Conditioned taste aversion elicited in anaesthetized rats by scorpion venom

Conditioned saccharin aversion was elicited in rats by the use of scorpion venom. After 15 min of saccharin drinking, groups of rats were injected with venom, Nembutal, LiCl or isotonic saline. Two groups were anaesthetized 10 min after saccharin drinking and injected with venom or with LiCl. During retention test saccharin aversion was observed in the venom and LiCl groups. It is concluded that anaesthesia does not prevent conditioned taste aversion engram formation.     

Dose-dependent effects of peptide YY(3-36) on conditioned taste aversion in rats

We used a conditioned taste aversion test to assess whether PYY(3-36) reduces food intake by producing malaise. Two-hour IV infusion of PYY(3-36) (8, 15, and 30 pmol/kg/min) at dark onset in non-food-deprived rats produced a dose-dependent inhibition of feeding and a conditioned aversion to the flavored chow paired with PYY(3-36) infusion. In food-deprived rats, PYY(3-36) at 2 and 4 pmol/kg/min inhibited intake of a flavored saccharin solution without producing conditioned taste aversion, whereas higher doses (8 and 15 pmol/kg/min) inhibited saccharin intake and produced taste aversion. These results suggest that anorexic doses of PYY(3-36) may produce a dose-dependent malaise in rats, which is similar to that reported for PYY(3-36) infusion in humans. Previous studies have shown that PYY(3-36) potently inhibits gastric emptying, and that gut distention can produce a conditioned taste aversion. Thus, PYY(3-36) may produce conditioned taste aversion in part by slowing gastric emptying.     

Symmetrical effect of pre-exposure between alcohol and morphine on conditioned taste aversion

It has previously been reported that pre-exposure to a psychoactive drug can block the conditioned taste aversion associated with that drug. This study was an attempt to investigate alcohol-morphine interactions using this pre-exposure paradigm. After two weeks of adaptation to a schedule of daily 30-minute access to water, rats were pre-exposed to morphine, ethanol, or the respective vehicle control every second day for three days before (Days 1, 3, 5) and after the first conditioning day (Days 8, 10, 12). On conditioning days (Days 7, 14), animals were first presented with a saccharin solution for 30 minutes following which animals that were pre-exposed to morphine were injected with ethanol while those pre-exposed to ethanol were administered with morphine. Saccharin was again presented on three more occasions (Days 21, 28, 35) without drug injection. Using the percent change in saccharin consumed from the first presentation as a measure of aversion, it was found that pre-exposure to morphine blocked ethanol conditioned taste aversion. Similarly, animals pre-exposed to ethanol showed less aversion to the saccharin paired with morphine. This is the first demonstration of a symmetrical relationship between alcohol and the opiates.     

Saccharin exposure increases the potency and aversive property of naloxone in drug-naive rats

In naive rats previously given saccharin (0.1%) as the only drinking fluid for 14 days, naloxone produced a conditioned taste aversion at a dose (0.09 mg/kg, SC) that had little or no effect in normal controls. The magnitude of this effect of the saccharin increased between 2 and 7 days after cessation of the treatment. Under these experimental conditions, evidence of an interaction between the saccharin exposure and a naloxone response was also seen with rectal temperature measurements. Therefore, in rats having no history of morphine, previous consumption of saccharin may potentiate various actions of naloxone including its aversive property.     

Acquisition and extinction of conditioned suppression of a graft-vs-host response in the rat

Injection of rats with cyclophosphamide (CY) after their consumption of a novel saccharin-flavored drinking solution results in a conditioned aversion to saccharin and a conditioned suppression of immune responses. In this study, female Lewis X Brown Norwegian F1 rats were conditioned by pairing saccharin with 50 mg/kg CY. Seven weeks later (day 0), a graft-vs-host response (GvHR) was induced in these animals by injecting splenic leukocytes from Lewis donors into a rear footpad. At this time, some conditioned animals were reexposed to saccharin, the conditioned stimulus. During the 7-wk interval between conditioning and immunization, subgroups of conditioned rats were given 0, 4, 9, or 18 extinction trials (saccharin followed by saline injections). Animals receiving 4, 9, or 18 extinction trials showed a greater preference for saccharin on day 0 than did animals receiving no extinction trials, but these groups did not differ among themselves; all conditioned groups showed a lower preference for saccharin than placebo-treated animals. There was a clear effect of number of extinction trials on the GvHR. Animals receiving 9 or 18 extinction trials did not differ from controls, whereas animals receiving 0 or 4 trials had a milder GvHR than did conditioned rats that were not reexposed to saccharin at the time of immunization. These results confirm a previous report of conditioned suppression of a GvHR, demonstrate that conditioned immunopharmacologic responses are subject to experimental extinction, and indicate that conditioned immunosuppression can be dissociated from conditioned taste aversion.     

