Effect of exposure to lithium-paired or amphetamine-paired saccharin solution on open arm avoidance in an elevated plus maze

Recent evidence suggests that drug-induced conditioned taste avoidance may be mediated by conditioned fear (e.g., Parker, 2003). The experiments reported here evaluated the effect of exposure to a drug-paired flavor on open arm exploration in an elevated plus maze (EPM), a measure of fear. When rats were tested on a familiar (trial 2) EPM, but not on a novel (trial 1) EPM, prior exposure to a lithium-paired saccharin solution enhanced open arm activity relative to saline-paired saccharin. On the other hand, when rats were exposed to lithium-paired saccharin during plus maze exposure, they displayed suppressed open arm activity relative to unpaired controls when tested in a familiar maze. The pattern of results was specific to the conditional affective properties of the taste, because exposure to unconditional sickness produced by administration of lithium, and unconditionally unpalatable quinine solution did not produce this pattern. These results were interpreted in terms of the opponent process model of motivation; that is, exposure to a lithium-paired flavor elicits conditioned fear which is immediately followed by conditioned relief when the exposure is terminated. On the other hand, exposure to an amphetamine-paired flavor either before or during EPM testing enhanced open arm exploration. Since the strength of taste avoidance did not differ among amphetamine and lithium conditioned rats, these results provide further evidence that the nature of a saccharin-lithium association differs from that of a saccharin-amphetamine association.     

Behavioral conditioned responses across multiple conditioning/testing trials elicited by lithium- and amphetamine-paired flavors

The present experiment measured the pattern of conditioned responses across 10 conditioning/testing trials which were elicited by an intraoral presentation of either a lithium- or an amphetamine-paired flavor. A nonspecific conditioned response pattern of suppressed limb flicking after five conditioning trials and of suppressed scratching after six conditioning trials was supported by both drugs. Lithium-specific increased activity level after one conditioning trial and chin rubbing after two conditioning trials were observed across conditioning/testing days. The lithium-specific conditioned responses were not the result of a stronger flavor aversion, because both lithium and amphetamine produced equivalent flavor avoidance responses across the 10 conditioning/testing trials. The results support previous research which suggests that flavor aversions produced by lithium and amphetamine are produced by different unconditioned response mechanisms.     

Associative interference with taste aversions after contextual discrimination learning

In two experiments, rats were first given discriminative training with two distinctive contexts, such that a flavor was paired with lithium chloride (LiCl) in one context, alternating with presentations of the flavor alone in another context. Contextual control of the fluid ingestion was observed in that rats reduced the fluid intake in the LiCl-paired context but drank the solution in the context never paired with lithium. Having learned this discrimination, the rats were now given a second flavor in their home cage before being injected with LiCl and transferred to the previously lithium-paired context. In Experiment 1, the acquisition of an aversion to the novel flavor was blocked when this flavor and the contextual cues are conditioned as a compound. In Experiment 2, the blocking effect and the conditional control over fluid consumption were abolished when the associative strength of the LiCl-paired context had been extinguished by exposing the animals to water in the contexts after discriminative training. These results are interpreted as evidence that context dependency of conditioned taste aversions is mediated by a summative effect of the context–LiCl and flavor–LiCl associations.     

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.     

Unconditioned stimulus devaluation effects in nutrient-conditioned flavor preferences

Experiments with different temporal relations between the conditioned stimulus (CS) and the unconditioned stimulus (US) in conditioning assessed whether US devaluation effects can be obtained after nutrient-conditioned flavor preference learning. One flavor (CScarb) was paired with a carbohydrate, Polycose; a 2nd flavor (CSprot) was paired with a protein, casein; and a 3rd flavor (CS-) was presented by itself. Following conditioning, one of the nutrients was devalued through pairings with lithium chloride in the absence of the CS flavors. In a subsequent 2-bottle test, rats preferred CScarb over CSprot; however, this preference was smaller when the carbohydrate was devalued than when the protein was devalued. Results suggest that CS flavors are able to form associations with the sensory features of nutrient USs under a wide variety of circumstances.     

