Shelley K. Cross-Mellor

Exposure to a context previously associated with nausea elicits conditioned gaping in rats: A model of anticipatory nausea

Following one or more chemotherapy treatments, many patients report that they experience anticipatory nausea. This phase of nausea has been interpreted as a classically conditioned response where a conditional association develops between the contextual clinic cues and the nausea and/or vomiting that developed following treatment. Although rats do not vomit, they display a distinctive gaping reaction when exposed a flavored solution previously paired with a toxin. Here we report that, even in the absence of a flavored solution, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium (Experiment 1 with a distinctive odor and Experiment 3 without a distinctive odor), a low dose of lithium (Experiment 2) or provocative vestibular stimulation (Experiment 2). These results suggest that the conditioned gaping reaction in rats is selectively elicited by nausea-paired contextual stimuli, as well as flavors. This rat model of anticipatory nausea may serve as a valuable preclinical tool to evaluate the effectiveness of anti-nausea treatments and the side effect of nausea produced by newly developed pharmaceutical compounds intended for other clinical treatments.

Comparing immune activation (lipopolysaccharide) and toxin (lithium chloride)-induced gustatory conditioning: lipopolysaccharide produces conditioned taste avoidance but not aversion.

Feeding and drinking typically involve both appetitive and consummatory behaviors. Appetitive behaviors include those behaviors produced by an animal prior to the actual consumption, such as approach movements, whereas consummatory behaviors (such as licking and chewing) are involved in the actual consumption of food. The present research compared the gustatory conditioning effects of bacterial lipopolysaccharide (LPS) and lithium chloride (LiCl) in two different paradigms, conditioned taste avoidance and conditioned taste aversion which differentially affect the appetitive and consummatory components of feeding. Male rats were implanted with intraoral cannulae and habituated to a water deprivation schedule and afterwards received two conditioning days (Days 1 and 4). Each conditioning day consisted of 1 h access to a novel sucrose solution (0.3 M) immediately followed by a systemic injection of LPS (200 microg/kg), LiCl (0.15 M, 3 meq) or NaCl vehicle. Conditioned taste aversion was assessed using the taste reactivity test on Day 7, where orofacial and somatic responses were videotaped and analyzed during 3 brief (1 min) exposures to the sucrose solution. Conditioned taste avoidance was assessed on Days 8 and 9 using a two-bottle preference test (sucrose versus water). Animals conditioned with LiCl displayed typical aversive-like responses in the taste reactivity paradigm evidenced by significant reductions in positive ingestive responses (P<0.05) and an increase in active aversive responses (P<0.05) relative to controls. Furthermore, LiCl treatment resulted in conditioned avoidance of sucrose in the two-bottle preference test characterized by a decreased sucrose preference (P<0.05). Conditioning with LPS produced a reduced sucrose preference (P<0.05) relative to controls, comparable to the avoidance seen in LiCl-treated rats. In contrast, conditioning with LPS resulted in similar positive ingestive responses to intraorally infused sucrose as seen in controls. The present results demonstrate that LPS treatment produces conditioned avoidance but not aversion and suggest that LPS can selectively condition the appetitive aspects of feeding whereas the consummatory behaviors remain unaffected.

Examining the effects of lipopolysaccharide and cholecystokinin on water ingestion: comparing intake and palatability.

Lipopolysaccharide (LPS) and cholecystokinin (CCK) have been shown to have anorectic properties in a variety of species. The present study examined the effects of LPS and CCK, both alone and in combination, on two different aspects of water ingestion, water intake and palatability. On test days, animals were first injected intraperitoneally (i.p.) with either LPS (200 microg/kg) or NaCl vehicle, and 2 h later received a second injection of either CCK (8 microg/kg) or NaCl vehicle. In Experiment 1, water intake was monitored for 1 h on 3 separate test days 72 h apart; while in Experiment 2, water palatability was assessed using the taste reactivity test (TRT), on two separate test days 72 h apart. Both LPS and CCK significantly (p<0.05) reduced water intake, with the effects of combined LPS with CCK being more pronounced than either agent injected alone. Rats developed a rapid tolerance to the effects of LPS on water intake on subsequent exposures to LPS. Results from the TRT indicated that LPS enhanced water palatability (p<0.05), as evidenced by a high level of ingestive responding, whereas CCK produced a pattern of responding indicative of satiety. LPS plus CCK reduced ingestive responding on the first test day, but these responses were significantly increased on the second test day (p<0.05). These results demonstrate that although LPS reduces water intake, it enhances water palatability. The results further underscore the necessity for examining palatability changes in addition to intake measures when studying the regulation of feeding and drinking.

