lithium-chloride and Nausea

A review is presented of experimental studies, using rats as the subjects, that were designed to establish an animal model of the clinical phenomenon of anticipatory nausea. Experiments 1 and 2 demonstrated that pairing a distinctive context with an illness-inducing injection of lithium chloride endowed the context with new properties, consistent with the proposal that classical conditioning had established an association between the context as the conditioned stimulus and nausea as the unconditioned stimulus. The conditioned response to the context constitutes a form of anticipatory nausea. Experiment 3 examined overshadowing, showing that the presence of a novel salient cue (a flavour) during context conditioning reduced the magnitude of the aversion conditioned to the context. Experiments 4-7 examined the effects of giving exposure to the context prior to conditioning. They demonstrated a latent inhibition effect, that is, a reduction in the magnitude of the aversion in pre-exposed animals. It is suggested that these ways of modulating conditioned aversions could form the basis of interventions for use in the chemotherapy clinic. Anticipatory nausea is assumed to be a consequence of the formation of an association between the cues that constitute the clinic and the drug-induced nausea experienced in their presence. By restricting the development of this association, latent inhibition and overshadowing procedures should be effective in alleviating the problem of anticipatory nausea.

Topics: Animals; Avoidance Learning; Conditioning, Classical; Disease Models, Animal; Humans; Lithium Chloride; Nausea; Rats; Taste; Vomiting, Anticipatory

Anticipatory nausea is a classically conditioned response to cues (e.g. contexts) that have been previously paired with a nauseating stimulus, such as chemotherapy in humans. In rodents, anticipatory nausea can be modeled by pairing a novel context with lithium chloride (LiCl), which leads to conditioned disgust behaviours (such as gaping) when exposed to the context alone. Growing evidence suggests that selective immune activation attenuates various forms of learning and memory. The present study investigated the effects of the endotoxin lipopolysaccharide (LPS) on LiCl-induced anticipatory nausea across critical stages of associative memory including acquisition, consolidation, and extinction. Adult male Long Evans rats were subject to intraperitoneal (i.p.) LiCl (127 mg/kg) or vehicle control (NaCl) paired with a 30 min conditioning trial in a distinct context for a total of 4 trials. To study acquisition, rats were administered either LPS or NaCl (200 μg/kg, i.p.) 90 mins before the conditioning trials. To study consolidation, different rats were administered either LPS or NaCl (200 μg/kg, i.p.) immediately after the conditioning trials. These trials were followed by 4 drug-free extinction trials within the same context. LPS significantly reduced conditioned gaping behaviours by the 4th conditioning trial and on the 1st drug-free extinction trial when administered 90 mins before or immediately after the conditioning trials. LPS had no significant effect on extinction. The present study provides strong evidence for the attenuating effects of LPS exposure on the acquisition and consolidation of LiCl-induced anticipatory nausea.

Topics: Animals; Behavior, Animal; Disgust; Lipopolysaccharides; Lithium Chloride; Male; Nausea; Rats; Rats, Long-Evans; Sodium Chloride

Pica refers to eating nonfood substances. The pica behavior has been the focus of attention in physiological and pharmacological studies, because its consumption is a good marker of nausea in laboratory rats, which cannot vomit due to neuroanatomical reasons. Almost all pica studies with rats have used kaolin clay pellets as nonfood substances. The present study primarily aimed to explore an alternative (or more suitable) substance to kaolin for detection of nausea induced by emetic drugs. Two calcium compounds, gypsum and lime, were evaluated in this study. An injection of lithium chloride (LiCl) increased pica behavior not only in the rats given kaolin but also in the rats given gypsum, suggesting that gypsum consumption could be used as an indicator of nausea. However, its sensitivity was no greater than that of kaolin consumption. In addition, lime is not a useful marker for nausea because the size of pica was small in the LiCl-injected rats, and did not differ from the control in the cisplatin-injected rats. In short, the superiority of kaolin as a test substance for nausea could not be overturned. However, the fact that nauseous rats displayed pica behavior with gypsum and lime refutes the claim that aluminosilicate, the main component of kaolin, is the critical determinant of emetic-caused pica in laboratory rats.

Topics: Animals; Antineoplastic Agents; Calcium Compounds; Calcium Sulfate; Cisplatin; Emetics; Kaolin; Lithium Chloride; Nausea; Pica; Rats

No prior studies have shown that gaping reactions are produced with the avoidance of conditioned taste caused by cisplatin and emetine. Therefore, we tried to demonstrate it using a taste reactivity test in rats and found the gaping reactions induced when saccharin is readministered after gustatory conditioning that paired saccharin with cisplatin or emetine. Since conditioned gaping reactions indicate the aversion to saccharin taste and conditioned nausea, the present study suggest that the taste aversion is induced by cisplatin and emetine. It was also found that with intraperitoneal injections of emetine alone, gaping almost never occurs.

Topics: Animals; Avoidance Learning; Cisplatin; Emetine; Lithium Chloride; Nausea; Rats; Saccharin; Taste

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

Topics: Animals; Conditioning, Classical; Fear; Female; Humans; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Nausea

The fatty acid amide oleoyl glycine (OlGly) and its more stable methylated form oleoyl alanine (OlAla) reduce naloxone-precipitated morphine withdrawal (MWD)-induced conditioned gaping (nausea) responses in rats. In addition, OlGly has been shown to reduce lithium chloride (LiCl)-induced conditioned gaping in rats and vomiting in Suncus murinus (house musk shrews).. Here, we compared the potential of these fatty acid amides to maintain their anti-nausea/anti-emetic effect over a delay. The following experiments examined the potential of a wider dose range of OlGly and OlAla to interfere with (1) LiCl-induced conditioned gaping in rats and (2) LiCl-induced vomiting in shrews, when administered 20 or 70 min prior to illness.. OlAla (1, 5, 20 mg/kg) reduced LiCl-induced conditioned gaping, with OlGly only effective at the high dose (20 mg/kg), with no effect of pretreatment delay time. At the high dose of 20 mg/kg, OlGly increased passive drips during conditioning suggesting a sedative effect. In shrews, both OlGly and OlAla (1, 5 mg/kg) suppressed LiCl-induced vomiting, with no effect of pretreatment delay. OlAla more effectively suppressed vomiting, with OlAla (5 mg/kg) also increasing the latency to the first vomiting reaction.. OlAla was more effective than OlGly in reducing both LiCl-induced gaping in rats and LiCl-induced vomiting in shrews. These findings provide further evidence that these fatty acid amides may be useful treatments for nausea and vomiting, with OlAla demonstrating superior efficacy.

Topics: Alanine; Animals; Glycine; Lithium Chloride; Nausea; Rats; Rats, Sprague-Dawley; Shrews; Vomiting

Twenty-five to fifty percent of patients undergoing chemotherapy will develop anticipatory nausea and vomiting (ANV), in which symptoms occur in anticipation of treatment. ANV is triggered by environmental cues and shows little response to traditional antiemetic therapy, suggesting that unique neural pathways mediate this response. Understanding the underlying neural mechanisms of this disorder is critical to the development of novel therapeutic interventions. The purpose of the present study was to identify brain areas activated during ANV and characterize sex differences in both the behavior and the brain areas activated during ANV. We used a rat model of ANV by pairing a novel context with the emetic drug lithium chloride (LiCl) to produce conditioned nausea behaviors in the LiCl-paired environment. We quantitated gaping, an analog of human vomiting, after acute or repeated LiCl in a unique environment. To identify brain regions associated with gaping, we measured c-fos activation by immunochemical staining after these same treatments. We found that acute LiCl activated multiple brain regions including the supraoptic nucleus of the hypothalamus, central nucleus of the amygdala, nucleus of the solitary tract and area postrema, none of which were activated during ANV. ANV activated c-fos expression in the frontal cortex, insula and paraventricular nucleus of the hypothalamus of males but not females. These data suggest that therapies such as ondansetron which target the area postrema are not effective in ANV because it is not activated during the ANV response. Further studies aimed at characterizing the neural circuits and cell types that are activated in the conditioned nausea response will help identify novel therapeutic targets for the treatment of this condition, improving both quality of life and outcomes for patients undergoing chemotherapy.

