A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites

Most drugs induce conditioned taste aversions and are therefore commonly supposed to produce nausea or sickness. Paradoxically, some drugs appear to lose induction capability when made to serve as a cue for a second drug that produces more severe sickness, perhaps through selective association with a hypothetical homeostatic or antisickness aftereffect of sickness. Using drug-drug pairings had made antisickness conditioning theory difficult to validate. We report here that rotation serves in lieu of a drug cue in rats. Rotation-drug pairings eliminate drug interactions and enable the sorts of parametric manipulations required to validate the theory. By postulating a common sickness mechanism to explain both taste aversion and aversion failure, the theory places the phenomenon within an adaptive evolutionary framework. Successful application could yield a direct countermeasure to severe nausea in clinical settings.     

Pairings of a drug or place conditioned stimulus with lithium chloride produce conditioned sickness, not antisickness.

In different experiments, pairings of a drug (pentobarbital or morphine) or place as the conditioned stimulus (CS) with lithium-induced sickness as the unconditioned stimulus (UCS) were given to rats to produce Pavlovian conditioning. Control rats received unpaired exposures. In the test, each rat was exposed to the CS, injected with lithium, and then offered food. If such pairings produce conditioning of antisickness (i.e., a compensatory response that opposes lithium sickness), then the experimental rats should eat more than the controls. The reverse occurred. Thus, pairings of a drug or place CS with a lithium UCS resulted in conditioned sickness rather than antisickness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The state of the reward comparison hypothesis: Theoretical comment on Huang and Hsiao (2008).

Rats avoid intake of a gustatory cue following pairings with a drug of abuse, such as morphine or cocaine. Despite the well-established rewarding properties of these drugs, the reduction in intake of the taste cue has been interpreted as a conditioned taste aversion for decades. In 1997, I proposed the reward comparison hypothesis suggesting that rats avoided intake of the drug-associated taste cue because the value of the taste cue pales in comparison to the highly rewarding drug of abuse expected in the near future. In this issue of Behavioral Neuroscience, A. C. W. Huang and S. Hsiao (see record 2008-17011-002) challenge the reward comparison hypothesis by showing parallels between amphetamine and LiCl-induced suppression of CS intake. This commentary addresses the current state of the reward comparison hypothesis in the context of the experiments completed by Huang and Hsiao and their new task-dependent drug effects hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cell fate and cell differentiation status in the Arabidopsis root

In a direct test of conditioned antisickness (CAS; B. T. Lett, 1983) theory, the authors measured emesis in ferrets and found those with a history of forward pairings of pentobarbital and lithium to have fewer and shorter bouts of emesis on test, whether induced by lithium or, in a subsequent test, by the highly emetogenic anticancer drug cisplatin. In an indirect test of her CAS theory, B. T. Lett (1992) paired interoceptive (drug) or place cues with lithium chloride toxicosis and found that rats with a forward-pairings history ate less food than controls on a forward-pairing test, consistent with conditioned sickness rather than CAS. But rats eat dirt or clay in response to sickness and adaptively eat small amounts of food when clay is not available. We substituted clay (kaolin) for food in a partial procedural replication of B. T. Lett's (1992, Experiment 1) experiment and found that rats with a history of forward pairings of pentobarbital and lithium ate less kaolin, which is consistent with CAS.     

Conditioned antisickness: Indirect evidence from rats and direct evidence from ferrets that conditioning alleviates drug-induced nausea and emesis.

In a direct test of conditioned antisickness (CAS; B. T. Lett, 1983) theory, the authors measured emesis in ferrets and found those with a history of forward pairings of pentobarbital and lithium to have fewer and shorter bouts of emesis on test, whether induced by lithium or, in a subsequent test, by the highly emetogenic anticancer drug cisplatin. In an indirect test of her CAS theory, B. T. Lett (1992) paired interoceptive (drug) or place cues with lithium chloride toxicosis and found that rats with a forward-pairings history ate less food than controls on a forward-pairing test, consistent with conditioned sickness rather than CAS. But rats eat dirt or clay in response to sickness and adaptively eat small amounts of food when clay is not available. We substituted clay (kaolin) for food in a partial procedural replication of B. T. Lett's (1992, Experiment 1) experiment and found that rats with a history of forward pairings of pentobarbital and lithium ate less kaolin, which is consistent with CAS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned antisickness: Heat as an internal stimulus in conditioning taste aversion and aversion failure in rats.