Vestibular Lesions Selectively Abolish Body Rotation-Induced, but Not Lithium-Induced, Conditioned Taste Aversions (Oral Rejection Responses) in Rats

Pairing a novel taste with provocative vestibular stimulation results in conditioned taste aversions in both rats and humans. Vestibular system involvement in gustatory conditioning was examined in sham-lesioned or labyrinthectomized rats. Three conditioning trials consisted of 30 min access to asaccharin (0.1%) solution followed by 30 min of rotation (70 rpm) or sham rotation. In a taste reactivity test with saccharin, rotated sham-lesioned rats, but not labyrinthectomized rats, exhibited increased oral rejection reactions compared with control rats. When conditioned with lithium chloride, both labyrinthectomized and sham-lesioned rats displayed robust conditioned rejection reactions. The finding that normal vestibular function is necessary in obtaining rotation-induced conditioned taste aversions supports the face and construct validity of a rat model of motion sickness.

Differential effects of lipopolysaccharide and cholecystokinin on sucrose intake and palatability

The differential effects of CCK and lipopolysaccharide (LPS) on sucrose intake and palatability were examined. Rats were injected with LPS (200 μg/kg ip) or NaCl (0.9%, vehicle) and 2 h later received a second injection of either CCK (8 μg/kg ip) or NaCl. In experiment 1, sucrose (0.3 M) intake was monitored for 1 h on three different test days 72 h apart, while in experiment 2, palatability was assessed by means of the taste reactivity test (TRT) on two separate days (72 h apart). In the TRT, orofacial and somatic responses to brief (30 s) intraoral infusions of sucrose were recorded and analyzed for response frequency. Singly, LPS and CCK reduced sucrose intake, with a more pronounced effect from combined LPS and CCK. LPS by itself did not alter sucrose palatability, as evidenced by continuous high levels of ingestive responding. In contrast, CCK-treated rats displayed a pattern of responding indicative of satiety, as did the combined LPS-CCK-treated rats. These results suggest that LPS does not induce hypophagia by altering palatability.

Acute effects of corticosterone on LiCl-induced rapid gustatory conditioning in rats: a taste reactivity analysis.

Previous research has shown that acute corticosterone treatment can have rapid effects on learning and memory. Using the taste reactivity test (TRT), the present study examined the effect of acute administration of corticosterone on sucrose palatability and the development of LiCl-induced rapid gustatory conditioning. On each of two conditioning days rats were injected with either a low dose of lithium chloride (LiCl; 0.75 mEq, i.p.) or saline (NaCl; 0.9%, i.p.) and 10 min later, received a second injection of either corticosterone (5 mg/kg, i.p.) or cyclodextrin vehicle. Rats were then placed in the TRT chamber, where 1 min intraoral infusions of sucrose (0.3 M) were delivered every 10 min. Taste reactivity responses were videotaped and later analyzed for frequency of occurrence. Rats treated with both LiCl and corticosterone showed enhanced aversive responding and reduced ingestive responding relative to control rats treated with LiCl and vehicle. The implication that corticosterone may have a rapid enhancing effect on gustatory conditioning is discussed.

Lipopolysaccharide (LPS) blocks the acquisition of LiCl-induced gaping in a rodent model of anticipatory nausea

The effects of systemic treatment with lipopolysaccharide (LPS) on conditioned gaping in a rodent model of anticipatory nausea were examined. Stimulation of the immune system has been found to enhance, impair, or have no effect on various learning and memory tasks. The development of anticipatory nausea is formed through a classically conditioned response to a context that has been paired previously with toxin-induced nausea and/or vomiting. Rats display a distinctive conditioned gaping response when injected with a nausea-inducing drug such as LiCl. In the present study, male Long-Evans rats were injected intraperitoneally with LPS (200microg/kg) or saline (NaCl) followed 90min later by an injection of the toxin LiCl or saline before being placed in a distinctive context on four conditioning days (72h apart). On the condition test day, rats (n=6/group) were placed in the distinctive context in a drug-free state and behavioral responses were videotaped. Rats given LPS followed by LiCl were found to have significantly fewer gaping responses when compared to rats given NaCl followed by LiCl. All groups were also found to have similar levels of spontaneous ingestive behaviors suggesting that the decrease in gaping was not due to motor impairment. The present results suggest that activation of the immune system with LPS administration significantly impairs the acquisition of anticipatory nausea.