Topics: Animals; Antiemetics; Brain; Female; Humans; Lithium Chloride; Male; Nausea; Proto-Oncogene Proteins c-fos; Rats; Vomiting

Lithium chloride (LiCl) is an emetic drug that has been used to create animal models of anticipatory nausea and conditioned place aversion. In this study we examined escape behaviours from a context in which rats experienced the aversive effects of LiCl treatments. The experiment had two phases: acquisition of context conditioning, which consisted of pairing a distinct context with the pharmacological effects of a moderate dose of the toxin LiCl, and extinction of context conditioning, which consisted of placement in the distinct context in a drug free state. During context conditioning, 16 adult male Long-Evans rats were injected intraperitoneally with 96 mg/kg lithium chloride (LiCl; n = 8) or 0.9% saline (NaCl; n = 8) and placed individually in an automated locomotor activity apparatus for 30 min every other day for 4 days. During the extinction phase, rats were placed in the apparatus for 30 min every other day without injections during a 4 day extinction phase. A significant Drug x Trial interaction was found for the time spent in vertical position in the open field apparatus during trials 1-3 of the extinction phase. The LiCl treated rats exhibited significantly increased rearing behavior, relative to the control rats, indicative of conditioned aversion. The results of this study suggest that escape behavior (vertical activity) occurs in rats experiencing the aversive conditioned effects of LiCl in a distinct context. In the context of current theoretical accounts, the LiCl-conditioned increase in apparent escape behaviors can be considered a reflection of anticipatory nausea.

Topics: Animals; Avoidance Learning; Behavior, Animal; Conditioning, Psychological; Lithium Chloride; Male; Nausea; Rats; Rats, Long-Evans; Taste

When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT. To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these anti-nausea effects were mediated by the 5-HT. When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT

Topics: Animals; Antiemetics; Cannabidiol; Cannabinoids; Drug Administration Schedule; Female; Lithium Chloride; Male; Nausea; Rats; Rats, Sprague-Dawley; Shrews; Treatment Outcome; Vomiting

Pairing a taste with either internal pain or nausea, despite equivalent effects on voluntary consumption, has dissociable effects on hedonic responses: Only pairing with nausea results in the production of disgust reactions, while pairing with internal pain results in conditioned fear as indicated by immobility. Here, we use orofacial reactions to examine the hedonic responses elicited by contextual, nonflavor, cues paired with nausea produced by injection of lithium chloride (LiCl) or internal pain caused by injection of hypertonic saline. In Experiment 1, aversive orofacial responses were the specific context-elicited behaviors in the rats injected with LiCl, whereas immobility was seen in the animals injected with hypertonic saline. In Experiment 2, rats first received discriminative training with two contexts, where one context was paired with LiCl or hypertonic saline, and the other context with isotonic saline. After this, rats were intraorally infused with a flavor (conditioned stimulus (CS) +) in the paired context, and with a different flavor (CS-) in the unpaired context. Second-order conditioning was then examined in a test conducted in the unpaired context. The infusion of the CS + flavor produced aversive orofacial responses in the rats injected with LiCl but immobility in the subjects injected with hypertonic saline. The results suggest that nonflavor cues support conditioned hedonic responses in the same way as flavor cues, which implies that the quality of aversion learning (conditioned nausea vs. fear) is primarily determined by the nature of the aversive event and not the type of conditioned cue. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Topics: Affect; Animals; Avoidance Learning; Behavior, Animal; Conditioning, Classical; Cues; Lithium Chloride; Male; Nausea; Pain; Rats, Wistar; Taste

Here we investigate the involvement of the ventral pallidum (VP) in the anti-nausea effect of fatty acid amide hydrolase (FAAH) inhibition with PF-3845, and examine the pharmacological mechanism of such an effect. We explored the potential of intra-VP PF-3845 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) in male Sprague-Dawley rats. As well, the role of the cannabinoid 1 (CB

Topics: Amidohydrolases; Animals; Basal Forebrain; Butyrates; Infusions, Intraventricular; Lithium Chloride; Male; Nausea; Phenylurea Compounds; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley

Kaolin clay eating has been considered as a marker of nausea in rats, because a variety of treatments, which evoke nausea in humans, generate consumption of kaolin clay in rats. The present study with two experiments replicated kaolin clay ingestion induced by an injection of emetic lithium chloride (LiCl). The LiCl injection, however, did not generate eating of wooden objects in rats. The present study also provides a new finding that consumption of kaolin clay alleviates rats' taste aversion learning caused by an LiCl injection. This finding is congruent with the contention that consumption of kaolin clay is not only a useful index of, but also an effective remedy for, drug-induced nausea in rats.

Topics: Analysis of Variance; Animals; Antidiarrheals; Antimanic Agents; Avoidance Learning; Body Weight; Eating; Kaolin; Lithium Chloride; Male; Nausea; Rats; Rats, Wistar; Taste

The role of sex and estrous phase in the conditioning of toxin-induced disgust reactions (anticipatory nausea) to a novel context were examined in adult rats. Conditioned oral gaping responses have been shown to be a reliable index of nausea in rats. In Experiment 1 male and female rats were injected with LiCl (0, 64, 96, or 128 mg/kg) on each of 4 conditioning trials (72 h apart) and then placed in a novel context for 30 min. 72 h following the last conditioning trial each animal was re-exposed to this context in a toxin-free state for 10 min and disgust responses (gapes, forelimb flails, chin rubs, and paw treads) were scored from video records. A significant toxin dose-related monotonic increase in conditioned gaping showed a significantly greater increase in females, relative to males. In Experiment 2 female rats were conditioned, using the same paradigm, on either diestrus or proestrus days (trials 96 h apart) with LiCl (96 mg/kg) or saline control injections. Disgust responses were recorded on each of the 4 conditioning trials and a toxin-free test trial. Significant increases in conditioned disgust were obtained on proestrus relative to diestrus days on the toxin-free test trial. However no significant estrous cycle differences in disgust responding were obtained on the acquisition trials. The sex difference in conditioned gaping and the increased conditioned disgust responses in proestrus suggest that increased levels of estradiol likely enhance the strength of the association of the toxin-induced nausea with the novel context in rats.

Topics: Animals; Conditioning, Classical; Disgust; Estrous Cycle; Female; Lithium Chloride; Male; Nausea; Rats; Rats, Long-Evans; Sex Factors

Pairing a taste with either internal pain (e.g., from hypertonic saline injection) or nausea (e.g., from LiCl administration) will reduce subsequent consumption of that taste. Here we examine the responses to a taste paired with either hypertonic saline or LiCl using the analysis of licking microstructure (mean lick cluster size: Experiments 1-3), taste reactivity (examining the distribution of appetitive and aversive orofacial responses: Experiments 2-3), and immobility (as a measure of fear: Experiments 2-3). At both high (10 ml/kg 0.15 M LiCl, 10 ml/kg 1.5 M NaCl) and low dose levels (2 ml/kg 0.15 M LiCl, 4 ml/kg 1.5 M NaCl), pairing a taste with either LiCl-induced nausea or internal pain produced by hypertonic NaCl caused reductions in voluntary consumption, in appetitive taste reactivity responses, and in lick cluster size. However, only pairing with LiCl resulted in conditioned aversive taste reactivity responses to the taste. In contrast, pairing with hypertonic NaCl resulted in the taste eliciting higher levels of immobility (reflecting fear) than did pairing the taste with LiCl. The clearly dissociable effects of LiCl and hypertonic saline on aversive taste reactivity and fear responses, despite equivalent effects on consumption, demonstrates selective conditioning effects between internal pain and nausea. (PsycINFO Database Record

Topics: Analysis of Variance; Animals; Appetite; Avoidance Learning; Conditioning, Classical; Dose-Response Relationship, Drug; Drinking Behavior; Fear; Lithium Chloride; Male; Nausea; Pain; Rats; Rats, Wistar; Saline Solution, Hypertonic; Taste; Water Deprivation

This study examined sex differences in the establishment of lithium chloride (LiCl)-induced conditioned disgust behavior (anticipatory nausea) to a distinct context in adult male and female rats. Also examined were potential sex differences in response to treatment with the bacterial endotoxin, lipopolysaccharide (LPS), and its effect on learning and memory. Twenty-nine male and 31 female naïve Long-Evans rats were injected (intraperitoneally; i.p.) with either 200μg/kg LPS or 0.9% (NaCl), 90min prior to i.p. injections of either 128mg/kg LiCl or 0.9% NaCl, and immediately placed into a distinctive context for 30min (repeated over 4 conditioning days, spaced 72h apart). 72h following the final conditioning day, each subject was re-exposed to the context on a drug-free test day where orofacial and somatic behaviors were recorded. Results showed that LiCl-treated females conditioned stronger disgust reactions, relative to LiCl-treated males, as evidenced by significantly higher frequencies of conditioned "gaping" behavior (p<0.02) and forelimb flailing (p<0.01) in females. Pre-treatment with LPS during conditioning led to strong inhibition of conditioned disgust behavior, to levels that did not significantly differ from controls. Although there was no apparent sex difference in the degree of inhibition produced by LPS in this context-based rodent disgust model, males did exhibit significantly greater 24h body weight losses following LPS injections on the first two conditioning days, relative to females. The results of the current study provide strong evidence for a sex difference in the establishment of anticipatory nausea, as well as, evidence for a sex difference in the acute-phase response to endotoxin treatment.