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.     

Effects of hepatic denervation on the anorexic response to epinephrine, amphetamine, and lithium chloride: a behavioral identification of glucostatic afferents

Intraperitoneal injections of epinephrine (20, 40, 80, and 160 microgram/kg) and amphetamine (.1, .2, and .4 mg/kg) were administered to rats with various forms of hepatic denervation. In Experiment 1, destruction of the esophageal trunks of the vagus attenuated epinephrine and amphetamine anorexia, but destruction of the hepatic vagus did not. In Experiment 2, rats with celiac ganglionectomy, subdiaphragmatic vagotomy, or the combined operation all exhibited decreased epinephrine anorexia to the same extent. However, ganglionectomized rats were less responsive to amphetamine anorexia than were vagotomized ones. Vagotomized rats were significantly more reactive to lithium chloride (10, 20, and 30 mg/kg) than were controls. These results suggest that the major component of hepatic metabolic afferent fibers travels from the liver, through the celiac ganglion, and into the esophageal vagal trunks where they ascend to the brain. The anorexic action of amphetamine appears to result from a centrally induced sympathetic action on the liver.     

Developmental flavor experience affects utilization of odor, not taste in toxiphobic conditioning

Feeding experiences were varied in developing rats and the effects upon flavor neophobia and lithium chloride-induced flavor aversions were observed. In Experiment 1, nursing experience of neonate rats was reduced by artificial feeding via intragastric cannula; the rats then were tested with apple juice paired with lithium chloride injection at weaning or maturity. Conditioned aversions were not affected, but neophobia to novel apple juice was attenuated in artificially-reared rats tested at maturity. In Experiment 2, rats received enriched feeding experience after weaning, which consisted of (a) obtaining many complex flavors, a few of which were paired with poisoning, effortlessly in the home cage, or (b) foraging for various foods on an elevated maze. No dramatic effects on neophobia or conditioned taste aversion for saccharin water were apparent. In Experiment 3, rats were given experience after weaning with vanilla-scented water either paired or unpaired with quinine water, and then tested with the odor of almond or that odor compounded with saccharin water for neophobia and lithium-induced aversions. Flavor-experienced rats exhibited more pronounced odor conditioning and more resistance to extinction of the odor aversion after both simple and compound conditioning. In contrast, saccharin taste aversions were relatively unchanged. Apparently, enriched feeding and drinking experience facilitates the utilization of odor more than taste cues.     

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.     

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.     

Effects of flavor salience on aversion performance following relatively long-delay backward conditioning procedures

Male albino rats (n = 144) received a 0.15 M injection of lithium chloride (at 2.0% body wt), followed 10, 30, or 75 min later by a 5.0% casein CS or a 10.0% sucrose CS, casein being the more salient CS. For each CS one-third of the rats received no fluid during the toxin-CS interval. The remaining two-thirds of the rats received 2-min access to distilled water or to a novel flavor 5 min after onset of the toxin-CS interval. For sucrose CS groups, the novel flavor was casein; for casein CS groups, the novel flavor was sucrose. Groups which received no fluid during the toxin-CS interval showed reliably greater aversion effects to the casein CS than to the sucrose CS. Results of Test Trial 1 showed that aversion to casein was relatively unchanged across toxin-CS intervals, while aversion to sucrose decreased reliably from the 10-min to the 30- and 75-min intervals. However, for each toxin-CS interval, aversion to the sucrose CS was reliably enhanced when casein access occurred in the interval, relative to that for distilled water or no fluid access. For the casein CS, access to sucrose or distilled water in the toxin-CS interval altered aversion effects, relative to the no fluid condition, depending on the interval.     

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.     

