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The cholinergic system is important for learning, memory, and responses to novel stimuli. Exposure to novel, but not familiar, tastes increases extracellular acetylcholine (ACh) levels in insular cortex (IC). To further examine whether cholinergic activation is a critical signal of taste novelty, in these studies carbachol, a direct cholinergic agonist, was infused into IC before conditioned taste aversion (CTA) training with a familiar taste. By mimicking the cholinergic activation generated by novel taste exposure, it was hypothesized that a familiar taste would be treated as novel and therefore a salient target for aversion learning. As predicted, rats infused with the agonist were able to acquire CTAs to familiar saccharin. Effects of carbachol infusion on patterns of neuronal activation during conditioned stimulus-unconditioned stimulus pairing were assessed using Fos-like immunoreactivity (FLI). Familiar taste-illness pairing following carbachol, but not vehicle, induced significant elevations of FLI in amygdala, a region with reciprocal connections to IC that is also important for CTA learning. These results support the view that IC ACh activity provides a critical signal of taste novelty that facilitates CTA acquisition., (APA, all rights reserved)

To examine the role of incentive sensitization in the potentiation of salt appetite by prior depletions, the authors assessed the motivation to obtain salt ("wanting") and the palatability of salt ("liking") independently in salt-sensitized rats. Breakpoint on a progressive ratio reinforcement schedule was used to measure salt wanting and taste reactivity was used to measure salt liking in rats with and without a history of Na+ depletion. Salt-sensitized rats displayed higher breakpoints relative to controls. However, a history of Na+ depletion was not associated with a greater positive shift in taste reactivity measures. The data suggest that these components of reward are separable in this model and support the general proposition that sensitization may alter wanting but not liking.

Taste novelty can strongly modulate the speed and efficacy of taste aversion learning. Novel sweet tastes enhance c-Fos-like immunoreactivity (FLI) in the central amygdala and insular cortex. The present studies examined whether this neural correlate of novelty extends to different taste types by measuring FLI signals after exposure to novel and familiar polysaccharide (Polycose) and salt (NaCl) tastes. Novel Polycose not only failed to elevate FLI expression in central amygdala and insular cortex, but also failed to induce stronger taste aversion learning than familiar Polycose. Novel NaCl, on the other hand, showed patterns of FLI activation and aversion learning similar to that of novel sweet tastes. Possible reasons for the resistance of Polycose to typical pre-exposure effects are discussed., (Copyright (c) 2006 APA, all rights reserved.)

Novel tastes are more effective than familiar tastes as conditioned stimuli (CSs) in taste aversion learning. Parallel to this, a novel CS-unconditioned stimulus (US) pairing induced stronger Fos-like immunoreactivity (FLI) in insular cortex (IC), amygdala, and brainstem than familiar CS-US pairing, suggesting a large circuit is recruited for acquisition. To better define the role of IC, the authors combined immunostaining with lesion or reversible inactivation of IC. Lesions abolished FLI increases to novel taste pairing in amygdala, suggesting a role in novelty detection. Reversible inactivation during taste preexposure increased FLI to familiar taste pairing in amygdala and brainstem. The difference between temporary inactivation, which blocked establishment of "safe" taste memory, and lesions points to a dual role for IC in taste learning., (Copyright (c) 2005 APA, all rights reserved.)

Taste novelty strongly modulates the speed and strength of taste aversion conditioning. To identify molecular signals responsive to novel tastes, immunostaining for c-fos protein (Fos-like immunoreactivity [FLI]) was used to mark neurons that responded differentially to taste novelty. Novel saccharin induced larger increases in FLI than familiar saccharin. This pattern was seen in central amygdala and insular cortex, but not in basolateral amygdala, parabrachial nucleus, or nucleus of the solitary tract. Other parameters known to influence aversion learning were tested for effects on FLI. Manipulations known to reduce the strength of learning blunted the FLI response, supporting the idea that FLI marks neural pathways critical to taste processing during acquisition, and that c-fos expression is a key transcriptional event underlying this plasticity., ((c) 2003 APA)

The present experiments examined whether inhibition of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activity interferes with conditioned taste aversion (CTA) memories. Rats were centrally infused with the selective PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) before conditioning. Direct infusions of Rp-cAMPS into the amygdala showed no interference with short-term memory but did show significant attenuation of long-term memory and more rapid extinction. Results suggest that PKA activity is involved in the consolidation of long-term memory of CTAs, and that the amygdala may be 1 site that is important for this activity.