Heat was found to be effective as a conditional stimulus in the aversion failure procedure (S. Revusky et al; see record 1980-27581-001) and was also found to be effective as an unconditional stimulus using a taste aversion procedure in which rats exposed to high ambient temperature following saccharin consumption showed robust saccharin aversions relative to unpaired and unheated controls. The antisickness and taste aversion conditioning evidence force reexamination of the view that toxic heat effects are referred to the external environment. Together with other recent evidence from this laboratory, these data support the hypothetical antisickness mechanism of aversion failure, which requires that toxic heat serve as an internal stimulus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned taste aversions and drugs of abuse: A reinterpretation.

A new hypothesis (and supporting data) provides a solution to the 25-yr-old paradox whereby positively reinforcing drugs of abuse also support a conditioned taste aversion (CTA). The results show that unlike LiCl-induced CTAs, morphine- and cocaine-induced suppression of conditioned stimulus (CS) intake depends on the rewarding properties of the gustatory CS. This finding argues against the long-standing CTA interpretation in favor of a new reward comparison account. That is, rats decrease intake of a gustatory CS following taste–drug pairings because the value of the CS is outweighed by that of a highly reinforcing psychoactive drug. Suppression of CS intake, then, is a consequence of the well-documented positive reinforcing, rather than the hypothetical aversive, properties of drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pavlovian drug–sickness pairings result in the conditioning of an antisickness response.

Previous findings indicate that after a drug CS has been injected prior to LiCl as the UCS on 5 occasions, the drug CS has the capability to evoke a conditioned antisickness response (CAR). This CAR is implied by the finding that the CS drug mitigates the conditioned saccharin aversion produced by Li when it is administered in the interval between saccharin consumption and Li injection. The present study, with 60 male Sprague-Dawley rats, tested the CAR hypothesis. The following drugs were tested and are listed in approximate order of their effectiveness in producing a conditioned antisickness effect: pentobarbital, ethanol, morphine, amphetamine, and chlordiazepoxide. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A comparison of taste aversions induced by radiation and lithium chloride in CS-US and US-CS paradigms.

Describes 3 experiments with a total of 454 albino male Charles-River rats. Conditioned taste aversions induced by ionizing radiation and lithium chloride (LiCl) were compared with both forward (CS-UCS, conditioned stimulus-unconditioned stimulus) and backward (UCS-CS) conditioning paradigms. Taste aversions were produced when a saccharin CS preceded or followed a 100-r radiation UCS by as much as 6 hrs, but a 2%-of-body-weight, .15-mol LiCl UCS was effective only in CS-UCS pairings. It is argued that the ineffectiveness of an LiCl stimulus in UCS-CS pairings was not attributable to differences in the "strength" of the respective LiCl and radiation doses in that these doses yielded comparable aversions in forward pairings. These results are related to inadequacies of a "sickness" model of taste aversion conditioning. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned nausea in rats: Assessment by conditioned disgust reactions, rather than conditioned taste avoidance.

The terms conditioned taste avoidance and conditioned taste aversion are often used interchangeably in the literature; however, considerable evidence indicates that they may represent different processes. Conditioned taste avoidance is measured by the amount that a rat drinks in a consumption test that includes both appetitive phases and consummatory phases of responding. However, conditioned taste aversion is more directly assessed using the taste reactivity (TR) test that includes only the consummatory phase of responding. Rats display a conditioned taste aversion as conditioned disgust reactions (gapes, chin rubs, and paw treads) during an intraoral infusion of a nausea-paired flavored solution. Only treatments that produce nausea produce conditioned disgust reactions, but even rewarding drugs produce conditioned taste avoidance. Furthermore, treatments that alleviate nausea prevent the establishment and the expression of conditioned disgust reactions, but they do not necessarily modify conditioned taste avoidance. Considerable evidence exists indicating that these two measures can be independent of one another. The potential of a compound to produce conditioned disgust reactions is a reflection of its nausea-inducing properties. Taste avoidance may be motivated by conditioned fear rather than conditioned nausea, but conditioned disgust is motivated by conditioned nausea. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disruption of conditioned taste aversion in the rat by stimulation of amygdala: A conditioning effect, not amnesia.

