The present study examined the multi-variable locomotor activity effects of lithium chloride (LiCl) treatment in male rats. Of interest was a determination of which variables might show a ...dose–response relationship in LiCl-induced conditioned place aversions. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. A control group n=8 received saline (NaCl; 0.15 M) paired with both chambers while three LiCl groups (0.15 M; 32 mg/kg n=7, 95 mg/kg n=7, 127 mg/kg n=7) received LiCl paired with the normally preferred chamber and saline paired with the non-preferred chamber. During extinction trials, rats were allowed to choose between the two chambers to provide an index of conditioned place aversions. Locomotor activity and its distribution within the chambers were also assessed during both conditioning and extinction trials. Dose-dependent decreases occurred in all measures of locomotor activity following LiCl administration during conditioning. During extinction trials, place aversions developed in animals conditioned with LiCl. LiCl-treated rats spent significantly less time in the LiCl-paired chamber relative to controls but not in a dose-dependent manner. Animals that had been conditioned with 95 or 127 but not 32 mg/kg LiCl, displayed significantly more vertical activity in the LiCl-paired chamber than controls during extinction trials. These findings indicate that, in addition to producing dose-dependent unconditioned effects on locomotor activity, LiCl also produces dose-dependent conditioned effects on vertical activity. These conditioned rearing response effects provide a valid measure of the conditioned avoidance response that provides evidence for dose-dependent LiCl-induced conditioned place aversions.
BACKGROUND AND PURPOSE Cannabinoid CB1 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 CB1 receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.
EXPERIMENTAL APPROACH The conditioned gaping model of nausea in rats was used to compare the CB1 receptor antagonist/inverse agonist, AM251, and the CB1 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.
KEY RESULTS 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 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl‐induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.
CONCLUSIONS AND IMPLICATIONS Inverse agonism, but not neutral antagonism, of CB1 receptors potentiated toxin‐induced nausea. This effect may be peripherally mediated or may be mediated centrally by action on CB1 receptors, located distal to the cerebral ventricles.
► Propionic acid is produced by colonic bacteria and suggested to play a role in satiety and obesity. ► Systemic (intraperitoneal) propionic acid conditions a taste avoidance. ► Systemic propionic ...acid conditions a place avoidance. ► Systemic propionic acid induces aversive internal cues and may activate the poison defence system.
Propionic acid, an enteric bacterial fermentation product, has received recent attention in regards to satiety and obesity in humans. The possibility that propionic acid might produce internal aversive cues was investigated in two experiments using conditioned taste avoidance and place avoidance procedures to index the potential aversive nature of systemic treatment with propionic acid in male rats. Experiment 1 examined the effect of systemic treatment with propionic acid (500
mg/kg), LiCl (95
mg/kg) or vehicle (all corrected to pH 7.5) on the formation of conditioned taste avoidance using a lickometer procedure. On 3 acquisition days three groups of rats were injected with propionic acid, LiCl or vehicle, following 30
min access to 0.3
M sucrose solution. Both the Propionic acid group and the LiCl group evidenced a conditioned taste avoidance by the end of the acquisition period. During a drug free extinction phase the Propionic acid group showed extinction of the taste avoidance whereas the LiCl group did not. Experiment 2 involved place preference conditioning with propionic acid treatment associated with one novel context and vehicle with a different novel context on 6 conditioning trials for each type of injection. Place avoidance was assessed on two drug free extinction trials. Multi-variable assessment of the unconditioned (Acquisition Trials) and conditioned effects (Extinction Trials) of propionic acid on locomotor activity was quantified as was chamber choice time on the extinction trials. Propionic acid induced a significant place avoidance and significantly reduced locomotor activity on some acquisition trials. During the extinction trials rats exhibited enhanced locomotor activity levels in the propionic acid associated chamber, likely due to the conditioned aversive nature of this chamber.
BACKGROUND AND PURPOSE
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.
EXPERIMENTAL APPROACH
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.
KEY RESULTS
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 µg) or the 4th ventricle (2.5, 12.5 and 125 µg) did not potentiate LiCl‐induced conditioned gaping reactions, but all doses attenuated saccharin palatability during the subsequent test.
CONCLUSIONS AND IMPLICATIONS
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.
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.
Administration of bacterial agents, such as muramyl dipeptide (MDP) or lipopolysaccharide (LPS), induces a number of illness symptoms including decreased locomotor activity and weight loss. This ...study provides a detailed multivariate assessment of the effects of repeated exposures of various doses of MDP and LPS, alone and in combination, on various aspects of locomotion in male and female rats. Animals were given a single intraperitoneal injection of either MDP (0.8 or 1.6 mg/kg), LPS (100 or 200 μg/kg), a combination of MDP and LPS (0.8 mg/kg and 100 μg/kg, respectively), or vehicle on Days 1, 4, and 7. Two hours after each injection, locomotor activity was recorded for 30 min in an automated open-field. Both doses of LPS and the high dose of MDP produced significant decrements in locomotor activity in male and female rats, with tolerance becoming evident over repeated administrations, although LPS decreased activity more robustly than MDP. Sex differences were evident in the combined effects of MDP and LPS. Together, MDP and LPS reduced male activity levels in an additive manner but significantly potentiated both horizontal and vertical activity decrements in females. In addition, the rate of behavioral tolerance development to repeated bacterial injections was significantly higher in females than in males. These findings provide evidence for sex differences in the actions of MDP and LPS on various aspects of locomotor activity and in the development of behavioral tolerance to infection.