The induction of c-Fos-like immunoreactivity (c-FLI) in the nucleus of the solitary tract (NTS) has been shown to be correlated with behavioral expression of a conditioned taste aversion (CTA). However, because this cellular response is also dependent on an intact amygdala, it may represent the activation of a stress-related autonomic response. The present experiments addressed this possibility by evaluating the correlation between c-FLI in the intermediate division of the NTS (iNTS) and 2 measures of conditioned fear: freezing and changes in mean arterial pressure (MAP) and heart rate (HR). Exposure to the taste conditioned stimulus (CS) resulted in a marked induction of c-FLI in the iNTS, whereas exposure to a fear CS did not. Further, exposure to a taste CS did not selectively lead to increases in MAP or HR. Results suggest that induction of c-FLI in the iNTS may reflect the activation of a cell population whose function is unique to the CTA paradigm.

With c-Fos immunoreactivity as a marker for neural activity, we examined whether environmental cues associated with ethanol injection influence the expression of tolerance to ethanol-induced c-Fos activation. Over 24 training days, male Long-Evans rats received ethanol injection (2.5 g/kg) in one environment and saline injection in a different environment. Relative to rats that received ethanol for the first time, ethanol-induced c-Fos expression in the paraventricular nucleus of the hypothalamus (PVN) and the locus coeruleus (LC) was significantly reduced in rats that had received multiple prior ethanol administrations. However, tolerance was partially reversed when ethanol was given in the saline-paired, rather than the ethanol-paired, environment. Results suggest that tolerance to ethanol, as indexed by c-Fos expression in the PVN and the LC, is mediated in part by Pavlovian conditioned responses to cues that predict ethanol administration.

Sodium (Na) ingestion in rats depleted of Na is a strong, motivated behavior that is enhanced further when depleted rats are sham drinking. Dopamine plays a critical role in motivation, including reward associated with consumption of palatable tastes. The present studies assessed the role of dopamine in real and sham drinking of NaCl solutions after Na depletion with the diuretic furosemide (10 mg/kg). Dopamine (D2) receptor antagonists were evaluated (Haloperidol [0.1 mg/kg] and raclopride [0.2 mg/kg]), for their effects on sham and real drinking of 0.3 M NaCl. Sham drinking was markedly reduced by both antagonists whereas real drinking was unaffected. These effects did not appear to be due to malaise or suppression of motor behavior because drug-treated animals were able to increase ingestion substantially when offered less concentrated NaCl (0.1 M). These results suggest that the positive motivating properties of NaCl stimulation in depleted, sham-drinking rats are mediated by central D2 receptors.

Conditioned taste aversion (CTA) learning is a robust form of classical conditioning in which animals rapidly associate a flavor with aversive internal symptoms. The present study assessed CTA learning in transgenic mice deficient in a specific nonreceptor tyrosine kinase (the fyn mutant). Fyn mutants show impaired long-term potentiation and marked deficits in acquisition of spatial learning tasks. To assess whether they are also impaired in CTA learning, fyn mutant and wild-type mice received 2 conditioning trials consisting of access to a flavored solution followed by administration of LiCl. Fyn mutant mice acquired significant CTAs following a single conditioning trial and these aversions were comparable to those seen in wild-type mice. These results indicate that the fyn mutation does not interfere with the acquisition of CTAs and hence that this mutation is not associated with a global learning deficit.

The immature gustatory system of the neonatal rat is characterized by sensitivity to disruption by early interventions such as receptor or nerve damage. The present studies examined the effect of chorda tympani transection (neoCTX) of neonates on adult preference for salt and nonsalt stimuli. NeoCTX at 10 days of age led to a striking change in adult rats' preference for NH4Cl solutions but little change in preference for other solutions, including NaCl and KCl. Permanent anatomical effects of neoCTX included failure of the nerve to regenerate and a loss of all fungiform taste buds. Preference for NH4Cl was not due to an inability to discriminate it from NaCl. Following taste aversion conditioning to NaCl, neoCTX rats clearly distinguished between NaCl and NH4Cl. The effects on NH4Cl preference reflect a sensitive period during development because adult rats receiving similar surgery did not show any change in NH4Cl preference.

Temporal parameters of taste aversion learning are known to differ markedly from other learning paradigms in that acquisition occurs despite lengthy delays between exposure to conditioned (CS) and unconditioned stimulus (US). Far less consideration has been paid to very brief CS-US intervals and the possibility that this learning may also be distinguished by an ineffectiveness of close temporal contiguity between CS and US. The effectiveness of a very brief CS-US interval (10 s) was compared with that of 2 lengthier intervals (15 and 30 min). Temporal control of CS delivery (0.15% saccharin solution) into the oral cavity and US delivery (7.5 mg/kg apomorphine hydrochloride) into circulation involved infusion pumps and indwelling catheters. Using a 1-trial learning paradigm, CS-US delays of 15 and 30 min led to significant aversions whereas the 10-s CS-US interval did not, suggesting that close temporal contiguity between CS and US is neither necessary nor sufficient for conditioned taste aversion acquisition.

