Early handling effects on neophobia and conditioned taste aversion

The purpose of this study was to determine whether early handling, a manipulation which affects both behavioral and pituitary-adrenal responsiveness to novel and aversive situations, will affect responses in adult rats confronted with novel substances (neophobia) or with substances associated with illness (conditioned taste aversion). We found that (1) early handling reduces the neophobia shown by adult animals and that handled animals appear better able to distinguish between a preferred and a nonpreferred substance. (2) Handling reduces the magnitude of the initial taste aversion and also increases the rate of recovery of drinking to pretoxicosis levels. (3) These behavioral differences between handled and nonhandled animals are not due to differential pituitary-adrenal responses to LiCl. (4) Early handling does affect the conditioned elevation of plasma corticoids upon reexposure to milk under a Forced Extinction procedure. In this situation nonhandled animals show greater corticoid elevations than handled animals. (5) Manipulation of the number of exposures to a substance prior to pairing that substance with LiCl affects the magnitude of both the aversion and the elevation of plasma corticoids which are produced upon reexposure. As number of preexposures increase, both the magnitude of the aversion and the elevation of corticoids decrease.     

Differential effects of amygdaloid lesions on conditioned taste aversion learning by rats

Rats with electrolytic lesions placed in either the basolateral or corticomedial divisions of the amygdala acquired a conditioned taste aversion to sucrose. Comparisons with a surgical control group indicated that damage to the corticomedial amygdala did not alter the animals' performance, while damage in the basolateral nuclei resulted in a small but significant attenuation of the aversion. Furthermore, these amygdaloid lesions did not alter the acceptability of two quinine hydrochloride solutions (0.01% and 0.001%). The daily drinking behavior of the rats with basolateral amygdaloid lesions appeared consistent with the hypothesis that this lesion affected the animals' appreciation of the novelty of the sucrose solution, and hence attenuated the subsequent aversion.     

Interactions of temperature and taste in conditioned aversions

The influence of temperature on taste cues and the ability to discriminate and learn about different temperatures of foods are important factors regulating ingestion. The goal of this research was to demonstrate that thermal orosensory input can serve as a salient stimulus to guide ingestive behavior in the rat, and also that it interacts with gustatory input during choice and conditioned aversion experiments. A novel apparatus with Peltier refrigerators was used to control the temperature of solutions in 10-min, 2-bottle tests. It was determined that naive rats preferred cold water (10 °C) to warm water (40°). When cold water was paired with a toxic LiCl injection, rats avoided cold water and drank warm water, thus demonstrating that cold water could serve as the conditioned stimulus in a conditioned temperature aversion. Rats conditioned against cold water could discriminate 10 °C water from 16 °C water, but not from 13 °C water, thus showing an ability to discriminate orosensory thermal cues to within 3-6 °C. Rats also generalized conditioned aversions from cold water to cold saccharin and cold sucrose solutions. However, if rats were conditioned against a compound taste and thermal stimulus (10 °C, 0.125% saccharin), the rats could distinguish and avoid each component individually, i.e., by avoiding cold water or warm saccharin. Finally, daily 2-bottle extinction tests were used to assess the strength of aversions conditioned against a taste cue (0.25 M sucrose), a thermal cue (10 °C water), or the combination. Aversions to taste or temperature alone persisted for 7-14 days of extinction testing, but the combined taste-temperature aversion was stronger and did not extinguish after 20 days of extinction testing. These results demonstrate that temperature can serve as a salient cue in conditioned aversions that affect ingestion independent of taste cues or by potentiating taste cues.     

High doses of vasopressin delay the onset of extinction and strengthen acquisition of LiCl-induced conditioned taste avoidance

When low doses of vasopressin are given 50 min after pairing sucrose consumption with a high dose of LiCl, extinction of the LiCl-induced conditioned taste avoidance is accelerated. These low doses of vasopressin do not themselves induce conditioned taste avoidance when paired with sucrose consumption. Predicated on previous studies administering two avoidance-inducing agents after sucrose consumption, studies were designed to determine whether high doses of vasopressin capable of inducing conditioned taste avoidance would (1) delay rather than accelerate extinction of a conditioned taste avoidance induced by a high dose of LiCl and (2) strengthen acquisition of a conditioned taste avoidance induced by a low dose of LiCl. The results of three studies showed that doses of 9 and 18 microg/kg of vasopressin induced a conditioned taste avoidance when injected 50 min after sucrose consumption, delayed the onset of extinction when injected 50 min after pairing sucrose consumption with a high dose of LiCl, and strengthened acquisition of a conditioned taste avoidance when injected 50 min after pairing sucrose consumption with a low dose of LiCl. Taken together, these data suggest that the delay in onset of extinction is due to a strengthening of acquisition. It has been suggested that vasopressin is a mnemonic neuropeptide that delays extinction of learned tasks. However, for conditioned taste avoidance, the evidence for the effects of low doses of vasopressin on extinction do not support this hypothesis and the evidence for high doses of vasopressin can be accounted for by the avoidance-inducing properties of vasopressin.     