Examination of factors which might disrupt a learned association between pentobarbital and LiCl

Injections of a sedative dose of pentobarbital (Pent) were followed 30 min later by injections of a toxic dose of lithium chloride (LiCl). As a result of these Pent →LiCl pairings, injections of Pent after consumption of saccharin solution failed to produce the usual saccharin aversion. This loss of the capacity of Pent to produce a flavor aversion is called Avfail. Experiment 1 showed that the Avfail effect was obtained with saccharin even though the rats consumed a novel vinegar solution prior to the Pent→LiCl pairings in Phase 1. This was surprising since the novel flavor was associated with the LiCl and ought to have overshadowed the association of Pent with LiCl. Experiment 2 showed that one set of Pent→LiCl pairings can produce two Avfail effects in sequence: the first with a novel flavor and the second with a flavor previously paired with LiCl sickness. It also showed that insertion of Pent injections and handling cues between the Pent→LiCl and the Flavor→Pent phases did not reduce the magnitude of Avfail. Experiment 3 showed that the Avfail effect was not disrupted by the insertion of 54 saline injections between the Pent→LiCl and Flavor→Pent pairings, nor by interposing 26 saline injections between each pair of Flavor→Pent trials. This seemed to exclude an important role for injection cues. Experiment 3 also showed that 4 exposures to Pent and 50 exposures to saline between the Pent→LiCl trials and the Flavor→Pent trials and 26 exposures to saline injections between each pair of Flavor→Pent trials did not reduce the magnitude of Avfail. The same exposure to Pent and saline injections did reduce the magnitude of the saccharin aversion shown by the LiCl→Pent group. These data are viewed as consistent with Lett's (Drug-drug associations: Evidence for the conditioning of a compensatory response. Paper presented at a meeting of the Eastern Psychological Association, New York, 1981) suggestion that Avfail represents a learned antisickness response.     

Formation of associations of colored and flavored food with induced sickness in five avian species

Domestic ducks, geese, pigeons, quail, and chickens were given colored, flavored, or colored and flavored food and then injected with lithium chloride. Each species showed learning of color and taste aversions. Flavor facilitated the formation of color aversions in ducks, geese, and pigeons but not in quail or chickens. Color interfered with the formation of flavor aversions in quail and chickens but not in the other three species. These findings indicate that all birds can probably associate both colored and flavored food with induced sickness and that colored food is more easily associated with induced sickness than is colored water. Moreover, these findings suggest that the capacity to associate colored and flavored food with induced sickness and the interaction between color and flavor in food vary between species. Birds, such as quail and chickens, that eat relatively tasteless food rely more on color than on flavor cues when forming learned food aversions. Birds that can select their food on the basis of taste, such as ducks and geese, rely more on flavor than on color when forming aversions to food. Birds, such as pigeons, that are initially raised on tasty food before switching to predominantly tasteless food show tendencies that are similar to those of ducks and geese.     

Is blockade of conditioned flavor aversions by chlorpheniramine the result of state dependency?

Conditioned flavor aversions induced by pairing flavored fluids with ionizing irradiation, lithium chloride, estrogen, or centrifugal rotation have been blocked by prior administration of chlorpheniramine. The blockade may be due to state dependency. This possibility was evaluated in the present experiment, which assigned female Long-Evans rats to a factorial combination of chlorpheniramine (20 mg/kg) vs saline during training, centrifugal rotation (150 rpm for 15 min) vs none as an UCS, and chlorpheniramine vs saline in testing. Rats conditioned with saline and rotation showed strong aversions when tested with either same or chlorpheniramine. Rats conditioned with chlorpheniramine and rotation showed no change during conditioning; when tested with saline they showed no aversion, and when tested with chlorpheniramine they showed no change from conditioning. Rats conditioned with either chlorpheniramine or saline and no rotation showed high fluid intake when tested with saline and reduced fluid intake when tested with chlorpheniramine. The results were interpreted as offering little support for state dependency.     

