present s...

Running-based pica and taste avoidance in rats

“…Aberrant pica behavior (kaolin clay intake) has been regarded as a marker of nausea in rats (Andrews & Horn, 2006) that cannot vomit because of anatomical and/or neural reasons (Horn et al, 2013). Pica behavior is generated by a variety of nausea-inducing treatments, including irradiation (e.g., , motion sickness (e.g., Mitchell, Laycock, & Stephens, 1977), and administration of emetic drugs such as lithium chloride (LiCl; e.g., Mitchell et al, 1976), cyclophosphamide (e.g., Tohei, Kojima, Ikeda, Hokao, & Shinoda, 2011), cisplatin (e.g., Takeda, Hasegawa, Morita, & Matsunaga, 1993), ritonavir (e.g., Aung et al, 2005), morphine (e.g., Aung, Mehendale, Xie, Moss, & Yuan, 2004), and apomorphine (e.g., Takeda et al, 1995), among others (see the introduction of Nakajima, 2016a, for a more detailed review).…”

The effects of cisplatin, an emetic agent, on behavior and plasma cortisol levels in goats

“…A similar increase in plasma glucocorticoids levels was also reported in dogs and rats: Kenward et al ( 2014 ) reported that CDDP administration to dogs increased plasma Cor levels simultaneously with the vomiting. Similarly, Tohei et al ( 2011 ) reported that the administration of cyclophosphamide, another emetic agent, induced pica, and a significant increase in plasma corticosterone levels in rats. The blood levels of corticoids are the most popular physiological indicator of the stress.…”

“…Similarly, Tohei et al (2011) reported that the administration of cyclophosphamide, another emetic agent, induced pica, and a significant increase in plasma corticosterone levels in rats. The blood levels of corticoids are the most popular physiological indicator of the stress.…”

Effect of niacin supplementation on nausea-like behaviour in an isoniazid-induced mouse model of pellagra

“…Using our system, we could evaluate whether each medicine causes mild pellagra or not. Furthermore, previous studies indicated that mice with cisplatin-related pica were improved by antiemetic agents such as ondansetron, which were used in a clinical site (30). Because this INH-related pica was significantly attenuated after niacin treatment only in rodents, it needs further investigations in clinical research.…”