Topics: Animals; Avoidance Learning; Behavior, Animal; Body Weight; Conditioning, Psychological; Emotions; Female; Immune System; Lipopolysaccharides; Lithium Chloride; Male; Nausea; Rats; Sex Characteristics

The hedonic value of a sweet food reward, or how much a taste is 'liked', has been suggested to be encoded by neuronal firing in the posterior ventral pallidum (VP). Hedonic impact can be altered by psychological manipulations, such as taste aversion conditioning, which can make an initially pleasant sweet taste become perceived as disgusting. Pairing nausea-inducing LiCl injection as a Pavlovian unconditioned stimulus (UCS) with a novel taste that is normally palatable as the predictive conditioned stimulus (CS+) suffices to induce a learned taste aversion that changes orofacial 'liking' responses to that sweet taste (e.g., lateral tongue protrusions) to 'disgust' reactions (e.g., gapes) in rats. We used two different sweet tastes of similar initial palatability (a sucrose solution and a polycose/saccharin solution, CS ± assignment was counterbalanced across groups) to produce a discriminative conditioned aversion. Only one of those tastes (arbitrarily assigned and designated as CS+) was associatively paired with LiCl injections as UCS to form a conditioned aversion. The other taste (CS-) was paired with mere vehicle injections to remain relatively palatable as a control sweet taste. We recorded the neural activity in VP in response to each taste, before and after aversion training. We found that the safe and positively hedonic taste always elicited excitatory increases in firing rate of VP neurons. By contrast, aversion learning reversed the VP response to the 'disgusting' CS+ taste from initial excitation into a conditioned decrease in neuronal firing rate after training. Such neuronal coding of hedonic impact by VP circuitry may contribute both to normal pleasure and disgust, and disruptions of VP coding could result in affective disorders, addictions and eating disorders.

Topics: Action Potentials; Animals; Association Learning; Avoidance Learning; Basal Forebrain; Catheters, Indwelling; Conditioning, Classical; Dietary Sucrose; Electrodes, Implanted; Glucans; Lithium Chloride; Male; Motor Activity; Nausea; Neurons; Rats, Sprague-Dawley; Reward; Saccharin; Taste Perception

Anticipatory nausea (AN) is a conditioned nausea reaction experienced by chemotherapy patients upon returning to the clinic. Currently, there are no specific treatments for this phenomenon, with the classic antiemetic treatments (e.g., ondansetron) providing no relief. The rat model of AN, contextually elicited conditioned gaping reactions in rats, provides a tool for assessing potential treatments for this difficult to treat disorder. Systemically administered drugs which elevate the endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), by interfering with their respective degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) interfere with AN in the rat model. We have shown that MAGL inhibition within the visceral insular cortex (VIC) interferes with acute nausea in the gaping model (Sticht et al., 2015). Here we report that bilateral infusion of the MAGL inhibitor, MJN110 (but neither the FAAH inhibitor, PF3845, nor ondansetron) into the VIC suppressed contextually elicited conditioned gaping, and this effect was reversed by coadministration of the CB1 antagonist, AM251. These findings suggest that 2-AG within the VIC plays a critical role in the regulation of both acute nausea and AN. Because there are currently no specific therapeutics for chemotherapy patients that develop anticipatory nausea, MAGL inhibition by MJN110 may be a candidate treatment. (PsycINFO Database Record

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cerebral Cortex; Endocannabinoids; Glycerides; Lithium Chloride; Models, Animal; Monoacylglycerol Lipases; Nausea; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Serotonin; Vomiting, Anticipatory

We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5mg/kg, i.p.) suppressed, but did not completely block, LiCl-induced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting.

Topics: Animals; Antiemetics; Cannabinoids; Conditioning, Psychological; Indoles; Lithium Chloride; Male; Nausea; Rats; Receptor, Cannabinoid, CB2; Shrews; Vomiting

Disgust has been proposed to have evolved as a means to rid the body and mouth of noxious substances and toxins, as well as to motivate and facilitate avoidance of contact with disease-causing organisms and infectious materials. Nonemetic species, such as the rat, show distinctive facial expressions, including the gaping reaction, indicative of nausea-based disgust. These conditioned disgust responses can be used to model anticipatory nausea in humans, which is a learned response observed following chemotherapy treatment. As social factors play a role in the modulation and expression of conditioned disgust responses in rats, and the nonapeptide, oxytocin (OT), is involved in the modulation of social behavior, the present study examined the effects of an OT antagonist, L-368 899, on the development and expression of socially mediated conditioned disgust in male rats. When administered 10 min before testing in a distinct context (different from the original conditioning context), L-368 899 (5 mg/kg) significantly decreased gaping behavior in rats that were conditioned with a social partner. LiCl-treated rats administered L-368 899 before testing also showed decreased social initiations toward their social partner. These findings suggest that OT may play a role in the modulation and expression of socially mediated conditioned disgust in rats.

Topics: Animals; Avoidance Learning; Behavior, Animal; Camphanes; Conditioning, Psychological; Facial Expression; Lithium Chloride; Male; Nausea; Oxytocin; Piperazines; Rats; Rats, Long-Evans; Social Behavior; Vomiting, Anticipatory

The visceral insular cortex (VIC) has previously been shown to play a critical role during acute nausea-induced conditioned gaping in rats. Specifically, localized administration of the conventional anti-emetic, ondansetron or the synthetic cannabinoid, HU210, interferes with the establishment of conditioned gaping, likely by reducing the effects of an illness-inducing treatment. However the precise role of the VIC in endocannabinoid-suppression of nausea remains unknown; thus we investigated the potential of localized intra-VIC endocannabinoid administration to interfere with acute nausea-induced conditioned gaping behavior in male Sprague-Dawley rats. Animals received an intraoral infusion of saccharin (0.1%) followed by intra-VIC exogenous N-arachidonoylethanolamide (AEA; 0.4, 4 μg) or 2-arachidonoylglycerol (2-AG; 0.5, 1 μg), and were subsequently injected with nausea-inducing LiCl (0.15M) 15 min later. Bilateral intra-VIC infusions of 2-AG (1 μg, but not 0.5 μg) dose-dependently suppressed conditioned gaping, whereas exogenous AEA was without effect. Interestingly, 2-AG reduced conditioned gaping despite additional pretreatment with the selective cannabinoid receptor type 1 (CB1) antagonist, AM-251; however, concomitant pretreatment with the cyclooxygenase inhibitor, indomethacin (0.5 μg), blocked the suppressive effects of intra-VIC 2-AG. These findings suggest that the modulatory role of the endocannabinoid system during nausea is driven largely by the endocannabinoid, 2-AG, and that its anti-nausea effects may be partly independent of CB1-receptor signaling through metabolic products of the endocannabinoid system.

Topics: Animals; Antiemetics; Arachidonic Acids; Cannabinoid Receptor Agonists; Cerebral Cortex; Endocannabinoids; Glycerides; Lithium Chloride; Male; Nausea; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley

Δ(9)-Tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) found in cannabis both reduce the distressing symptom of nausea, but their combined effects are not understood.. The potential of combined doses of THC and CBDA to reduce acute nausea and anticipatory nausea in rodent models was assessed.. For acute nausea, the potential of cannabinoid pretreatment(s) to reduce LiCl-induced nausea paired with saccharin was evaluated in a subsequent drug free taste reactivity test, followed by a taste avoidance test. For anticipatory nausea, the potential of the cannabinoid pretreatment(s) to reduce the expression of LiCl-induced contextually elicited conditioned gaping was evaluated.. Combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) reduced acute nausea. Higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses also reduced acute nausea. THC (10 mg/kg) interfered with conditioned taste avoidance, an effect attenuated by CBDA (10 μg/kg). On the other hand, combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) did not suppress contextually elicited conditioned gaping in a test for anticipatory nausea. However, higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses, also reduced anticipatory nausea. Only at the highest dose (10 mg/kg) did THC impair locomotor activity, but CBDA did not at any dose.. Combined subthreshold doses of THC:CBDA are particularly effective as a treatment for acute nausea. At higher doses, CBDA may attenuate THC-induced interference with learning.

