Effect of pairings of pentobarbital with lithium chloride on the capacity of pentobarbital to maintain a conditioned aversion

Rats with conditioned aversions to NaCl water were exposed to either an injection of pentobarbital (Pent) followed 30 min later by an injection of lithium chloride (LiCl) on four separate occasions or to injections of LiCl alone, Pent alone, or LiCl followed by Pent. These injections were followed by pairings of NaCl consumption with injections of Pent. The Pent leads to LiCl pairings eliminated the capacity of Pent to maintain the animals' conditioned aversion to NaCl water relative to the other groups. These findings are consistent with the idea that Pent leads to LiCl pairings cause the Pent state to elicit a compensatory response. This compensatory response seems to eliminate the properties of Pent which normally produce or maintain flavor aversions.     

Long-delay associations between drug states produced in rats by injecting two drugs in sequence

Injection of pentobarbital after a rat has consumed saccharin solution usually produces a mild aversion to the saccharin. However, the pentobarbital-produced aversion is eliminated or attenuated by prior pairings of pentobarbital injections with lithium injections. This is called the Avfail (aversion failure) effect. The present experiments dealt with the effect of the temporal relation of the pentobarbital injection to the lithium injection. After forward pairings (pentobarbital before lithium) with delays between the two injections varying among groups from 2.5 min to 320 min, Avfail was invariably obtained. There was little effect of the length of the forward delay, although the Avfail effect appeared to be slightly stronger at 30-40 min or so. When the two drugs were injected simultaneously or in a backward sequence, there was a weakening of the flavor aversion produced by pentobarbital, but this is attributable to habituation to the drugs, not to Avfail.     

Pavlovian conditioning with ethanol and lithium: effects on heart rate and taste aversion in rats

Rats received paired injections of either ethanol or saline as the conditioned stimulus and lithium chloride as the unconditioned stimulus (US) in a Pavlovian differential conditioning paradigm. Lithium chloride evoked a large deceleration in heart rate (80-100 beats per minute) as an unconditioned response. As a result of 10 conditioning trials, the substance paired with LiCl elicited a lower average heart rate than that elicited by the unpaired substance. Moreover, animals that received ethanol-LiCl injections subsequently were more averse to the taste of ethanol than animals receiving saline-LiCl pairings. However, there were no differences in ethanol's ability to serve as the US to induce an aversion to a novel flavor solution (i.e., the Avfail phenomenon was not observed). The overall pattern of results underscores the value of using multiple indexes of learning in drug-drug conditioning paradigms.     

Effects of preexposure flavor concentration on conditioned aversion and neophobia

In Experiment 1, 128 experimentally naive, water-deprived rats (Rattus norvegicus) received pretraining access to either 0.25 or 1.5% saccharin, distilled water, or 2.0% saline, followed either by a pairing of 0.25 or 1.5% saccharin with an intraperitoneal injection of 0.15 M lithium chloride (LiCl) or by a pairing of distilled water with LiCl. Preexposure to either saccharin concentration reliably reduced conditioned aversion effects to 0.25% saccharin, relative to that for preexposure to distilled water or saline. But only preexposure to 1.5% saccharin reduced aversion effects to that concentration. In Experiment 2, 48 naive, water-deprived rats received preexposure procedures as in Experiment 1. Afterwards, the rats were tested for neophobia to 0.25 or 1.5% saccharin. Neophobia was reliably greater to the 1.5% concentration. However, preexposure to either saccharin concentration obliterated evidence for neophobia to saccharin, relative to that following preexposure to distilled water or saline.     

Conditioned Inhibition Produced by Extinction of a Conditioned Stimulus

Four experiments used a conditioned taste aversion procedure to examine the potential for CS-alone extinction treatment to produce a conditioned stimulus that possesses inhibitory properties. In Experiment 1, saccharin was paired with LiCl, and then saccharin was presented alone for several trials to produce extensive behavioral extinction. Animals receiving this treatment were retarded in reacquiring conditioned responding to saccharin relative to control subjects receiving conditioning to the flavor for the first time. In Experiment 2, the extinguished saccharin stimulus was shown to decrease conditioned responding to a known excitor when the two stimuli were presented in compound as a summation test. Experiments 3A and 3B replicated the findings of Experiments 1 and 2 while providing evidence that the effects were not due to the differential effects of neophobia during testing. These three experiments revealed that an extinguished conditioned excitor passes retardation and summation tests for conditioned inhibition. Experiment 4 found that extinction of a known excitor was slowed when the excitor was extinguished in compound with a previously extinguished conditioned stimulus. That is, an extinguished CS provided protection from extinction to another CS, a finding also consistent with the view that extinction produces conditioned inhibition.     