Conducted 2 experiments with a total of 143 male Wistar rats to determine whether the disruption of conditioned taste aversion by amygdaloid brain stimulation (BST) during conditioning could be attributed to the stimulus properties of the BST. In Exp I, Ss receiving BST (a) while drinking saccharin, (b) during the onset of LiCl toxicosis, or (c) in the interval between taste exposure and toxicosis drank significantly more saccharin solution during a 48-hr retest than implanted or unoperated controls receiving similar taste–toxicosis pairings. In contrast, Ss receiving BST during both conditioning and retention trials developed a strong conditioned aversion. Exp II confirmed that BST formed a compound with the taste of the saccharin solution. A small but significant aversion was displayed by groups exposed to BST plus taste during conditioning and to either taste alone or BST alone during the retest. Again, the group presented with BST and taste prior to and following LiCl toxicosis displayed a strong conditioned aversion. Results suggest that disruption of conditioned taste aversion with amygdaloid BST represents a conditioning effect, not amnesia. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Drug exposure and the acquisition and retention of a conditioned taste aversion

Two experiments examined the effects of preexposure and postexposure to a drug on the acquisition and retention of a conditioned taste aversion induced by that drug. Experiment 1 demonstrated that although drug preexposure attenuated a subsequent conditioned aversion, repeated taste-drug pairings reversed the initial attenuation effect and resulted in nearly complete avoidance of consumption. Experiment 2, however, demonstrated that drug postexposure did not alter a previously established conditioned aversion, although the postexposure experiences were effective in attenuating a conditioned aversion to a second novel solution. It was suggested that conditioned aversions are mediated by ACTH and that preexposure to a drug results in tolerance to that drug, yielding a smaller ACTH response and thereby a weaker aversion.     

Pairing pentobarbital with one toxin causes it to attenuate taste aversions produced by a different toxin: Implications for conditioned antisickness theory.

Previous research has shown that after a preconditioning series in which pentobarbital was injected prior to a toxic dose of lithium or amphetamine in the absence of saccharin drinking, the pentobarbital attenuated the saccharin aversion (SA) normally produced by the toxin. B. T. Lett (see record 1984-09008-001) theorized that a conditioned antisickness response (CAR) to pentobarbital is responsible for this conditioned attenuation of SA. Five experiments, with 315 male Sprague-Dawley rats, showed that this attenuation of taste aversion occurred even if the toxin paired with pentobarbital differed from the toxin used during SA conditioning. Preconditioning pentobarbital with a high dose of amphetamine allowed it to attenuate SA produced by lithium and by gamma radiation (as well as by amphetamine itself). Preconditioning pentobarbital with a high dose of lithium allowed it to attenuate aversions produced by amphetamine, gamma radiation, cisplatin, mechlorethamine, dactinomycin, doxorubicin, and lithium itself. This suggests that the CAR cannot be due to conditioned amelioration of specific effects of specific toxins and that there is a central alleviation of nausea, perhaps like the alleviation of pain by endogenous opiates. However, aversions produced by intraperitoneal copper sulfate were not attenuated by lithium-conditioned pentobarbital. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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

20 female albino Simonsen rats received paired injections of either ethanol or saline as the CS and LiCl as the UCS in a Pavlovian differential conditioning paradigm. LiCl evoked a large deceleration in heart rate (80–200 beats/min) as a UCR. 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, Ss that received ethanol–LiCl injections subsequently were more averse to the taste of ethanol than Ss receiving saline–LiCl pairings. However, there were no differences in ethanol's ability to serve as the UCS 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. (21 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gustatory insular cortex lesions disrupt drug-induced, but not lithium chloride-induced, suppression of conditioned stimulus intake.

Rats suppress intake of a normally preferred 0.15% saccharin conditioned stimulus (CS) when it is paired with an aversive agent like lithium chloride (LiCl) or a preferred substance such as sucrose or a drug of abuse. The reward comparison hypothesis suggests that rats avoid intake of a saccharin cue following pairings with a drug of abuse because the rats are anticipating the availability of the rewarding properties of the drug. The present study used bilateral ibotenic acid lesions to examine the role of the gustatory cortex in the suppression of CS intake induced by cocaine, morphine, and LiCl. The results show that bilateral lesions of the insular gustatory cortex (1) fully prevent the suppressive effects of both a 15 and a 30 mg/kg dose of morphine, (2) attenuate the suppressive effect of a 10 mg/kg dose of cocaine, but (3) are overridden by a 20 mg/kg dose of the drug. Finally, these same cortical lesions had no impact on LiCl-induced conditioned taste aversion. The current data show that the insular taste cortex plays an integral role in drug-induced avoidance of a gustatory CS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Taste preconditioning augments odor-aversion learning.