Amiloride-sensitive sodium channels in taste buds appear to play a key role in the response to NaCl stimulation, at least in adult rats. The researchers examined whether neonatal rats, which display an exaggerated preference for hypertonic NaCl solutions, lack functional amiloride-sensitive sodium channels. NaCl intake was significantly reduced by amiloride pretreatment, but water and ammonium chloride, NH4Cl, were unaffected. The researchers assessed whether the early appearance of amiloride sensitivity was mediated by effects on chorda tympani (CT) activity by sectioning the CT before testing. CT transection reduced intake of NaCl solutions and eliminated evidence of amiloride sensitivity. Amiloride sensitivity was also assessed by recording of whole-nerve CT activity at 8-11 days of age; the response to NaCl stimulation was significantly suppressed by amiloride. These data indicate that amiloride-sensitive sodium channels develop earlier than previously believed.

Acute sodium depletion in rats leads to dramatic increases in intake of hypertonic NaCl solutions, a behavior known as sodium appetite. The importance of signals conveyed by the chorda tympani (CT) nerve to the expression of sodium appetite is unclear. We examined the effects of bilateral CT transection on the short- and long-term response to sodium depletion in Wistar and Fischer 344 (F344) rat strains, because Wistar rats normally display a NaCl preference in the absence of need whereas F344 rats avoid NaCl. In both strains, sodium appetite after CT transection and treatment with the diuretic furosemide was delayed and blunted or eliminated. The results suggest that signals conveyed by the CT nerve are important in the expression of a sodium appetite. Effects on F344 rats are particularly interesting because CT transection surgery appears to have opposite effects on NaCl intake depending on whether F344 rats are sodium replete or deplete.

Peripheral gustatory mechanisms that may contribute to the expression of sodium (Na) appetite have been a focus of interest for many years. Because amiloride-sensitive Na transport is involved in the generation of neural signals in response to NaCl stimulation, the present study assessed whether changes in amiloride sensitivity of the neural response to NaCl accompany the induction of a Na appetite in the rat. Na deprivation was achieved by acute depletion with the diuretic furosemide. The magnitude of the whole-nerve chorda tympani response to 0.5 M NaCl was reduced in Na-depleted, compared with Na-replete, rats, which provides qualified support for previous reports that the induction of a Na appetite is associated with reduced neural responses to NaCl. However, changes in sensitivity to the specific Na channel blocker amiloride hydrochloride as a result of Na depletion were not evident. These findings suggest that the behavioral and neural changes that occur after Na depletion are not based on changes in amiloride sensitivity in the taste bud.

Fischer 344 (F344) rats are atypical in their lack of preference for any concentration of NaCl solution over water. It was hypothesized that abnormal signals mediated by the chorda tympani nerve (CT) could be causally involved in NaCl avoidance by F344 rats. This study assessed whether CT transection would normalize the salt preference of F344 rats. Preference for NaCl solutions (0.6%, 0.8%, and 1.0%) versus water was assessed using two-bottle preference tests. At all concentrations tested, CT-transected animals preferred NaCl solutions to water. This preference differed dramatically from the avoidance of these solutions by controls. These findings are striking, particularly because CT transections have generally failed to significantly affect NaCl preference in other rat strains. The results are consistent with the hypothesis that in F344 rats the avoidance of the taste of NaCl stems from input mediated by the CT.

The present experiments examined whether behavioral conditioned responses (CRs) develop to lithium chloride (LiCl)-paired tastes and whether these CRs are similar to the behaviors that follow administration of the drug. Rats were exposed to a saccharin solution via intraoral infusions before being injected with either LiCl or saline. CRs were assessed after conditioning when the saccharin conditioned stimulus was delivered alone. The unconditioned response to LiCl delivery is a very distinctive posture that has been termed "lying-on-belly." The present study indicates that this behavior pattern also occurs after the delivery of a LiCl-paired taste solution. The similarity between these unconditioned and conditioned behaviors is consistent with the hypothesis that responses are conditioned during taste aversion acquisition and that CRs are similar to those that are generated by the drugs used in conditioning.

Nausea in response to an appetizing food stimulus was assessed in bulimic women and healthy control subjects. Nausea was assessed via subjects' self-report and changes in levels of plasma arginine vasopressin (AVP), a hormonal correlate of nausea. Converging evidence was obtained indicating that bulimic women experienced nausea in response to the sight, smell, or taste of the palatable food stimulus. The possibility that the observed nausea is a learned response that may contribute to the bulimic binge/purge pattern is discussed.