An extended comparator hypothesis account of superconditioning

Three conditioned taste aversion experiments with rats investigated superconditioning. In each experiment, alternate exposures of 2 flavor compounds with a common element (i.e., AB/AS) were administered to establish an inhibitory relationship between the 2 unique elements, B and S, and prior to testing, S was paired with lithium chloride (LiCl). In Experiment 1, pairings of a neutral cue (X) with S in compound with B after the AB/AS exposures resulted in superconditioning between X and S. Extinction of the common element (A) just before the S-LiCl pairing attenuated both the inhibitory relationship between B and S (Experiment 2) and superconditioning between X and S (Experiment 3). These observations suggest that superconditioning consists of enhanced performance rather than enhanced associative acquisition.     

Characterization of a dose-response curve for nicotine-induced conditioned taste aversion in rats: relationship to elevation of plasma beta-endorphin concentration

In the first experiment a conditioned taste aversion paradigm was used to characterize a dose-response curve for the aversive properties of nicotine in male Sprague-Dawley rats. Doses of nicotine ranging from 0.01 to 0.46 mg/kg, 2.0 ml of 0.47 M lithium chloride, or saline were injected, ip, 10 min after exposure to a novel saccharin solution. Amount of saccharin consumed in a two-bottle test was assessed 72 h later. Nicotine doses of 0.046 mg/kg and above produced a significant degree of conditioned taste aversion. In a second experiment, four groups of 10 rats each were injected with saline, 0.022 mg/kg nicotine, 0.46 mg/kg nicotine, or 2.0 ml 0.47 of M LiCl. Doses of 0.46 mg/kg nicotine and 0.47 M LiCl elevated plasma beta-endorphin concentrations significantly above saline control values. The 0.022 mg/kg dose, the highest dose that did not produce conditioned taste aversion in Experiment 1, did not significantly increase plasma beta-endorphin concentrations. This finding suggests that doses of nicotine that produce conditioned taste aversion also promote the release of pituitary stress hormones. Taken together these data suggest that some of the pharmacological and behavioral effects attributed to nicotine, including the release of endogenous neuromodulators, may be dose-dependent concomitants of the aversive effects of nicotine in nicotine-naive animals.     

Aversion conditioning and enhanced neophobia: role of test stimuli

In Experiment 1, 100 rats (Rattus norvegicus) received 10% sucrose or 5% casein hydrolysate followed, after 10 min, by a LiCl or saline injection or, after 12 h, by a LiCl injection. Subsequently, rats received aversion testing to the CS or neophobia testing to the opposite novel flavor. Aversion effects were reliably greater to casein than to sucrose. However, conditioning with sucrose yielded a reliably greater increase in neophobia to casein (relative to controls) than conditioning with casein yielded to sucrose. In Experiment 2, 60 rats received distilled water followed, after 10 min, by LiCl or saline injection or, after 12 h, by LiCl injection. Aversion effects occurred to distilled water. Neophobia testing to casein and sucrose showed that, relative to controls, neophobia increased reliably more to casein. The results of Experiments 1 and 2 were not attributable to differences in baseline intakes between casein and sucrose flavors. Together, these experiments indicated that the demonstration of conditioning-enhanced neophobia may depend more on the characteristics of the neophobia test flavor than on the strength of aversion established because of CS characteristics.     

