Ondansetron interferes with unconditioned lying-on belly and acquisition of conditioned gaping induced by LiCl as models of nausea-induced behaviors in rats
Highlights
► Ondansetron attenuates LiCl-induced malaise (LOB in rats). ► Conditioned gaping and LOB are highly correlated. ► Validation of conditioned gaping as measure of nausea in rats.
Introduction
Nausea is a common side effect associated with many therapeutic treatments, but little is known about the mechanisms underlying this distressing symptom. One reason for this has been the lack of a reliable animal model. Traditionally, taste–illness associations have been investigated using the conditioned taste avoidance paradigm (CTA). In this paradigm, a rat approaches a bottle with a flavored solution that has been previously paired with a drug and either consumes the solution or not. Suppressed intake (i.e. avoidance) is considered to reflect taste–nausea associations. Paradoxically, avoidance of the taste is not exclusively produced by emetic drugs as even rewarding drugs, such as amphetamine, will also elicit a CTA [1], [2], [3]. Therefore, CTA is not necessarily a reflection of the nauseating properties of a drug.
Considerable recent evidence suggests that conditioned gaping reactions in the Taste Reactivity (TR) test developed by Grill and Norgren [4], [5] may serve as a preclinical rodent model of nausea-induced behavior. Unlike CTA, conditioned gaping is selectively produced by emetic agents [2], [6] and prevented by anti-emetic drugs [7], [8]. Therefore, conditioned gaping may reflect conditioned nausea-induced behavior in rats.
The most effective available anti-emetic drugs are 5-HT3 antagonists such as ondansetron (OND). OND reduces chemotherapy-induced nausea and vomiting in humans [9], [10] as well as drug-induced vomiting in cats, dogs, ferrets and Suncus murinus [11], [12]. OND has also been shown to interfere with the establishment of conditioned gaping, but not CTA, in rats [7] produced by a single pairing of saccharin with a high dose of LiCl. It was suggested that OND attenuated the nausea produced by LiCl, thereby interfering with the establishment of conditioned gaping reactions. OND did not attenuate unconditional gaping elicited by bitter quinine solution. As well, it did not interfere with learning per se, because the OND pretreated rats still learned to avoid the LiCl-paired saccharin solution.
However, the preclinical animal model of conditioned gaping in rats relies upon conditioning and is therefore an indirect measure of nausea-like behavior. Rats do not gape in response to an acute LiCl injection, but following pairing with either a flavor or a context, they gape when presented the LiCl-paired cue [13]. When LiCl is paired with a flavor, a single conditioning trial is necessary for the expression of conditioned gaping, but when LiCl is paired with a contextual stimulus, at least 3 conditioning trials are necessary for the expression of conditioned gaping [13], [14]. Although rats do not gape unconditionally following an injection of LiCl, they display the behavior of Lying on Belly (LOB) which is reflective of unconditioned malaise [15], [16], [17]; that is, rats lie with a flattened belly pressed against the floor of their cages. If OND reduces the establishment of LiCl-induced conditioned gaping by interfering with LiCl-induced nausea, then it should also reduce LiCl-induced LOB. In order to answer this question, rats were pretreated with OND or Saline prior to each of two pairings of saccharin and LiCl or Saline to produce robust conditioning. Immediately after the LiCl or Saline injections they were placed in an observation chamber to measure LOB; the first conditioning trial assessed the potential of OND to interfere with this unconditional malaise-induced behavior. Because rats display conditioned gaping to a context following several conditioning trials [13], an initial control experiment evaluated whether the LOB test immediately following the saccharin conditioning trial would interfere with the saccharin–LiCl association.
Section snippets
Animals and housing
Male Sprague–Dawley rats were obtained from Charles River Canada, QC and singly-housed in polycarbonate cages (44 × 25 × 21 cm). Subjects were provided with food pellets (Highland Rat Chow) ad libitum. The animal quarters were kept on a reversed 12-h light/dark cycle (lights on from 19:00 to 07:00 h) and maintained at 22 ± 2 °C and 45 ± 20% relative humidity. All animals were handled prior to testing and the guidelines set out by the Canadian Council on Animal Care and the Animals for Research Act were
Experiment 1: Does post-LiCl LOB chamber exposure interfere with saccharin–LiCl association?
Placing rats in the LOB chamber after the TR conditioning trials did not modify conditioned gaping elicited by LiCl-paired saccharin solution (see Fig. 1). The 2 × 3 mixed-factor ANOVA only revealed a significant main effect of trial, F(2, 26) = 18.72; p < .001. Rats displayed significantly more gaping reactions across trials, but this effect did not vary by post TR context condition (i.e. LOB chamber and home cage).
Placing rats in the LOB chamber also did not alter saccharin taste avoidance in
Discussion
Not only did OND interfere with the establishment of robust LiCl-induced conditioned gaping reactions, but it also interfered with the unconditional malaise behavior of LOB (see [15], [17]) on conditioning trial 1 (as well as on trial 2). The results of the experiments reported here confirm previous reports [7] that after a single conditioning trial (on C2) with LiCl, OND pretreatment prevented LiCl-induced conditioned gaping. However this effect was surmountable by additional conditioning,
Acknowledgments
The authors would like to thank Cheryl Limebeer for assistance with various aspects of these experiments. This work was supported by an NSERC grant (#92057) to LAP and an NSERC Canadian Graduate Scholarship to KJT. Please send reprint requests to [email protected]
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