Aversive effects of vagotomy in the rat: a conditioned taste aversion analysis

Subdiaphragmatic vagotomy suppresses food intake and water intake in normal rats. Since human patients report some nausea and discomfort following vagotomy, the present study assessed the aversive consequences of vagotomy in rats using a conditioned taste aversion paradigm. Rats were given a total subdiaphragmatic vagotomy or sham vagotomy, and were then maintained on either plain water (Vag-Water and Sham-Water groups) or a novel cherry solution (Vag-Cherry and Sham-Cherry groups). When subsequently tested for their water vs. cherry preferences on postoperative days 6, 16, and 26, the Vag-Cherry group displayed a greater aversion to the cherry solution than did the remaining three groups. This result suggests that vagotomy produces visceral malaise in rats which may contribute to the feeding and drinking suppressive effects of the surgery.     

Disparity between formation of conditioned flavor aversions and neophobia during grooming in rats and mice

Mice (Mus musculus) allowed to groom a paste containing saccharin from their fur before injection with lithium chloride displayed a saccharin aversion in subsequent drinking preference tests. No attenuation of neophobia was observed in mice grooming saccharin because the animals failed to display a neophobia towards saccharin in drinking tests. Rattus norvegicus displayed neophobia towards saccharin in two- and single-bottle drinking tests but this neophobia was not attenuated by grooming experience with the saccharin paste. Rats apparently learn that if a taste is hazardous in the grooming context it is also likely hazardous in an appetitive context. Learned safety in grooming, however, does not generalize into the appetitive context. The results support the view that neophobia and learned taste aversion depend upon different mechanisms.     

Behavioral and corticosterone effects in conditioned taste aversion following hippocampal lesions

Hippocampal-lesioned rats engaged in more drinking bouts during the retention of a conditioned taste aversion, but failed to show the elevation of plasma cortocosterone levels seen in the neocortical-lesioned and unoperated control animals, thus showing a disassociation of behavioral and hormonal responses to the retention situation. The presence or absence of anomalous sympathetic innervation in the hippocampal-lesioned rats was demonstrated to be without any behavioral significance.     

Disruption of conditioned taste aversion by the combined effects of LiCl and ECS

Rats were taught a conditioned taste aversion by allowing them to drink sucrose (CS) for 5 min and 30 min later poisoning them with LiCl (UCS). Experimental animals were given ECS (80 mA for 250 msec) at 0, 15, 20, 25, 27.5, 30, 32.5, 35, 40, or 45 min after the CS. Only animals given ECS both within the CS-UCS interval and in close temporal proximity to the UCS (within 5 min) showed a significant, although limited, disruption of learning. At least two explanations are possible. The first is that apart from its toxicity, LiCl may also possess amnesic properties which interact with those of the ECS. Alternatively, ECS may have impaired the ability of the animals to fully experience the lithium-induced illness.     

Effects of desglycinamide-lysine vasopressin on a conditioned taste aversion in rats

Vasopressin and other pituitary peptides have been shown to increase resistance to extinction of active and passive shock-avoidance responses. Both paradigms use external cues as warning and punishing stimuli. The present work asked if a variant of vasopressin would have a similar effect on conditioned taste aversions (CTA), which use internal cues as warning and punishing stimuli. Eight groups of rats were defined by factorial combination of Pretreatment during Neophobia and Conditioning (vasopressin vs saline), UCS during Conditioning (pairing saccharin-flavored water with injections of lithium chloride or saline), and Pretreatment during Extinction (vasopressin vs saline). Rats given three saccharin-lithium pairings developed strong aversions. Of the rats with CTAs, those given vasopressin during conditioning, extinction, or both showed increased resistance to extinction on the last four of eight extinction days. Vasopressin had no other effect on drinking of saccharin. Vasopressin thus appears to enhance resistance to extinction of avoidance responses in both external and internal milieus.     

Aversive consequences of jejunoileal bypass in the rat: a conditioned taste aversion analysis

Jejunoileal bypass (JIB) surgery reduces food intake and body weight in obese humans and rats. Human bypass patients report visceral discomfort following surgery, and the present study assessed the aversive consequences of JIB in rats using a conditioned taste aversion paradigm. In Experiment 1 rats given a cherry-flavored solution immediately after JIB surgery subsequently displayed a strong aversion to the cherry flavor compared to Bypass and Sham-Bypass control groups. Rats in Experiment 2 were familiarized with cherry solution prior to surgery and they did not display an aversion to the solution after receiving a JIB. In Experiment 3, Bypass rats who developed a cherry flavor aversion after JIB subsequently lost this aversion following reconnection of their intestinal tract. The rats in Experiment 4 displayed an aversion to a saccharin-flavored chow that was eaten shortly after JIB surgery, although the aversion was not as pronounced as that obtained with the cherry solution. The results suggest that JIB produces a persisting malaise in rats that may contribute to the feeding and weight inhibitory effects of the operation.     