The influence of context and UCS intensity on the UCS preexposure effect in a flavor aversion paradigm

Three studies were conducted to evaluate the influence of environmental context and UCS preexposure intensity on the acquisition of a flavor aversion. In the first study, rats were exposed to two UCS-alone presentations at one of three dose levels of LiCl. The rats were given the two UCS preexposures in one of two contexts (familiar or novel). Following the UCS-alone treatment, all of the subjects received two pairings of sucrose and LiCl (1.25 meq) in the familiar context. Animals receiving UCS preexposures in the same context as used during conditioning consumed significantly more sucrose than did saline control animals. In contrast, the influence of prior UCS preexposure was not evident when UCS preexposure was experienced in a context different from that experienced during conditioning. In Experiment 2, all animal received UCS preexposure and conditioning in the novel room. Animals received either two or four preexposures at 0, 1.25, or 3.75 meq dose of LiCl. Two UCS preexposures at 3.75 meq dose produced a stronger UCS preexposure effect than did the 1.25 meq dose. Animals in Experiment 3 received two exposures to either 0-, 1.25-, or 3.75-meq LiCl in one of two contexts, followed by conditioning with the 1.25-meq LiCl dose in the same context as preexposure. Greater UCS interference occurred in animals preexposed to LiCl in the novel rather than familiar environment, with no specific dose effects in either context. These observations are discussed in terms of context blocking and generalization decrement models of the UCS preexposure effect.     

Taste aversion after ingestion of lithium chloride: An associative analysis

In five experiments with rats we examined the aversion established by consumption of a solution of lithium chloride (LiCl). Experiment 1 showed that consumption of LiCl established an aversion to saline (NaCl). Experiment 2 showed that the size of the aversion was reduced in rats given pre-exposure to saline (a latent inhibition effect). Experiment 3 showed that experience of a sucrose-saline compound prior to consumption of LiCl generated an aversion to sucrose (a sensory preconditioning effect). Experiments 4 and 5 examined the effects produced by consumption of a sucrose-LiCl compound and demonstrated reciprocal overshadowing between the two tastes. These results confirm that consumption of LiCl establishes an aversion to the taste of this substance. Their implications for the use of orally consumed LiCl as a technique for the control of predatory behaviour are discussed.     

Conditioned taste aversion is enhanced when the unconditioned stimulus is presented in a different context

Using a conditioned taste aversion procedure with rats as the subjects, two experiments examined the effect of presenting a conditioned stimulus (CS saccharin solution) in one context followed by an unconditioned stimulus (US LiCl) in a different context. Experiment 1 showed that animals which received the above-mentioned procedure (Group D) showed a more marked conditioned aversion to the CS than animals which were given both the CS and the US in the same context (Group S). Experiment 2 found that in both Group D and Group S, aversion to the CS increased when the subjects were exposed to the conditioned context after the conditioning. These findings supported the argument that the strength of the CS-US association acquired during conditioning is compared with that of the context-US to determine the magnitude of aversion revealed to the CS.     

Representation-mediated extinction of conditioned flavor aversions

Conditioned flavor aversions were extinguished by presenting without consequence auditory stimuli that had been previously paired with the aversive flavor. In Experiment 1, rats that received tone-sucrose pairings, then sucrose-lithium chloride (LiCl) pairings, and finally repeated tone-alone presentations showed greater sucrose consumption in subsequent testing than rats that received similar sucrose-LiCl pairings and tone-alone presentations but no initial tone-sucrose pairings. Experiment 2 demonstrated the stimulus specificity of the mediated extinction observed in Experiment 1. In Experiment 3, rats that received first-order light-food and second-order tone-light pairings prior to sucrose-LiCl pairings did not show greater subsequent sucrose consumption when extinction of the second-order tone intervened. These results suggest that conditioned stimulus (CS)-evoked representations of events can substitute for those events themselves in the extinction of previously established associations.     

Flavor preexposures in a conditioned taste aversion situation: a dissociation of behavioral and endocrine effects in rats