Characteristics of taste-mediated environmental potentiation in rats

When rats drink a novel flavor in a distinctive environment and are injected with lithium, potentiated aversions are established to the environment as evidenced by the animals' unwillingness to consume a familiar, nonaversive flavor in this environment. Experiment 1 demonstrates that this potentiation is due to the presence of both the distinctive taste and the environmental cues on the conditioning trials, not simply aversive conditioning to each element or to generalization between the two elements. This potentiation phenomenon was shown to be sensitive to the novelty of the potentiating flavor in Experiment 2. Experiment 3 demonstrated that second-order conditioning is difficult to establish using these procedures, although Experiment 4 revealed that postconditioning extinction of the aversive flavor interfered substantially with environmental potentiation. These outcomes are discussed in terms of their implications for adaptive adjustments in feeding behavior as well as for more general conceptions of associative learning.     

The interval between the CS and the UCS as a determiner of generalization performance

Rats were trained in a conditioned taste aversion paradigm in order to determine whether a trace interval between the conditioned stimulus (CS) and the unconditioned stimulus (UCS) would result in the forgetting of stimulus attributes. Accordingly, subjects were conditioned with milk (CS), given either an immediate or a delayed injection of lithium chloride (UCS), and tested 48 h later with either milk or chocolate milk, a generalized flavor. The rats conditioned immediately following the presentation of the CS avoided milk more than chocolate milk, indicating discrimination between the two flavors. Those conditioned after a trace interval avoided both flavors equally, suggesting a loss of stimulus attributes of the original CS. Delay rats, however, still exhibited substantial learning when compared with controls not experiencing the UCS. These results allege a role for the forgetting of stimulus attributes during a trace interval in addition to following a complete learning episode.     

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).     

Demonstration of a socially transmitted flavor aversion in rats? Kuan and Colwill (1997) revisited

In each of three experiments that differed only in procedural detail, observer rats interacted with pairs of conspecific demonstrators, one fed a cocoa-flavored diet (Diet Coc) and the other a cinnamon-flavored diet (Diet Cin). Immediately after both members of a pair of demonstrators had been fed, and 5 min before they interacted with an observer or observers, one of the demonstrators was made ill by intraperitoneal injection with lithium chloride. After interacting with a pair of demonstrators for 15 min, each observer was allowed to choose between Diet Cin and Diet Coc for 22 h. In all three experiments, observer rats consumed as much Diet Cin after interacting simultaneously with both an ill demonstrator that had eaten Diet Cin and a healthy demonstrator that had eaten Diet Coc as after interacting simultaneously with both a healthy demonstrator that had eaten Diet Cin and an ill demonstrator that had eaten Diet Coc. These results raise questions about the generality of Kuan and Colwill’s (1997) demonstration of socially transmitted flavor aversions in Norway rats.     

A flavor paired with lithium chloride blocks the formation of a pentobarbital-lithium chloride association

Thirsty rats were used in order to determine whether a vinegar solution, which had been paired with an injection of lithium chloride, could block the formation of an association between a pentobarbital- and a lithium chloride-induced state. During phase 1 the rats in the blocking group had a 2.0% vinegar solution paired with an injection of 240 mg/kg of lithium chloride, during phase 2 these rats were reexposed to the vinegar prior to each injection of 20 mg/kg of pentobarbital and 240 mg/kg of lithium chloride, and during phase 3 these rats were given access to a novel 0.75% saccharin solution and were injected with pentobarbital after saccharin removal. Animals with this history did not form an association between the pentobarbital- and lithium chloride-induced states during phase 2 as evidenced by their refusal to consume the saccharin solution over repeated pairings of saccharin with pentobarbital during phase 3. Control groups that received forward pairings of pentobarbital and lithium chloride, in the absence of a previously conditioned vinegar solution during phase 2, formed an association between pentobarbital and lithium chloride. These findings indicate that drug states and flavors can interfere with each others' capacity to predict the occurrence of lithium chloride.