Neophobia and conditioned taste aversion deficits in the rat produced by undercutting temporal cortex

Adult male hooded rats with parasagittal knife-cuts between the amygdala and temporal cortex (n = 8), with electrolytic basolateral amygdala lesions (n = 8), and sham-operated controls (n = 8), were tested for neophobia and LiCl-induced aversion to a 0.1% saccharin solution in a one-bottle forced choice paradigm. Both types of lesion produced equal deficits in neophobia and conditioned aversion. It was concluded that severing the connections between the amygdala and the temporal cortex produces the same deficits as basolateral amygdala damage. Possible anatomical substrates for these effects are discussed.     

The role of the lateral parabrachial nuclei in concurrent and sequential taste aversion learning in rats

The purpose of this study was to examine the role of the external lateral parabrachial subnucleus (PBNLe) in two different taste aversion learning (TAL) procedures. For the first, short-term (concurrent) TAL, two different-flavored stimuli were presented at the same time, one associated with simultaneous intragastric administration of an aversive product, hypertonic NaCl, and the other with saline. In the second, long-term (sequential/delayed) TAL, each gustatory stimulus was presented every other day and the intragastric products LiCl and saline were administered after a 15-min delay. Electrolytic lesions in the PBNLe blocked acquisition of concurrent TAL, in which the vagal visceral information is critical. But the same lesions failed to interrupt sequential TAL. This result was independent of the order in which the two tasks (concurrent and sequential) were presented. However, as found by other authors, the latter type of learning was impaired in the presence of larger lesions in this same area. This supports the existence of sensory information needed to establish sequential TAL in other subnuclei of the parabrachial complex. The results of these experiments suggest that the different modalities of TAL are anatomically specific.     

Investigations into the nature of the dexamethasone and ACTH effects upon learned taste aversion

Dexamethasone injected prior to the conditioning trial will attenuate a learned taste aversion. ACTH injections will prolong the recovery from a taste aversion when administered prior to recovery trials. Two experiments are reported here. In the first, the interaction between these effects was studied. Using a factorial design, four groups of rats received dexamethasone or ACTH prior to conditioning and prior to recovery trials. An additional group received isotonic saline throughout training and recovery. The primary finding was that animals receiving dexamethasone prior to conditioning and ACTH prior to recovery trials did not differ from the group pretreated with ACTH during both conditioning and recovery. That is, given the parameters of these experiments, the ACTH effect was prepotent. In the second experiment it was shown that the ACTH effect upon the performance of a taste aversion can occur in one trial. Taken together, the results of the two experiments support the idea that ACTH influences memory retrieval when administered prior to a test for retention of an avoidance response.     

Failure of ACTH to prolong extinction of a conditioned taste aversion in the absence of the testes

Both corticotropin (ACTH) and testosterone prolong the extinction of a conditioned taste aversion in water-deprived intact male rats. An investigation was made to determine whether ACTH affects extinction in the absence of the testes and also to determine the effect of ACTH on serum testosterone levels. Water-deprived intact males showed prolonged extinction after ACTH injections; water-deprived gonadectomized males and intact females did not. All three of these groups showed elevated testosterone levels after ACTH administration, but testosterone levels were higher in the intact males than in the gonadectomized males or intact females. These results clearly show that in the absence of the testes ACTH is unable to prolong extinction. It is proposed that the increased level of testosterone following ACTH injection in water-deprived intact males is responsible for the prolonged extinction of a conditioned taste aversion. Although testosterone levels may increase in females and castrated males following ACTH injection, the increase is not sufficient to prolong extinction in these water-deprived animals.     

Differential effect of paradoxical sleep deprivation on acquisition and retrieval of conditioned taste aversion in rats.

Paradoxical sleep deprivation (PSD) was used to interfere with acquisition or retrieval of conditioned taste aversion (CTA). PSD was achieved by confining rats to small pedestals placed on an electrified grid floor. Fifteen-min access to 0.1% sodium saccharin (conditioned stimulus-CS) by water deprived rats was followed 30–120 min later by intraperitoneal injection of lithium chloride (unconditioned stimulus-US, 0.15 M, 2% to 4% body weight). Retention was tested 1 to 5 days later by offering the animal saccharin again. A 24-hr PSD preceding saccharin drinking prevented CTA acquisition. CTA disruption was diminished by a 2-hr, and completely abolished by an 8-hr interval of home cage recovery inserted between the 24-hr PSD and saccharin presentation. CTA was slightly facilitated by 2-hr PSD in the CS-US interval. The 24-hr PSD preceding CS caused the same CTA disruption when followed by free sleep opportunity or by continued PSD in the 2-hr CS-US interval. Twenty-four-hr PSD preceding retention testing slightly improved retrieval of well established CTA. It is concluded that PSD interferes with the formation of the short-term gustatory trace of CTA but does not affect retrieval of CTA engrams. Gradual compensation for the PSD effect on CTA learning by pre-acquisition sleep suggests that the processes responsible for CTA disruption and recovery correspond to depletion and repletion of the same neurotransmitter stores.     