Taste aversion learning in preweanling rats exposed to alcohol prenatally

The effects of prenatal alcohol exposure on the development of a conditioned taste aversion were examined in preweanling rat pups. Mothers of these pups were fed isocaloric liquid diets containing either 35 or 0% ethanol-derived calories (EDC) from gestation days 6 through 20. A pair-feeding procedure was employed, and an ad lib lab chow control group was also included. At 5, 10, or 15 days of age, pups were infused with a saccharin solution through a cannula implanted in the oral cavity. Half of the pups in each group were then injected with lithium chloride (LiCl), which served as the poisoning agent, and the other half with sodium chloride (NaCl) as a control. Animals were subsequently tested for a conditioned aversion to the saccharin solution. At 15 days of age, all of the pups in the LiCl-poisoned group demonstrated a conditioned taste aversion to the saccharin solution, but the degree of this aversion was less in alcohol-exposed offspring. At 10 days of age, a taste aversion was learned, although it was not as strong as that shown by 15-day-old pups, and it appeared to be learned equally well by all of the prenatal treatment groups. At 5 days of age, there was marginal support for taste aversion learning. Again, it did not interact with prenatal treatment. The ontogenic differences in taste aversion learning exhibited by alcohol-exposed offspring relative to controls are discussed in terms of altered hippocampal development.     

The enigma of conditioned taste aversion learning: stimulus properties of 2-phenylethylamine derivatives

The functional aversive stimulus properties of several IP doses of (+/-)-amphetamine (1.25-10 mg.kg-1), 2-phenylethylamine (PEA, 2.5-10 mg.kg-1, following inhibition of monoamine oxidase with pargyline 50 mg.kg-1) and phenylethanolamine (6.25-50 mg.kg-1) were measured with the conditioned taste aversion (CTA) paradigm. A two-bottle choice procedure was used, water vs. 0.1 % saccharin with one conditioning trial and three retention trials. (+/-)-Amphetamine and phenylethanolamine induced a significant conditioned taste aversion but PEA did not. (+/-)-Amphetamine and PEA increased spontaneous locomotor activity but phenylethanolamine had no effects on this measure. Measurement of whole brain levels of these drugs revealed that the peak brain elevation of PEA occurred at approximately 10 min whereas the peak elevations of (+/-)-amphetamine and phenylethanolamine occurred at approximately 20 min. The present failure of PEA to elicit conditioned taste aversion learning is consistent with previous reports for this compound. The differential functional aversive stimulus effects of these three compounds are surprising since they exhibit similar discriminative stimulus properties and both (+/-)-amphetamine and PEA are self-administered by laboratory animals. The present data suggest that time to maximal brain concentrations following peripheral injection may be a determinant of the aversive stimulus properties of PEA derivatives.     

Taste aversions in the ontogeny of the rat

The characteristics of acquisition and extinction of conditioned taste aversion (CTA) were studied in rats of both sexes and various ages by pairing of saccharin solution consumption with discomfort (LiCl intoxication, rotation). Pairing of saccharin consumption with LiCl in adult rats led to acquisition of CTA, more profound in male rats than in female ones. In rats of both sexes 30 days old, a profound CTA, comparable in intensity with CTA of adult male rats was acquired. In 2 months after acquisition of CTA in adult rats its magnitude did not change, while in rats of the junior group which by that time had reached puberty, CTA was reduced in females and did not change in males. Pairing of saccharin intake and rotation led to acquisition of CTA only in rats 30 days old. The role of external factors in duration of retention of CTA acquired by pairing of saccharin solution consumption with LiCl injection was studied in male and female rats 1 and 3.5 months old. In all cases CTA was extinguished much sooner in home cages than in experimental chambers, and in the elder group sex dimorphism was found: in both situations CTA disappeared sooner in female rats. The obtained data allow to suggest modulating influences of hormonal background and of contextual stimuli on CTA acquisition and retention.     