Topics: Animals; Antiemetics; Cannabinoids; Conditioning, Psychological; Disease Models, Animal; Dronabinol; Drug Therapy, Combination; Lithium Chloride; Male; Nausea; Rats; Rats, Sprague-Dawley; Saccharin

Enhancement of the endocannabinoid (EC) system may reduce anticipatory nausea (AN).. The experiments evaluated the potential of the dual fatty acid amide hydrolase (FAAH)/monoacylglycerol lipase (MAGL) inhibitor, JZL195, on its own and combined with anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) to reduce contextually elicited gaping, a measure of AN in rats.. Following four context lithium chloride (LiCl) pairings, rats were injected with vehicle (VEH) or JZL195 (10 mg kg(-1), intraperitoneally) 105 min before an injection of VEH, 2-AG (1.25 mg kg(-1)), or AEA (5.0 mg kg(-1)). Fifteen minutes later, all rats were placed in the LiCl-paired context for 5 min and in a different context for a 15-min locomotor test. Whole brains were extracted for EC analysis. The potential of the CB1 antagonist, SR141716, to reverse the suppression of AN by both JZL195 and AEA and of the CB2 antagonist, AM630, to reverse the suppression of AN by JZL195 was then evaluated.. JZL195 suppressed gaping and elevated AEA, palmitoylethanolamine, and oleoylethanolamide. As the suppression of gaping was reversed by SR141716, but not by AM630, the effect was CB1 mediated. The suppressive effect of JZL195 on gaping, as well as elevation of AEA and 2-AG, was amplified by pretreatment with either AEA or 2-AG. On its own, AEA, but not 2-AG, also suppressed gaping-an effect that was also prevented by CB1 antagonism.. JZL195 reduces AN primarily by acting as a FAAH inhibitor, but MAGL inhibition is also indicated.

Topics: Amidohydrolases; Animals; Anticipation, Psychological; Arachidonic Acids; Brain; Cannabinoid Receptor Antagonists; Carbamates; Endocannabinoids; Enzyme Inhibitors; Glycerides; Indoles; Lithium Chloride; Male; Monoacylglycerol Lipases; Motor Activity; Nausea; Oleic Acids; Piperazines; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

We trained rats in a context discrimination paradigm by pairing a sucrose solution with lithium chloride in one context (conditioning context) and simple exposure to the same fluid in a second (neutral) context to establish a context-dependent aversion to the conditioned fluid. We then investigated whether transfer of the context dependency to a test fluid (a sodium chloride solution) was affected by two post-discrimination training treatments, an extended context discrimination training, and non-reinforced exposure to the conditioning context (context extinction). We found that the context-dependent flavor aversion that had been specific to sucrose transferred to the test fluid after the extensive training (Experiment 1). Context extinction eliminated the transfer effect that had been observed immediately after the context discrimination training (Experiment 2). In addition, an aversion acquired by sucrose through a simple conditioning of sucrose-LiCl pairings did not generalize to the test fluid (Experiment 3). These results emphasize the importance of a Pavlovian excitatory association between the conditioning context and nausea as a primary source of transfer of the context dependency, rather than a generalization of aversion acquired by the conditioned fluid to the test fluid.

Topics: Animals; Avoidance Learning; Conditioning, Operant; Cues; Discrimination Learning; Extinction, Psychological; Lithium Chloride; Male; Nausea; Rats; Rats, Wistar; Reinforcement, Psychology; Sodium Chloride; Sucrose; Sweetening Agents; Taste; Transfer, Psychology

The effectiveness of cannabidiolic acid (CBDA) was compared with other potential treatments for anticipatory nausea (AN), using a rat model of contextually elicited conditioned gaping reactions.. The potential of ondansetron (OND), Δ(9)-tetrahydrocannabinol (THC), chlordiazepoxide (CDP), CBDA, and co-administration of CBDA and tetrahydrocannabinolic acid (THCA) to reduce AN and modify locomotor activity was evaluated.. Following four pairings of a novel context with lithium chloride (LiCl), the rats were given a test for AN. On the test trial, they received pretreatment injections of the following: vehicle, OND (0.1 or 1.0 mg/kg), THC (0.5 mg/kg), CBDA (0.0001, 0.001, 0.01, 0.1 mg/kg or 1.0 mg/kg), CDP (1, 5, or 10 mg/kg) or co-administration of subthreshold doses of CBDA (0.1 μg/kg), and THCA (5 μg/kg). Immediately following the AN test trial in all experiments, rats were given a 15 min locomotor activity test. Finally, the potential of CBDA (0.001, 0.01, 0.1, and 1 mg/kg) to attenuate conditioned freezing to a shock-paired tone was assessed.. THC, CBDA, and CDP, but not OND, reduced contextually elicited gaping reactions. Co-administration of subthreshold doses of CBDA and THCA also suppressed AN, and this effect was blocked by pretreatment with either a cannabinoid receptor 1 (CB1) receptor antagonist or a 5-hydroxytryptamine 1A (5-HT1A) receptor antagonist. CDP (but not CBDA, THC or CBDA and THCA) also suppressed locomotor activity at effective doses. CBDA did not modify the expression of conditioned fear.. CBDA has therapeutic potential as a highly potent and selective treatment for AN without psychoactive or locomotor effects.

Topics: Animals; Anticipation, Psychological; Antiemetics; Cannabinoids; Chlordiazepoxide; Conditioning, Psychological; Dronabinol; Electroshock; Fear; Hypnotics and Sedatives; Lithium Chloride; Male; Motor Activity; Nausea; Ondansetron; Rats; Rats, Sprague-Dawley

Voluntary running in an activity wheel establishes aversion to paired taste in rats. A proposed mechanism underlying this taste aversion learning is gastrointestinal discomfort caused by running. We tested this hypothesis by measuring the pica behavior (kaolin clay intake) of rats, because it is known that rats engage in pica behavior after various nausea-inducing treatments including irradiation, motion sickness, and injection of emetic drugs such as lithium chloride (LiCl). Following a demonstration of the already-known phenomenon of LiCl-based pica in Experiment 1, we successfully showed running-based pica behavior in Experiment 2 where the running treatment was compared with a non-running control treatment (i.e., confinement in a locked wheel). These results suggest that not only LiCl but also running induces nausea in rats, supporting the gastrointestinal discomfort hypothesis of running-based taste aversion learning.

Topics: Abdominal Pain; Aluminum Silicates; Animals; Avoidance Learning; Behavior, Animal; Clay; Disease Models, Animal; Dysgeusia; Emetics; Injections, Intraperitoneal; Kaolin; Lithium Chloride; Male; Models, Biological; Motor Activity; Nausea; Physical Exertion; Pica; Rats, Wistar; Stress, Physiological

To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5-0.1 μg·kg⁻¹) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, ondansetron (OND).. We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined.. CBDA (at doses as low as 0.5 μg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping.. CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.

Topics: Animals; Antiemetics; Antineoplastic Agents; Behavior, Animal; Cannabinoids; Conditioning, Psychological; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Injections, Intraperitoneal; Lithium Chloride; Male; Nausea; Ondansetron; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Taste

We evaluated the anti-emetic and anti-nausea properties of the acid precursor of Δ(9) -tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models.. We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1 ) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist).. In rats, THCA (0.05 and/or 0.5 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-hydroxytryptamine-1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg·kg(-1) ) reduced LiCl-induced vomiting, an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg·kg(-1) ) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples.. THCA potently reduced conditioned gaping in rats and vomiting in S. murinus, effects that were blocked by SR. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting.

Topics: Animals; Antiemetics; Behavior, Animal; Body Temperature Regulation; Brain; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dronabinol; Lithium Chloride; Male; Motor Activity; Nausea; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Shrews; Time Factors; Vomiting

The cannabinoid 1 (CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV), for their ability to produce these behavioural effect characteristics of CB1 receptor inverse agonism in rats.. In experiment 1, we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour) in the same manner as SR and AM251. In experiment 2, we investigated the potential of THCV and CBDV to enhance conditioned gaping produced by a toxin in the same manner as CB1 receptor inverse agonists.. SR (10 and 20 mg·kg(-1) ) and AM251 (10 mg·kg(-1) ) produced conditioned gaping; however, THCV (10 or 20 mg·kg(-1) ) and CBDV (10 or 200 mg·kg(-1) ) did not. At a subthreshold dose for producing nausea, SR (2.5 mg·kg(-1) ) enhanced lithium chloride (LiCl)-induced conditioned gaping, whereas Δ(9) -tetrahydrocannabinol (THC, 2.5 and 10 mg·kg(-1) ), THCV (2.5 or 10 mg·kg(-1) ) and CBDV (2.5 or 200 mg·kg(-1) ) did not; in fact, THC (2.5 and 10 mg·kg(-1) ), THCV (10 mg·kg(-1) ) and CBDV (200 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential.. The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea.