Effect of medial septal lesions on conditioned taste aversion in the rat.

Rats that had sustained lesions of the medial septum developed a conditioned food aversion to sweetened condensed milk at the same rate as controls. This aversion was produced by post-ingestion administration of lithium chloride in ascending doses given on alternate days. Although development of the aversion was the same in lesioned animals as in controls, recovery from it was more rapid in the lesioned animals.     

Role of the vagus nerves in neophobia and conditioned-reflex taste aversion

Combination of ingestion of water with discomfort in rats with intact vagus nerves on selection between water and saccharine solution (an unknown taste) produced aversion not to water but to saccharine, with sharp increases in water consumption. In vagotomized rats, this combination led to a significant increase in saccharine consumption with no change in water intake. After extinction of neophobia to saccharine, combination of ingestion of water with rotation induced aversion to water in both groups (this being delayed in vagotomized rats). Vagus nerve signaling activity in selection conditions appears to determine the choice of behavior strategy. This report marks the 90th anniversary of the birth of Academician V. N. Chernigovskii. Laboratory for the Ontogenesis of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarov Bank, St. Petersburg 199034, Russia. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 9, pp. 1–11, September, 1997.     

Recall of a previously acquired conditioned taste aversion in rats following lesions of the area postrema

A conditioned taste aversion was produced by pairing a novel sucrose solution with either 3 mEq lithium chloride or with 100 rad gamma radiation in rats with the area postrema intact. Lesions of the area postrema were then made in half of the rats exposed to each treatment and in rats that were not treated with the unconditioned stimulus. When tested for a conditioned taste aversion, all treated rats showed a significant aversion to the sucrose solution compared to the untreated control rats. There were no significant differences between rats with area postrema lesions and those with the area postrema intact, indicating that the lesions had no effect on the recall of the previously acquired aversion. The results are interpreted as being consistent with the hypothesis that the role of the area postrema in taste aversion learning is to monitor blood and cerebrospinal fluid for potential toxins and to transmit that information to the central nervous system.     

Metabotropic glutamate receptor antagonists but not NMDA antagonists affect conditioned taste aversion acquisition in the parabrachial nucleus of rats

The effect of glutamate receptor antagonists on conditioned taste aversion (CTA) was studied in rats. The association of the short-term memory of a gustatory conditioned stimulus (CS) with visceral malaise (unconditioned stimulus, US) in the CTA paradigm takes place in the parabrachial nuclei (PBN) of the brainstem. The first direct evidence of participation of glutamatergic neurotransmission in the PBN during CTA demonstrated that the extracellular level of glutamate rises during saccharin drinking (Bielavska et al. in Brain Res 887:413–417, 2000). Our results show an effect of microdialysis administration of selective GluR antagonists into the PBN on the formation of CTA engram. We used four glutamate receptor (GluR) antagonists of different types (D-AP5, MK-801 as antagonists of ionotropic GluR and L-AP3, MSPG as antagonists of metabotropic GluR). The disruptive effect of MK-801 on CTA formation in the PBN is concentration-dependent, with the greatest inhibition under the higher concentrations eliciting significant disruption. The application of D-AP5 (0.1, 1, 5 mM) did not elicit a statistically significant blockade of CTA acquisition. This indicates that the association of the US–CS in the PBN is not dependent on NMDA receptors. On the contrary, application of L-AP3 (0.1, 1, 5 mM) blocked the CS–US association.     

Effects of central amygdaloid nucleus lesions on ingestion, taste reactivity, exploration and taste aversion.

Central amygdaloid nucleus lesions in rats had no effect on recovery of preoperative body weight and food consumption levels. The brain damaged rats also recovered preoperative levels of water consumption as rapidly as control rats but then developed a mild but persistent hypodipsia. The experimental rats also drank less than control rats when food deprived and showed marginally reliable decreases in 0.1% quinine solution consumption and latency to consume a novel food. There was no detectable lesion effect on 0.1% saccharin solution consumption, exploration of a novel environment or formation of a learned taste aversion. It is suggested that the central amygdaloid nucleus has a role in mediating the relationship between food and water intake and in some taste mediated consummatory behavior.