A series of experiments examined the effects of flavor preexposures on pituitary-adrenal/behavior relations in a conditioned taste aversion paradigm. It was found that reexposure to a novel milk solution paired earlier with lithium chloride (LiCl) elicited conditioned activation of the pituitary-adrenal system (Experiment 1). The unconditioned response to LiCl (measured by changes in plasma levels of corticosterone) did not vary as a function of prior (2 and 5 vs. 10) exposures to the milk solution (Experiment 2). Increased familiarity with the substance (resulting from 10 prior exposures) rendered the conditioning of a taste aversion to this substance less effective. Further, reexposure to this familiar substance after its pairing with LiCl was not accompanied by the characteristic conditioned pituitary-adrenal activation (Experiment 3). By titrating the number of conditioned stimulus (CS) preexposures (Experiment 4) it was found that within the range of preexposures manipulated (5-10), subjects exhibited (a) a coupling of behavioral and pituitary-adrenocortical responses when the conditioned taste aversion to the milk solution was paralleled by elevated plasma corticosterone (5-6 preexposures), (b) a coupling of these two response systems when flavor consumption was accompanied by suppressed plasma titers of corticoids (9-10 preexposures), or (c) a dissociation of the two system when the conditioned taste aversion was not accompanied by conditioned adrenocortical activity (7-8 preexposures). These data are discussed in terms of a dissociation in the effects of CS preexposures on conditioned adrenocortical and behavioral response systems.     

Odor-aversion learning and retention span in neonatal mouse pups

One hundred and sixty-four litters of Swiss CD-1 random-bred mice were used to assess learning and retention capacities during the first postnatal week. In Experiment 1, whole 7-day litters were exposed for 65 min to commercial extracts of either mint or lemon sprinkled over wood shavings. Five minutes after the beginning of the exposure, half of the litters were injected ip with the illness-inducing agent lithium chloride (LiCl; 0.20 M, 2% of body weight); the other half was treated with saline solution (8% NaCl). On Postnatal Day 10, the animals were singly introduced in a warmed arena for a 180-s preference test, and the time spent in the mint- and lemon-scented areas of the apparatus was recorded. When compared with saline-injected pups, mice that experienced lemon-LiCl pairings showed a significant aversion for the lemon-scented area, while the mint aversion in the mint-LiCl group just missed statistical significance. Three additional control groups (unhandled on Day 7, or only LiCl- or saline-injected) did not show significant preferences for either the mint or the lemon odor. In Experiment 2, litters of 3, 5, or 7 days were similarly exposed to lemon-scented shavings for either 5 or 20 min, injected with LiCl or saline, and then exposed for an additional 60 min to the shavings. On Postnatal Day 10, tests like those of Experiment 1 showed a significant odor-aversion in animals conditioned on Day 7, but not in those conditioned on Day 3 or 5. In Experiment 3, 3- and 5-day old pups were exposed to lemon odor-LiCl or -NaCl pairings, and tested for aversion after 3 or 7 days (CS duration 5 min before injection and either 30 or 60 min after injection). Only when the conditioning-testing interval was limited to 3 days did LiCl-injected groups show a significant aversion, which did not depend on duration of CS exposure.     

Blocking of a taste aversion by prior pairings of exteroceptive stimuli with illness

Although rats preferentially associate gustatory stimuli with illness, this does not imply that other types of stimuli cannot be associated with illness. In Experiment 1, rats consuming tap water in a distinctive environment prior to illness subsequently suppressed ingestion in that environment, whereas rats poisoned or injected with saline 10 hr later did not. It was also found that rats poisoned after drinking saccharin in the environment paired with illness developed weaker saccharin aversions than identically trained rats which drank saccharin in a different location. In Experiment 2, degrading the correlation between injection-related cues and illness by interpolating saline injections between LiCl preexposures attenuated the decremental effects of illness preexposure. The strength of the exteroceptive cue-illness associations observed in these studies suggests that theories based on evolutionary arguments are not the most appropriate frame of reference for analyzing stimulus selection in poison-induced avoidance.     

Acquisition of representation-mediated conditioned food aversions

Food aversions were established in rats by administering lithium chloride (LiCl) immediately after the presentation of an exteroceptive conditioned stimulus (CS) which previously had been paired with a food substance. In Experiment 1, rats which received first tone-food and then tone-LiCl pairings showed less food consumption in subsequent testing than rats which received only tone-food or tone-LiCl pairings. Experiments 2 and 3 demonstrated the stimulus specificity of aversions established in this manner. Rats which first received pairings of light and tone CSs with two different food substances and then received pairings of one of those CSs with LiCl showed greater aversion to the food previously associated with the LiCl-paired CS than to the other food substance. Experiment 3 also showed that specific aversions were not acquired if rats received CS-shock rather than CS-LiCl pairings. These results suggest that CS-evoked representations of events can substitute for those events themselves in the formation of new associations.     