Activation of the immune system in rats with lipopolysaccharide reduces voluntary sucrose intake but not intraoral intake

Traditional intake measures of voluntary consumption of food or fluid from a specific location involve both appetitive and consummatory behaviors. Appetitive behaviors are food finding behaviors displayed by an animal prior to the consumption of the food, whereas consummatory behaviors are the behaviors involved in the actual consumption of the food. Intraoral intake of a fluid can be measured by directly infusing it into the oral cavity of an animal and quantifying the consummatory behaviors. The present study compared the effects of immune activation (lipopolysaccharide, LPS) and toxin (lithium chloride, LiCl)-induced changes on both a traditional intake measure (bottle drinking) and an intraoral intake measure. In Experiment 1, rats were injected intraperitoneally with LPS (200 microg/kg), LiCl (0.15 M, 20 ml/kg) or NaCl vehicle, and voluntary sucrose (0.3 M) intake was monitored for 1 h from a graduated drinking tube. Voluntary intake was again assessed on a second test day, 72 h later under the same conditions. In Experiment 2, a continuous intraoral infusion of sucrose (0.3 M) was given via intraoral cannulae following systemic injections of LPS, LiCl or NaCl vehicle on two different test days, 72 h apart. Rats injected with LiCl displayed reduced sucrose intake on both the voluntary intake measure and the intraoral intake measure relative to controls (Ps<.05). The reduced intake observed was of greater magnitude on the second test day of both experiments, consistent with conditioning effects. In contrast, LPS reduced sucrose intake only when assessed with the traditional intake measure. Intraoral sucrose intake remained unchanged relative to controls. The present results provide further evidence that activation of the immune system has adverse effects on the appetitive phase of ingestion, whereas the consummatory aspects are unaffected.

Acute effects of corticosterone on LiCl-induced rapid gustatory conditioning in rats: a microstructural analysis of licking patterns.

Acute administration of corticosterone (Cort) has been shown to potentiate a variety of learning processes. Here, the effects of Cort on rapid gustatory conditioning were examined using a lick monitoring system. Over a 3-day period, animals were given intraperitoneal (ip) injections of either a low dose of lithium chloride (LiCl; 0.75 mEq, ip) toxin or saline control (NaCl; 0.9%, ip) and then received an injection of Cort (5 mg/kg, ip) or cyclodextrin vehicle. In order to investigate the effect of acute increases in systemic Cort on gustatory conditioning, patterns of licking behavior were recorded while animals were exposed to a novel sucrose (0.3 M) tastant. Increased post-injection serum Cort levels were verified by radioimmunoassay analysis of trunk blood samples. Analysis of the licking patterns revealed evidence of rapid gustatory conditioning. Significantly reduced sucrose intake volumes and fewer total licks during the test sessions on Conditioning days were found in all groups that had received LiCl injections. Evidence of a Cort-potentiated conditioning effect was also found. Animals that had received Cort in addition to LiCl exhibited significantly shorter meal durations than did animals that had been administered LiCl alone and Cort significantly influenced the effects of LiCl on cluster number. These findings indicate that Cort facilitates conditioning, possibly by modulation of LiCl-induced visceral afferent and/or central feedback mechanisms.

Lipopolysaccharide dose dependently impairs rapid toxin (LiCl)-induced gustatory conditioning: A taste reactivity examination of the conditioned taste aversion

There is much debate on how immune activation affects cognitive processing. Research has shown that stimulation of the immune system can significantly impair, have no adverse effects, or enhance learning and memory processes in animals. The present experiment evaluated the effects of the bacterial endotoxin, lipopolysaccharide (LPS) on the acquisition of a rapidly acquired conditioned taste aversion using a toxin-containing food. Male Long Evans rats were fitted with intraoral cannulae and habituated to the taste reactivity procedure. Rats received two conditioning days, 72 h apart, in which they were injected systemically with LPS (200, 100, or 50 microg/kg) or NaCl (0.9% vehicle) and 90 min later placed in the taste reactivity test chamber. Rats were given 5 brief (1 min) intraoral infusions of either a LiCl-adulterated sucrose solution (0.15M LiCl+0.3M sucrose) or NaCl-sucrose solution (0.15M NaCl+0.3M sucrose) across a 1h period. On the test day (72 h after the last conditioning trial), rats were given a 2 min intraoral infusion of the respective taste in a drug-free state. Individual taste reactivity responses were recorded and analyzed. Results demonstrate that rats treated with LPS dose-dependently increased ingestive responding to the LiCl-sucrose flavor while at the same time showing reduced rejection response frequency on the two conditioning days. LPS treatment did not alter taste reactivity responding to the NaCl-sucrose solution. On the test day, the LPS groups again displayed a dose dependent increase in ingestive responses and a decrease in rejection responses to the LiCl-sucrose taste. The present results suggest that LPS-induced immune system activation, significantly impairs the rapid acquisition of a conditioned taste aversion.