Topics: Animals; Behavior, Animal; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; Dronabinol; Drug Partial Agonism; Lithium Chloride; Male; Nausea; Phytochemicals; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant

To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase-1-like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process.. The systemic administration of the anandamide transport inhibitor ARN272 ([(4-(5-(4-hydroxy-phenyl)-3,4-diaza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-2-ylamino)-phenyl)-phenylamino-methanone]) was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co-administration of SR141716.. The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg·kg(-1)) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg·kg(-1). SR141716 alone did not differ from the vehicle solution.. These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.

Topics: Amidohydrolases; Animals; Antiemetics; Arachidonic Acids; Behavior, Animal; Biological Transport; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Isoenzymes; Lithium Chloride; Male; Nausea; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; Shrews; Vomiting

We aimed to determine the potential of various doses of metoclopramide (MCP, a dopamine antagonist) to reduce lithium chloride (LiCl)-induced conditioned gaping (a nausea-induced behaviour) in rats, using the taste reactivity test. We then evaluated whether an ineffective low dose of cannabidiolic acid (CBDA, 0.1 μg/kg, Rock and Parker, 2013), the potent acidic precursor of cannabidiol (CBD, a non-psychoactive component of cannabis) could enhance the anti-nausea effects of an ineffective low dose of MCP. MCP (3.0 mg/kg) reduced conditioned gaping responses. Coadministration of ineffective doses of MCP (0.3 mg/kg) and CBDA (0.1 μg/kg) enhanced the suppression of conditioned gaping, over that of either drug alone, without interfering with conditioned taste avoidance. MCP dose-dependently reduced nausea-induced conditioned gaping in rats. As well, the suppression of conditioned gaping was enhanced when ineffective doses of MCP and CBDA were coadministered. These data suggest that CBDA could be a powerful adjunct treatment to anti-emetic regimens for chemotherapy-induced nausea.

Topics: Animals; Antiemetics; Cannabinoids; Conditioning, Psychological; Lithium Chloride; Male; Metoclopramide; Nausea; Rats; Rats, Sprague-Dawley; Taste

Anticipatory nausea is a classically conditioned response to a context that has been previously paired with toxin-induced nausea and/or vomiting. When injected with a nausea-inducing drug, such as lithium chloride (LiCl), rats will show a distinctive conditioned gaping response that has been suggested to be an index of nausea. Previous studies have found that immune system activation with an endotoxin, such as lipopolysaccharide (LPS), attenuates LiCl-induced conditioned gaping in rats. The present study examined the acquisition of LiCl-induced conditioned gaping in rats that were either LPS tolerant or LPS non-tolerant, as little is known about the effects of endotoxin tolerance on learning and memory. Male Long-Evan rats were given four systemic injections of LPS (200 μg/kg) or isotonic saline (NaCl) to induce LPS tolerance, indexed with 24 h changes in body weight following treatment. The animals were then given 4 acquisition trials in a LiCl-induced conditioned gaping paradigm. On conditioning days animals were treated with LPS (200 μg/kg) or saline followed 90 min later by injection of LiCl (127 mg/kg) or saline and then placed in a distinctive context for 30 min and their behavior video-recorded. On a drug free test day all animals were again placed in the distinctive context for 10 min and behavior was video-recorded. Gaping responses were scored for all acquisition days and the test day. Spleen and body weights were also obtained for all rats at the end of the experiment. Gaping responses were attenuated in rats treated with LPS in both the LPS tolerant and LPS non-tolerant groups. There were significant negative correlations between spleen weight as well as spleen/body weight ratios, and levels of conditioned gaping responses in LiCl treated rats, but not control rats. These results show that LPS interferes with learning/memory in the anticipatory nausea paradigm in rats that are both LPS tolerant and LPS non-tolerant.

Topics: Adjuvants, Immunologic; Animals; Behavior, Animal; Conditioning, Classical; Drug Tolerance; Endotoxins; Lipopolysaccharides; Lithium Chloride; Male; Memory; Nausea; Organ Size; Rats; Rats, Long-Evans; Spleen; Vomiting, Anticipatory

To evaluate the role of 2-arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea-like behaviour (conditioned gaping).. Vomiting was assessed in shrews (Suncus murinus), pretreated with JZL184, a selective monoacylglycerol lipase (MAGL) inhibitor which elevates endogenous 2AG levels, 1 h before administering the emetogenic compound, LiCl. Regulation of nausea-like behaviour in rats by exogenous 2AG or its metabolite arachidonic acid (AA) was assessed, using the conditioned gaping model. The role of cannabinoid CB(1) receptors, CB(2) receptors and cyclooxygenase (COX) inhibition in suppression of vomiting or nausea-like behaviour was assessed.. JZL184 dose-dependently suppressed vomiting in shrews, an effect prevented by pretreatment with the CB(1) receptor inverse agonist/antagonist, AM251. In shrew brain tissue, JZL184 inhibited MAGL activity in vivo. In rats, 2AG suppressed LiCl-induced conditioned gaping but this effect was not prevented by AM251 or the CB(2) receptor antagonist, AM630. Instead, the COX inhibitor, indomethacin, prevented suppression of conditioned gaping by 2AG or AA. However, when rats were pretreated with a high dose of JZL184 (40 mg·kg(-1) ), suppression of gaping by 2AG was partially reversed by AM251. Suppression of conditioned gaping was not due to interference with learning because the same dose of 2AG did not modify the strength of conditioned freezing to a shock-paired tone.. Our results suggest that manipulations that elevate 2AG may have anti-emetic or anti-nausea potential.. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Benzodioxoles; Brain; Endocannabinoids; Enzyme Inhibitors; Fear; Glycerides; Lithium Chloride; Male; Monoacylglycerol Lipases; Nausea; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Shrews; Vomiting

Rats selectively display conditioned gaping reactions when re-exposed to flavours previously paired with nausea-inducing treatments and drugs that reduce nausea also reduce these reactions, suggesting that they represent a model of nausea-induced behavior in rats. However, these reactions rely upon learning, they are not unconditional malaise-induced reactions. Here we compared the effectiveness of the anti-nausea drug, ondansetron (OND) to interfere with the establishment of conditioned gaping reactions and the unconditional malaise-induced reaction of lying on belly (LOB). Pretreatment with OND significantly reduced both LiCl-induced LOB and conditioned gaping reactions, without modifying conditioned taste avoidance. The frequency of gaping and duration of LOB were highly correlated. These results provide additional support for the validity of the conditioned gaping model as a rodent model of nausea-induced behavior.

Topics: Analysis of Variance; Animals; Antiemetics; Avoidance Learning; Conditioning, Classical; Disease Models, Animal; Lithium Chloride; Male; Nausea; Ondansetron; Rats; Rats, Sprague-Dawley; Saccharin; Single-Blind Method; Taste; Time Factors; Video Recording

The effects of the bacterial endotoxins, lipopolysaccharide (LPS) and muramyl dipeptide (MDP; Experiment 1), and the viral mimetic, polyinosinic: polycytidylic acid (poly I:C; Experiment 2), on the acquisition of "conditioned gaping" behavior in the rodent model of LiCl-induced anticipatory nausea were examined. Experimentally naïve adult male Long-Evans rats were injected (intraperitoneal, i.p.) with either 200 μg/kg LPS, 1.6 mg/kg MDP, or 0.9% saline (Experiment 1), or 4.0 mg/kg poly I:C or 0.9% saline (Experiment 2), 90 min prior to treatment with 127 mg/kg LiCl or saline control and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). On a drug-free test day (72 h following conditioning day 4), each animal was re-exposed to the context for 10 min, and orofacial and aversive behavioral responses were video recorded and analyzed. The results showed that pre-treatment with LPS, MDP (Experiment 1), or poly I:C (Experiment 2) prior to LiCl+context conditioning significantly impaired the establishment of conditioned gaping behavior, thus blocking the acquisition of anticipatory nausea. Results varied in regards to peripheral acute-phase response sickness behaviors, with significantly reduced weight loss in LPS-treated animals, less robust weight loss in poly I:C-treated animals, and no significant reductions in body weight in MDP-treated animals. The learning impairments observed in the current study suggest that endotoxin treatment with bacterial and viral endotoxin may have stronger central effects on learning and memory behavior, relative to peripheral effects on body weight and other sickness-related responses.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Acute-Phase Reaction; Animals; Behavior, Animal; Body Weight; Conditioning, Classical; Lipopolysaccharides; Lithium Chloride; Male; Nausea; Poly I-C; Rats; Rats, Long-Evans

This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 naïve adult male Long-Evans rats were injected (intraperitoneal) with either 200 μg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl+2.0% saccharin, 0.9% NaCl, or 0.9% NaCl+2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl+Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl+Saccharin. LPS pre-treatment also inhibited the formation of LiCl-induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS-LiCl+Saccharin relative to Group NaCl-LiCl+Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning.