Sex differences in rats' performance on a stationary hidden-platform task (spatial task) in the Morris water maze and the effects of initial nonstationary hidden platform training (NSP training) were ...examined. The NSP training was designed to familiarize rats with the general requirements of the water-maze task without providing spatial information. NSP training led to faster acquisition and improved retention of the subsequent spatial task in both males and females. There was a sex difference favoring males on acquisition and retention of the spatial task only in rats that had not received previous NSP training. Moreover, there was an apparent reversed sex difference favoring females on some measures of spatial performance in NSP-trained rats. These results suggest that performance on the water-maze task, including the expression of sex differences, can be altered by previous familiarization with nonspatial aspects of the task.
The relations between the estrous cycle, inflammatory responses and the development of tolerance to endotoxin were examined. Female Long-Evans rats were injected intraperitoneally with ...lipopolysaccharide (LPS; 200
μg/kg) or saline vehicle at 08:00
h on either diestrus (D) or proestrus (P). Ninety‐five minutes after injection locomotor activity was assessed in an automated non-novel open-field for 20
min. To assess tolerance development to LPS, rats were re-injected at the next identical stage (i.e. 4 days later; groups: DD, PP) or at the alternate stage (i.e. 6 days later; groups: DP, PD) of the estrous cycle and locomotor activity was again assessed. On Test Day 1 all groups injected with LPS exhibited similar significant activity decrements, regardless of the stage of the estrous cycle. However, on Test Day 2 rats which received both injections of LPS during proestrus (PP) showed no signs of tolerance development, whereas rats in all other groups were tolerant to LPS. In a follow up study, the time between injections was extended to 8 days. Still the animals injected both times at proestrus showed no signs of tolerance to LPS after the second injection. Thus, the stages of the estrous cycle both at the time of initial exposure and of re-exposure appear critical in the formation of behavioral tolerance to LPS in rats.
Acute administration of corticosterone (CORT) facilitates learning in a number of associative paradigms including lithium chloride (LiCl)-induced conditioned taste aversion learning. The present ...study examined the effects of acute CORT on LiCl-induced conditioned place aversions in male rats. Automated open-fields were partitioned into two chambers distinct in tactile and visual cues. Animals received either LiCl (64 mg/kg, 0.15 M) or saline (NaCl, 0.15 M) followed 10 min later by either CORT (5 mg/kg) or β-cyclodextrin vehicle (45%) prior to placement in one of the chambers. Control rats received NaCl-Vehicle paired with both chambers. Three experimental groups received either NaCl-CORT, LiCl-Vehicle or LiCl-CORT paired with the preferred chamber and NaCl-Vehicle (control) paired with the non-preferred chamber. During extinction trials, animals were allowed to choose between the two chambers. Locomotor activity and its distribution within the chambers were assessed during both conditioning and extinction trials. CORT administration produced significant increases in a variety of measures of locomotor activity during conditioning trials. During extinction trials both LiCl groups displayed a conditioned place aversion while the NaCl-CORT group did not. In addition, significant increases in vertical activity were recorded in both LiCl groups in the LiCl-paired chamber. Moreover, CORT administration had no effect on LiCl-induced conditioned place aversion as time spent in the LiCl-paired chamber did not significantly differ between LiCl-Vehicle and LiCl-CORT groups. Significant increases in a number of measures of horizontal activity were also observed in both CORT groups. The present study shows that acute CORT administration does not significantly influence LiCl-induced conditioned place aversions and suggests that the facilitatory effects of acute CORT administration on learning are highly context-dependent.
Sensitization of dopaminergic neural reward circuits has been hypothesized to be involved in the development of drug addiction. Highly palatable foods activate these same brain areas, specifically ...the nucleus accumbens. In this study, the effects of a highly palatable food (sucrose) on these circuits were investigated using the dopamine D
2/D
3 receptor agonist quinpirole. Male Long-Evans rats received 30
min daily access to 0.3
M sucrose solution or water over nine consecutive days, followed by nine daily injections of quinpirole (0.5
mg/kg, s.c.) or saline. Locomotor activity was assessed using an automated open-field system. Locomotor sensitization developed, as quinpirole-treated rats traveled significantly more, and exhibited a greater number of movements than saline controls. A characteristic pattern of an initial suppression of locomotor activity, followed by excitation of activity was observed in quinpirole-treated rats. Pre-exposure to sucrose attenuated the initial suppression of activity, and facilitated excitation of activity. Rats that were pre-exposed to sucrose exhibited a reduced suppression of activity as compared to rats pre-exposed to water. Rats receiving sucrose and quinpirole also displayed a significantly greater enhancement of locomotor activity as compared to rats receiving water and quinpirole. These results support the hypothesis that highly palatable foods can alter the same neural reward circuits as drugs of abuse, and may facilitate sensitization-related addiction. This may aid in further understanding the neural basis of eating disorders.
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