Rats with experimental tumors developed strong aversions to a novel diet they consumed during tumor growth. Aversions were not evident when the food available during tumor growth was familiar laboratory chow. The impact of learned food aversions on tumor anorexia was evidenced by more severe and long-lasting hypophagia in tumor-bearing animals maintained on a novel diet than in those maintained on laboratory chow. Thus, when a diet is a salient target for the development of learned aversions, the aversions that develop to it can make substantial contributions to the overall syndrome of tumor anorexia. In addition, frequent changes of the diet offered to tumor-bearing rats was associated with milder anorexia than that produced by maintaining tumor-bearing rats on a constant diet. Apparently, the prevention of learned food aversions, or the repeated replacement of aversive foods, can minimize the impact of learned food aversions and attenuate anorexia in tumor-bearing animals.

A modified learned food aversion paradigm simulated the prolonged food and illness exposure likely to characterize nutrient deficiencies or tumor growth. In this paradigm, a continuously available food was associated with a slow, continuous infusion of LiCl provided by osmotic minipump. Significant aversions were acquired when the available diet was novel but not when it was familiar. Effects of drug infusions on daily food intake were found to parallel those on aversion formation. Marked, persistent suppression of food intake was seen in drug-treated animals consuming a novel diet, but only transient declines were seen in those with a familiar diet. By separating the direct from the conditioned effects on food intake of chronic drug infusions, these studies provided strong evidence that learned food aversions can lead to anorexia.

Rats were allowed continuous access to protein and carbohydrate macronutrient sources during a sequence of cyclophosphamide (Cytoxan) injections. Significant aversions developed to the protein but not the carbohydrate source in three studies in which the composition of both protein and carbohydrate diets was varied. These results suggest that animals on a dietary self-selection regimen are more likely to develop conditioned aversions to the protein source than the carbohydrate source. In a final study, the generality of these findings was examined by determining whether aversions would selectively arise to protein but not carbohydrate when these nutrients were conditioned in a single trial, with a meal-feeding paradigm. Proteins again proved more salient targets for aversions than carbohydrates. These findings suggest that the tendency to associate proteins with drug-induced illness more readily than carbohydrates is not limited to a self-selection regimen. The possible role of taste factors and/or postingestive effects as the basis of the differential conditioning of proteins and carbohydrates is discussed.

Subdiaphragmatic vagotomy produces hypophagia and weight loss in normal rats and can reverse the hyperphagia and obesity of rats with ventromedial hypothalamic lesions. Vagotomy surgery can also produce symptoms of nausea and discomfort. Since such symptoms are highly effective as unconditioned stimuli in food aversion conditioning, the present studies examined whether some of the depression in food intake observed in rats with vagotomy could be due to the development of aversions to the foods eaten after their surgery. In the first study, significant aversions developed to the specific novel diet consumed after vagotomy, results indicating that the symptoms associated with vagotomy can serve as effective unconditioned stimuli in the acquisition of learned food aversions. The second study compared vagotomized animals consuming familiar laboratory chow with those consuming a novel diet. In contrast to the novel diets, learned aversions did not develop to the familiar chow, and hypophagia was less persistent and severe. It is concluded that learned food aversions can contribute to the appetite and weight loss exhibited by vagotomized animals. Consideration of the conditions under which these aversions arise after vagotomy surgery may allow for the design of studies so as to minimize the aversions and thereby separate these nonspecific effects from direct regulatory deficits produced by vagotomy.

A learned food aversion paradigm was developed to investigate characteristics of aversion learning likely to be involved in nutrient selection. The development of aversions to a relatively familiar, complete food was examined in rats with continuous access to that food. Learned food aversions were observed which were specific to the particular diet present during a sequence of toxic drug injections. In subsequent studies, novel liquids and solids were introduced in association with drug treatment to examine their effectiveness as interference stimuli. Flavored solutions, which have previously been reported to interfere with conditioned taste aversions, had little or no effect on learned aversions to the diet. This lack of interference by novel flavored liquids was coupled with significant conditioned aversions to the novel liquids themselves. Novel flavored solutions were contrasted with novel foods, which were extremely effective as interference stimuli in this paradigm. Possible bases for the observed differences in interference effects of foods and drinks are examined.

Proteins have proven to be more salient targets for aversion conditioning than carbohydrates. The present studies examined the contribution of flavor and postingestive factors to the salience of proteins as targets in aversion conditioning in the rat. Two methods for separating flavor and postingestive cues were used, sham feeding and intragastric gavage. Both methods agreed in indicating that postingestive consequences of protein consumption were neither necessary nor sufficient for the development of more severe protein than carbohydrate aversions. Differences in palatability did not appear likely to be the basis of protein salience because when acceptability or palatability of the nutrient solutions was matched, aversions to protein continued to be more severe. Differences in odor intensity of nutrient solutions may be important because when an odorant was added to a carbohydrate solution, the severity of aversions to protein and carbohydrate was no longer different. These results indicate that the presence of both taste and odor cues in target nutrients may contribute importantly to their salience.