Topics: Analysis of Variance; Animals; Anticipation, Psychological; Avoidance Learning; Behavior, Animal; Body Weight; Face; Fear; Lipopolysaccharides; Lithium Chloride; Male; Mouth; Nausea; Rats; Rats, Long-Evans; Saccharin; Sweetening Agents; Taste

Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB(1) ) agonists interfere with the establishment of nausea-induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB(1) receptors.. We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB(1) agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB(1) receptors.. Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB(1) agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB(1) receptors because it was prevented by co-administration of CB(1) antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.. The nausea-relieving effects of CB(1) agonists, but not the nausea-inducing effects of CB(1) inverse agonists, are mediated, at least in part, by their action at the VIC in rats.

Topics: Animals; Antiemetics; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cerebral Cortex; Dronabinol; Lithium Chloride; Male; Naphthalenes; Nausea; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

A taste associated with emetic drugs produces conditioned disgust reactions in rats (predominantly gaping), unlike nonemetic drugs that can still produce conditioned taste avoidance but not conditioned disgust. That difference suggests nausea is a prerequisite for learning disgust reactions to tastes. Depletion of forebrain serotonin (5-HT) by 5,7-dihydroxytryptamine (5,7-DHT) lesions of the dorsal raphe nucleus and median raphe nucleus prevents LiCl-induced conditioned disgust reactions (Limebeer et al., 2004). Here we demonstrate that partial depletion of 5-HT in the insular cortex (IC) prevents LiCl-induced conditioned disgust reactions. Furthermore, a double dissociation occurred in the partial regulation of disgust and taste avoidance by selective 5-HT(3) receptor antagonism/agonism in the posterior (granular) region of the IC and the anterior (dorsal agranular) region of the IC, respectively. Intracranial administration of the 5-HT(3) receptor antagonist, ondansetron (OND), to the posterior IC impaired the establishment of LiCl-induced conditioned gaping reactions, but not LiCl-induced conditioned taste avoidance (CTA). Likewise, posterior IC administration of the 5-HT(3) receptor agonist m-chlorophenylbiguanide (mCPBG) enhanced the establishment of LiCl-induced conditioned gaping and produced conditioned gaping on its own (which was prevented by intracranially administered OND), with no effect on CTA. On the other hand, anterior IC administration of OND partially reduced the establishment of LiCl-induced CTA, and mCPBG produced a weak CTA, both without effect on gaping. These results suggest that activation of 5-HT(3) receptors in the posterior IC is important for the production of nausea-induced conditioned disgust reactions, while activation of 5-HT(3) receptors in the anterior IC are involved in the production of CTA.

Topics: 5,6-Dihydroxytryptamine; Animals; Avoidance Learning; Biguanides; Cerebral Cortex; Conditioning, Classical; Emotions; Lithium Chloride; Male; Nausea; Ondansetron; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Saccharin; Serotonin 5-HT3 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists; Taste

Acute administration of corticosterone has been shown to facilitate learning in a number of associative paradigms, including LiCl-induced conditioned taste aversion learning. The present study examined the effects of acute corticosterone on LiCl-induced conditioned anticipatory nausea in male rats. Anticipatory nausea is produced by pairing a novel distinctive context with the nausea-inducing effects of a toxin, such as LiCl. Following a number of pairings of the context with the effects of the toxin, rats will display a distinctive conditioned "gaping" response when placed into the context in a drug free state. Adult male Long-Evans rats were injected (intraperitoneal, ip) with a LiCl solution (32, 64, or 128 mg/kg, 0.15M) or saline (NaCl, 0.15 M) followed 10 min later by either corticosterone (5 mg/kg) or β-cyclodextrin vehicle (45%) prior to placement in a distinctive context on four conditioning days (72 h apart) for 30 min. On the conditioning test day rats were placed in the distinctive context in a drug-free state and orofacial and somatic responses were video-recorded for 10 min. Gaping responses increased with increasing doses of LiCl in a linear fashion (P<0.01) but were not significantly influenced by the corticosterone treatment. In contrast, significant increases in the frequency of conditioned spontaneous orofacial behaviors on the drug free test day were produced by the corticosterone treatment during the acquisition phase, whereas LiCl treatment during acquisition had no significant effect on these behaviors. Thus, acute corticosterone did not alter the strength of conditioning of anticipatory nausea in rats.

Topics: Animals; Anticipation, Psychological; Behavior, Animal; Conditioning, Psychological; Corticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Face; Lithium Chloride; Male; Mouth; Movement; Nausea; Rats; Rats, Long-Evans

This study examined whether rats can simultaneously learn to associate lithium chloride (LiCl)-induced nausea with both contextual and intravascular taste cues. During the conditioning phase (4 days, 72h apart), 32 male Long Evans rats were injected intraperitoneally with either isotonic saline (NaCl), lithium chloride (LiCl, 127mg/kg), saline plus 2% saccharin (NaCl+Saccharin), or lithium chloride plus 2% saccharin (LiCl+Saccharin) immediately prior to a 30min exposure to a novel context. 72h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day. The next day, animals received a 24h 2-bottle preference test with a choice between water and a palatable saccharin solution. Results showed that animals treated with LiCl during conditioning, with or without saccharin, displayed significantly higher levels of conditioned gaping responses, indicative of nausea, upon re-exposure to the context, relative to NaCl and NaCl+Saccharin controls. Animals administered LiCl+Saccharin during conditioning also displayed significant conditioned taste avoidance to the saccharin solution during the two bottle choice test. These results indicate that systemic administration (intraperitoneal) of a LiCl+Saccharin solution is effective in simultaneously conditioning toxin elicited nausea to both internal (taste) and external (context) cues.

Topics: Animals; Anticipation, Psychological; Antimanic Agents; Avoidance Learning; Behavior, Animal; Conditioning, Classical; Cues; Disease Models, Animal; Lithium Chloride; Male; Nausea; Rats; Rats, Long-Evans; Saccharin; Sweetening Agents; Taste Perception

Cannabinoid CB(1) receptor antagonists/inverse agonists, potentiate toxin-induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB(1) receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.. The conditioned gaping model of nausea in rats was used to compare the CB(1) receptor antagonist/inverse agonist, AM251, and the CB(1) receptor neutral antagonists, AM6527 (centrally and peripherally active) and AM6545 (peripherally active), in potentiating conditioned gaping produced by lithium chloride (LiCl) solution. The effect of icv (lateral ventricle and 4th ventricle) administration of AM251 on LiCl-induced gaping in this model was also evaluated.. At a dose that did not produce conditioned gaping on its own, systemically administered AM251 (1.25 mg.kg(-1)) potentiated LiCl-induced conditioned gaping and reduced sucrose palatability; however, even doses as high as 8 mg.kg(-1) of AM6545 and AM6527 neither potentiated LiCl-induced conditioned gaping nor reduced sucrose palatability. Infusions of AM251 into the lateral ventricles (1.25, 12.5 and 125 microg) or the 4th ventricle (2.5, 12.5 and 125 microg) did not potentiate LiCl-induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.. Inverse agonism, but not neutral antagonism, of CB(1) receptors potentiated toxin-induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB(1) receptors, located distal to the cerebral ventricles.

Topics: Administration, Oral; Animals; Brain; Conditioning, Classical; Disease Models, Animal; Dose-Response Relationship, Drug; Feeding Behavior; Lithium Chloride; Male; Morpholines; Nausea; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Saccharin

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.