Low body temperature,time dilation,and long-trace conditioned flavor aversion in rats

Conditioned flavor aversion was examined in Wistar-derived albino rats that were immersed in cold water for 0, 2.5, 5, or 10 min immediately following 10-min exposure to a.1% saccharin solution and given an intraperitoneal (i.p.) injection of 0.15 M lithium chloride (LiCl) either 90, 135, 180, or 225 min later. Cold water immersion for 2.5, 5, and 10 min led to body temperature decreases of approximately 4.5, 7, and 10 degrees C, respectively. Rats whose body temperatures were not reduced (0 min immersion) showed no saccharin aversion when the LiCl was delayed 90 min. Rats whose body temperatures were reduced 4.5, 7, and 10 degrees C displayed conditioned aversions at LiCl delays up to 135, 180, and 225 min, respectively. These results were interpreted in terms of a cold-induced slowing of a biochemical clock that may uniquely govern specific timing processes involved in associative learning over long delays, such as long-trace conditioned flavor aversion, learned safety, and certain types of learning that involve an extensive time lapse (e.g., extinction of fear).     

Nonconsummatory and consummatory behavioral CRs elicited by lithium- and amphetamine-paired flavors

Various behavioral CRs elicited by saccharin solution previously paired with either lithium or amphetamine were measured in a series of four experiments. With one conditioning trial, lithium (Experiment 1), but not amphetamine (Experiment 2), produced nonconsummatory behavioral evidence of conditioning in the form of chin-rub CRs; both drugs, however, produced strong flavor aversions. With 3 conditioning trials, lithium- and amphetamine-paired flavors elicited a pattern of agitated activity, characterized by increased general activity, rearing duration, and body temperature, when the flavor was forcibly presented through an intraoral cannula (Experiment 3). When the flavor was presented in a single-bottle test (Experiment 4), 3 conditioning trials produced a similar pattern of agitated activity characterized by increased general activity, rearing (duration and frequency), stretching (duration and frequency), and limb flicking. Although both drugs supported the pattern of increased agitation-related CRs, only the lithium-paired flavors elicited chin-rub CRs (Experiments 1, 3, and 4). The difference between the drug conditions was not the result of a greater saccharin aversion in the lithium-conditioned group than in the amphetamine-conditioned group (Experiment 4). The results are related to findings that suggest that flavor aversions are mediated by a shift in the hedonic properties of the drug-paired flavors.     

Amnesia produced by anisomycin in an appetitive task is not due to conditioned aversion

Two experiments investigated the effects of lithium chloride (LiCl) and anisomycin (ANI) in a water reward Y-maze task. In Experiment 1, male CD-1 mice given weak or strong training were injected post-training with either saline or LiCl (150 mg/kg), which has been reported to produce conditioned aversion in mice. One day after training, both LiCl groups avoided the rewarded arm of the maze and drank less water than saline-injected controls. Two days after training, the strongly trained LiCl mice showed avoidance, while both LiCl groups drank less water. In Experiment 2, weakly trained mice given pre- and post-training ANI (30 mg/kg) were amnesic on the second test day compared to mice that received post-trial saline. However, water consumption was increased on the test day for both groups. LiCl produced a different pattern of results than ANI in this task. On the basis of these results, it is suggested that amnesia produced by ANI is due to impaired memory formation and not to conditioned aversion.     

Taste Aversion Learning Based on Swimming and Lithium Chloride Injection in Rats: Implications From Cross-familiarization Tests and Stimulus Selectivity1

In rats, swimming causes avoidance of the taste solution consumed immediately before the swimming. Several lines of research have shown that this taste avoidance reflects Pavlovian conditioned aversion based on correlations between the taste and swimming-induced nausea. The present research compared swimming-based taste aversion learning (TAL) with conventional TAL based on nausea-inducing lithium chloride (LiCl). By exploiting cross-familiarization techniques, Experiments 1A and 1B suggested that different physiological states are induced by swimming and LiCl. This claim was supported by Experiment 2, which reports stimulus selectivity in saccharin and sucrose aversions based on swimming and LiCl.