On the basis of previous work that has shown a taste can potentiate odor-aversion conditioning in AX+ conditioning, 6 experiments used rats to examine the effects of pairing a preconditioned taste (A) with a novel odor cue (X) in an A+/AX+ aversion conditioning design. Experiments 1A and 1B demonstrated that a preconditioned taste produced a robust odor aversion that was significantly stronger than a potentiated odor aversion. The results of Experiment 2 showed that the robust odor aversion produced by A+/AX+ conditioning was not the result of the potentiated odor aversion summating with generalization from the taste aversion. The augmented odor aversion was produced only when the taste and odor stimuli were presented simultaneously (Experiment 3) and the preconditioned taste aversion was intact at compound conditioning (Experiment 4). Pairing a novel odor with a preconditioned taste was not sufficient to condition an aversion to odor (Experiment 5), although other results implicated a role for an association between odor and taste in the odor augmentation effect (Experiment 6). The present results have implications for current models of taste + odor interactions in flavor-aversion conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reinforcer devaluation abolishes conditioned cue preference: Evidence for stimulus-stimulus associations.

In the conditioned cue preference (CCP) task, the subject is presented with a cue paired with food reward, resulting in a preference for the paired cue when allowed to choose later. To clarify the learning involved, the authors devalued the reinforcer after training by inducing a taste aversion to the food. In five 30-min sessions, rats were confined in 1 arm of a radial arm maze and presented with food. These reinforced sessions alternated with 5 unreinforced sessions in a nonadjacent arm. Devaluation was then accomplished in 1 group by inducing taste aversion; controls received either saline or unpaired lithium chloride treatment. When tested later, both the saline group and the unpaired group preferred the previously reinforced arm, but the devalued group showed aversion to it. Thus, CCP is mediated by the stimulus-reinforcer association; when the reinforcer is devalued, the preference is also abolished. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Taste aversions to mother's milk: The age-related role of nursing in acquisition and expression of a learned association.

Seven experiments examined the development of taste aversion learning to novel cues contained in mother's milk in 176 laboratory and 377 Sprague-Dawley pups. Ss receiving distinctive milk by experimenter-delivered oral infusions followed by toxicosis formed an aversion to the dam's diet. Robust aversions were learned as early as Day 10 and were retained for at least 11 days. When the same distinctive milk was obtained directly from a foster mother through nursing, only weanling-age Ss formed an aversion. X-ray analysis of nipple location in the mouths of suckling Ss suggested that they receive milk at a similar tongue locus between the ages of 10 and 21 days; flavored milk was then delivered at specific time intervals in controlled quantities through tongue cannulas implanted at loci corresponding to the nipple position. Cannulated preweanling Ss that were attached to a nipple during mild delivery failed to associate the taste cue with illness, whereas both preweanlings off the nipple and weanlings on the nipple acquired aversions to the taste cue in the milk. Results suggest that pups of all ages are incapable of expressing a taste aversion in a nursing situation and that preweanling pups in particular are also deficient in acquiring aversions within a suckling context. The inability of preweanling pups to acquire taste aversions in a nursing situation appears to result from a failure to associate taste cues with illness rather than a failure to detect taste cues obtained from a nipple. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Learned aversions to copulatory behaviors in male rats.

Used LiCl for an aversive effect on copulatory behavior in adult experienced and inexperienced male hooded rats (Exp I) and in inexperienced adult male Holtzman rats (Exp II). When males received an injection of LiCl immediately after an encounter with an estrous female, the vigor of subsequent copulatory responding was initially unaffected. After 5–20 such pairings, however, males displayed an aversion to copulatory behaviors; they ceased to copulate entirely. These aversions persisted when Ss were tested in a novel environment and extinguished after 4 nonreinforced trials. This multiple-trial adaptation of the conditioned taste aversion paradigm provides a new approach to the aversive control of sexual behavior. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)