Topics: Animals; Association Learning; Conditioning, Psychological; Disease Models, Animal; Immune System Phenomena; Lipopolysaccharides; Lithium Chloride; Male; Memory; Memory Disorders; Nausea; Pons; Rats; Rats, Long-Evans; Vomiting, Anticipatory

The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats) was evaluated.. The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce conditioned gaping in rats and of the 5-HT(3) antagonists (ondansetron and palonosetron) and the 5-HT(1A) autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated.. In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0, 2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT(3) antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each of three sucrose-fluoxetine (20 mg/kg) or sucrose-lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated with the 5-HT(1A) autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose-fluoxetine (20 mg/kg) pairings.. After two sucrose-fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions. These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT(3) antagonists. On the other hand, palonosetron administered 2 h prior to sucrose-LiCl pairings attenuated conditioned gaping reactions.. These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT(3) antagonists, but not 5-HT(1A) autoreceptor agonists.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antiemetics; Autoreceptors; Conditioning, Psychological; Dose-Response Relationship, Drug; Fluoxetine; Isoquinolines; Lithium Chloride; Male; Nausea; Ondansetron; Palonosetron; Quinuclidines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT3 Receptor Antagonists

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.

Topics: Animals; Behavior, Animal; Conditioning, Classical; Cues; Data Interpretation, Statistical; Lithium Chloride; Male; Motion Sickness; Nausea; Odorants; Physical Stimulation; Rats; Rats, Sprague-Dawley; Rotation; Taste; Vestibule, Labyrinth; Vomiting, Anticipatory

Anticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined.. The potential of cannabidiol (CBD) and the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (URB) to reduce conditioned gaping in rats were evaluated.. In each experiment, rats received four conditioning trials in which they were injected with lithium chloride immediately before placement in a distinctive odor-laced context. During testing, in experiment 1, rats were injected with vehicle (VEH), 1, 5 or 10 mg/kg CBD 30 min before placement in the context previously paired with nausea and in experiment 2, rats were injected with VEH, 0.1 or 0.3 mg/kg URB 2 h before placement in the context. Additional groups evaluated the ability of the CB(1) antagonist/inverse agonist, SR141716A, to reverse the suppressive effects of URB. Experiment 3 measured the potential of URB to interfere with the establishment of conditioned gaping.. When administered before testing, CBD (1 and 5, but not 10 mg/kg) and URB (0.3, but not 0.1 mg/kg) suppressed conditioned gaping. The effect of URB was reversed by pre-treatment with the CB(1) antagonist/inverse agonist, SR141716A. When administered before conditioning, URB also interfered with the establishment of conditioned gaping.. Manipulations of the EC system may have therapeutic potential in the treatment of AN.

Topics: Amidohydrolases; Animals; Antiemetics; Antineoplastic Agents; Benzamides; Cannabidiol; Carbamates; Conditioning, Classical; Disease Models, Animal; Dose-Response Relationship, Drug; Lithium Chloride; Male; Nausea; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Vomiting, Anticipatory

When rats are intraorally exposed to saccharin solution that has previously been paired with lithium chloride (LiCl), they display Pavlovian conditioned disgust reactions. When exposed to LiCl-paired saccharin solution by bottle, they display suppressed instrumental approach to the bottle resulting in suppressed consumption. The present experiments demonstrated that while neither neurotoxin-induced lesions of the basolateral amygdala (BLA) nor the central nucleus of the amygdala (CeA) attenuated the display of Pavlovian conditioned disgust reactions, lesions of the BLA (but not the CeA) attenuated instrumental conditioned avoidance of the taste. The results are discussed in light of current models of the role of the amygdala in aversive learning.

Topics: Amygdala; Animals; Association Learning; Avoidance Learning; Conditioning, Classical; Excitatory Amino Acid Agonists; Flavoring Agents; Lithium Chloride; Male; Nausea; Rats; Rats, Sprague-Dawley; Taste

The endogenous cannabinoid system plays a vital role in the control of nausea and emesis. Because of the rapid breakdown and hydrolysis of endocannabinoids, such as anandamide, the therapeutic effects may be enhanced by prolonging their duration of action.. The present experiment evaluated the potential of various doses of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, alone and in combination with systemic administration of anandamide to modulate the establishment of lithium-induced conditioned taste reactivity responses in rats.. In experiment 1, on the conditioning day, rats first received an injection of 0.3 mg/kg URB597, 0.15 mg/kg URB597, or vehicle and then received a second injection of anandamide (5 mg/kg) or vehicle, before a 3-min exposure of 0.1% saccharin by intraoral infusion. Immediately after the saccharin exposure, the rats were injected with lithium chloride. On each of three test days, rats received a 3-min intraoral infusion of saccharin solution, and the taste reactivity responses were videotaped and monitored. In experiment 2, the effects of pretreatment with the CB(1) antagonist, AM-251, on URB597 and anandamide-induced suppressed aversion was evaluated.. Administration of URB597 alone and in combination with anandamide reduced active rejection reactions elicited by a LiCl-paired saccharin solution; both effects were reversed by pretreatment with AM-251, suggesting that they were CB(1) receptor mediated.. The results suggest that prolonging the action of anandamide by pretreatment with the FAAH inhibitor, URB597, suppresses lithium-induced nausea in the rat.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Association Learning; Avoidance Learning; Benzamides; Carbamates; Conditioning, Classical; Dose-Response Relationship, Drug; Endocannabinoids; Injections, Intraperitoneal; Lithium Chloride; Male; Nausea; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1; Vomiting

Through associative learning, cues for biologically significant reinforcers such as food may gain access to mental representations of those reinforcers. Here, we used devaluation procedures, behavioral assessment of hedonic taste-reactivity responses, and measurement of immediate-early gene (IEG) expression to show that a cue for food engages behavior and brain activity related to sensory and hedonic processing of that food. Rats first received a tone paired with intraoral infusion of sucrose. Then, in the absence of the tone, the value of sucrose was reduced (Devalue group) by pairing sucrose with lithium chloride (LiCl), or maintained (Maintain group) by presenting sucrose and LiCl unpaired. Finally, taste-reactivity responses to the tone were assessed in the absence of sucrose. Devalue rats showed high levels of aversive responses and minimal appetitive responses, whereas Maintain rats exhibited substantial appetitive responding but little aversive responding. Control rats that had not received tone-sucrose pairings did not display either class of behaviors. Devalue rats showed greater FOS expression than Maintain rats in several brain regions implicated in devaluation task performance and the display of aversive responses, including the basolateral amygdala, orbitofrontal cortex, gustatory cortex (GC), and the posterior accumbens shell (ACBs), whereas the opposite pattern was found in the anterior ACBs. Both Devalue and Maintain rats showed greater FOS expression than control rats in amygdala central nucleus, GC, and both subregions of ACBs. Thus, through associative learning, auditory cues for food gained access to neural processing in several brain regions importantly involved in the processing of taste memory information.

Topics: Acoustic Stimulation; Amygdala; Animals; Avoidance Learning; Brain Mapping; Conditioning, Operant; Cues; Feeding Behavior; Food Preferences; Frontal Lobe; Gene Expression Regulation; Genes, fos; Genes, Immediate-Early; Lithium Chloride; Male; Nausea; Nerve Tissue Proteins; Nucleus Accumbens; Pleasure-Pain Principle; Proto-Oncogene Proteins c-fos; Rats; Rats, Long-Evans; Reinforcement, Psychology; Sucrose; Taste

Chemotherapy patients report not only acute nausea and vomiting during the treatment itself, but also report anticipatory nausea and vomiting upon re-exposure to the cues associated with the treatment. We present a model of anticipatory nausea based on the emetic reactions of the Suncus murinus (musk shrew). Following three pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit conditioned retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with each of the principal cannabinoids found in marijuana, Delta(9)-tetrahydrocannabinol or cannabidiol, at a dose that did not suppress general activity. On the other hand, pretreatment with a dose of ondansetron (a 5-HT(3) antagonist) that interferes with acute vomiting in this species, did not suppress the expression of conditioned retching during re-exposure to the lithium-paired context. These results support anecdotal claims that marijuana, but not ondansetron, may suppress the expression of anticipatory nausea.

Topics: Analysis of Variance; Animals; Antiemetics; Association Learning; Cannabidiol; Cannabinoids; Conditioning, Classical; Disease Models, Animal; Dronabinol; Female; Lithium Chloride; Male; Nausea; Ondansetron; Serotonin Antagonists; Shrews; Vomiting, Anticipatory

In conditioned taste aversion (CTA), a subject learns to associate a novel taste (conditioned stimulus, CS) with visceral malaise (unconditioned stimulus, US). Considerable evidence indicates that the noradrenergic system in the amygdala plays an important role in memory consolidation for emotionally arousing experiences. The specific aim of the present set of experiments was to determine the involvement of noradrenergic activity in the basolateral amygdala (BLA) during the US presentation and consolidation of CTA as well as during the consolidation of a nonaversive/incidental gustatory memory. Selective bilateral microinfusions of the beta-adrenergic antagonist propranolol administered into the BLA immediately before intraperitoneal (i.p.) lithium chloride (LiCl) injections disrupted CTA memory. Additionally, propranolol infused into the BLA immediately after a pre-exposure to the saccharin (CS) significantly attenuated latent inhibition. The present findings indicating that alterations in noradrenergic function in the BLA affect taste memory formation, provide additional evidence that the BLA plays a critical role in modulating the consolidation of memory and that the influence is mediated by interactions with other brain regions that support memory for different kinds of experiences.

Topics: Adrenergic beta-Antagonists; Amygdala; Animals; Avoidance Learning; Conditioning, Classical; Lithium Chloride; Male; Memory; Nausea; Norepinephrine; Propranolol; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Saccharin; Sweetening Agents; Taste

Little is understood about effective countermeasures to the expression of anticipatory nausea and vomiting (ANV) in chemotherapy patients. We present a model of ANV based on the emetic reactions of the Suncus murinus (musk shrew). Following two pairings of a novel distinctive contextual cue with the emetic effects of an injection of lithium chloride, the context acquired the potential to elicit retching in the absence of the toxin. The expression of this conditioned retching reaction was completely suppressed by pretreatment with THC at a dose that did not suppress general activity. This provides the first experimental evidence in support of anecdotal reports that THC suppresses ANV.

Topics: Animals; Antimanic Agents; Conditioning, Psychological; Dronabinol; Lithium Chloride; Male; Models, Animal; Nausea; Psychotropic Drugs; Shrews; Vomiting, Anticipatory

Estradiol accelerates extinction of LiCl-induced conditioned taste aversions when it is present during a period that starts 2-3 days after acquisition and extends throughout extinction (before and during extinction). It has been suggested that estradiol acts before, not during, extinction and that its effect on extinction is associated with its illness-inducing properties. This hypothesis is based on previous work which shows an attenuation of conditioned taste aversion learning when rats are exposed to illness-inducing agents during a period that starts 2 days after acquisition and ends 2 days before extinction trials are initiated. Four experiments were designed to test elements of this hypothesis. The first two experiments demonstrated that if an estradiol-filled Silastic capsule is implanted before extinction of a LiCl-induced aversion, when the conditioned taste is not present, it accelerates extinction, but if it is implanted during extinction, when the conditioned taste is present, it prolongs extinction. The third experiment showed that the same dose of estradiol that accelerates extinction of a LiCl-induced aversion was effective in producing a conditioned taste aversion when it was present for 18 h after consumption of a novel sucrose solution. The fourth experiment indicated that serum levels of estradiol were elevated during the 18 h. These results are consistent with the hypothesis that the acceleration of extinction by estradiol is associated with its illness-inducing properties. It is suggested that estradiol acts on neural areas that mediate illness information and that one of these areas, the area postrema is necessary for estradiol to accelerate extinction of a LiCl-induced aversion.

Topics: Analysis of Variance; Animals; Apomorphine; Avoidance Learning; Brain; Conditioning, Classical; Drinking; Estradiol; Extinction, Psychological; Female; Lithium Chloride; Models, Psychological; Nausea; Ovariectomy; Rats; Rats, Inbred F344; Sucrose; Taste; Time Factors

To identify a neuron within the area postrema (AP) that participates in producing nausea, neural responses of the rat AP to noxious, excessive distension of the stomach were recorded electrophysiologically under urethane-chloralose anesthesia. There were two types of the neural responses; one is characterized by increasing the frequency of discharges responding to the stomach distension (excitatory type), while the other shows the opposite response (decreasing the frequency) to the same stimulation (inhibitory type). After this identification, the effect of LiCl or apomorphine superfused on the floor of IVth ventricle was examined to ascertain a convergence of afferents responding to chemical (LiCl or apomorphine) as well as mechanical noxious stimulation (stomach distension) on the same AP neuron. It was revealed that the rat AP involves multimodality neurons responsive to various emetic stimuli, so indicating their participation in producing nausea.

Topics: Animals; Apomorphine; Cerebral Ventricles; Electrophysiology; Injections, Intraventricular; Lithium Chloride; Male; Nausea; Physical Stimulation; Rats; Rats, Sprague-Dawley; Stimulation, Chemical; Stomach

Administration of lithium chloride and copper sulfate to adult monkeys caused marked elevations in plasma vasopressin (AVP) levels without significant increases in plasma oxytocin (OT) levels. Emesis was produced in five of the seven animals given these agents, in support of nausea as the main stimulus to AVP release. A similar pattern of AVP release without OT release was found after administration of cholecystokinin (CCK). Although most monkeys vomited in response to 10 micrograms/kg of CCK, a significant increase in plasma AVP levels also was produced with a dose of 1 microgram/kg, which did not produce emesis in any animal. These findings are in marked contrast with previous results in rats, which indicated that lithium chloride, copper sulfate, and CCK each stimulated OT rather than AVP release. Despite this interspecies difference, the significant neurohypophysial hormone secretion in response to both nausea-producing agents and CCK suggests that AVP secretion in monkeys, similar to OT secretion in rats, might reflect activation of central pathways mediating nausea and/or inhibition of food intake, even when overt illness is not produced.

Topics: Animals; Arginine Vasopressin; Chlorides; Cholecystokinin; Copper; Copper Sulfate; Haplorhini; Lithium; Lithium Chloride; Nausea; Oxytocin; Rats; Vomiting

Topics: Animals; Avoidance Learning; Brain; Chlorides; Conditioning, Classical; Copper; Copper Sulfate; Lithium; Lithium Chloride; Nausea; Neurotransmitter Agents; Psychotropic Drugs; Rats; Receptors, Cholinergic; Receptors, Serotonin; Synaptic Transmission; Taste; Vomiting

In rats, the conditioned place and taste aversions produced by 31.8 mg/kg lithium chloride were compared with those produced by 10 mg/kg gallamine in Experiment 1 and 20 mg/kg or 2.5 mg/kg naloxone in Experiments 2 and 3, respectively. Lithium produced stronger taste aversions than gallamine or the two doses of naloxone, but gallamine and naloxone each produced stronger place aversions than lithium. These findings support the distinction between two kinds of drug-induced aversive effects, having different associative properties. One effect, called sickness, is more associable with taste than with place cues; the second effect is, like pain, more associable with place than with taste.

Topics: Animals; Association; Avoidance Learning; Chlorides; Gallamine Triethiodide; Lithium; Lithium Chloride; Male; Naloxone; Nausea; Pain; Rats; Rats, Inbred Strains; Spatial Behavior; Taste

The present series of studies was undertaken to investigate the hypothesis (von F. Steiniger, 1950, Zeitschrift für Tierpsychologie, 7, 356-379; K. A. Stierhoff, & M. Lavin, 1982, Behavioral and Neural Biology, 34, 180-189) that rats poisoned after eating a novel food will mark that novel food in such a way as to dissuade naive conspecifics from ingesting it. Our results provided no evidence of aversive marking of a novel food by rats poisoned after ingesting it. We did, however, find evidence of attractive marking of feeding sites by rats exploiting those sites. This attractive marking rendered exploited feeding sites more attractive to naive conspecifics than other portions of an enclosure that rats had visited. The present findings are consistent with the results of a number of experiments conducted in our laboratory over the last decade indicating that rats directly communicate learned food preferences, but not learned food aversions.

Topics: Animals; Chlorides; Discrimination Learning; Feeding Behavior; Lithium; Lithium Chloride; Nausea; Rats; Rats, Inbred Strains; Social Behavior

Two antiemetic drugs were tested on the expression of taste aversions previously conditioned in rats with lithium, amphetamine or morphine. Neither prochlorperazine nor scopolamine administered prior to testing attenuated established aversions, although both drugs are known to have antiemetic effects in other species. Negative findings were obtained with a range of dose of prochlorperazine and scopolamine, with strong and weak aversions, with one- and two-stimulus tests, in a repeated one-stimulus extinction procedure, with between- and within-group designs and with hooded, albino, male and female rats. The results do not support the widely accepted hypothesis that conditioned nausea mediates conditioned taste aversion.

Topics: Amphetamine; Animals; Avoidance Learning; Chlorides; Conditioning, Classical; Drinking; Extinction, Psychological; Female; Lithium; Lithium Chloride; Male; Morphine; Muridae; Nausea; Prochlorperazine; Scopolamine; Taste