Behaviorally conditioned suppression of the immune response by antilymphocyte serum

Previous studies have shown that cyclophosphamide, a drug with a broad spectrum of cytotoxic activity and one that produces noxious gastrointestinal side effects, can elicit taste aversion conditioning when paired with a non-immunosuppressive oral stimulus (saccharin) resulting in immunosuppression after subsequent exposure to the paired stimulus (1). The study reported here indicates that rabbit anti-rat lymphocyte serum (ALS) which is selectively cytotoxic for lymphocytes and does not produce sensory side effects can similarly induce taste aversion conditioning of the immune response. Rats were exposed to oral saccharin paired with ALS injection. Upon subsequent reexposure to saccharin alone the immunosuppressive effects of ALS were reenlisted and the primary mixed lymphocyte culture response of conditioned rats to allogeneic lymphocytes was suppressed by 35% compared to controls. The demonstrated influence of psychologic factors on the immune response has far reaching implications, especially to human medicine, and their role in the course of disease and recovery in man demands further investigation.     

Gamma-L-glutamyl-taurine (Litoralon) affects conditioned taste aversion in rats

The dipeptide gamma-L-glutamyl-taurine (Litoralon) reduced neophobia of rats at a dose of 5.0 mg/kg (i.p.) in a "one-bottle forced choice paradigm" for conditioned taste aversion (CTA), but did not significantly affect the rats' "memory" of intoxication following chronic treatment at doses of 0.05, 0.50 and 5.00 mg/kg (i.p.). Acute treatment with Litoralon (10-1000 micrograms/kg, i.p.) did not affect CTA checked in a "two-bottle test", when administered immediately following the unconditioned stimulus (LiCl injection). In contrast, when given 90 min prior to the retention test, the injection of Litoralon (50.0 micrograms/kg) and gamma-aminobutyryl ethanolamine phosphate (100 and 500 micrograms/kg) resulted in a significantly higher intake of saccharin solution by the rats. This effect is comparable to the action of diazepam tested in the same experimental procedure. The results support our hypothesis about the anti-conflict potencies of these dipeptides, exerted by reducing aversion of phobia and/or the anxiety level of the animals in the experimental situation.     

Estradiol benzoate can function as an unconditioned stimulus in a conditioned taste aversion paradigm

The extent to which gonadal steroid hormones can serve as unconditioned stimuli in a conditioned taste aversion paradigm was examined in Rockland-Swiss albino mice. With saccharin serving as the conditioned stimulus, subcutaneously injected estradiol benzoate, but not progesterone or testosterone propionate, was found to be a potent unconditioned stimulus in both male and female mice. Dose-response effects were also observed; increasing dosages of estradiol benzoate led to increasingly stronger conditioned aversions in both males and females. The aversion detected in males was more resistant to extinction than that seen in females. Prepubertal gonadectomy reversed the sex-dependent effects of estradiol benzoate in learned aversions in adulthood; castration of males promoted the extinction process, whereas ovariectomy of females retarded extinction. The results may be useful for our understanding of the mechanisms involved in conditioned taste aversion learning as well as a wide array of hormone-dependent behavioral responses.     

Neonatal thyroxine treatment enhances classical conditioning in the infant rat

Neonatal rats injected with either thyroxine (T₄) or vehicle (NaOH) on postnatal Days 1, 2, and 3 were given classical-conditioning pairings of an odor with footshock when 7, 9, or 11 days of age. In accord with the conventional acceleration of other indices of maturation following the T₄ treatment, 24-hr retention of the conditioned odor aversion was substantially enhanced among the 11 day-old rats given the earlier T₄ treatment. This effect was marginally significant among 9-day olds but not among 7-day olds.     

Taste aversion learning and aging: a comparison with the effect of dorsal hippocampal lesions in rats

The relationship between hippocampal function and aging was explored in Wistar rats using taste aversion learning by comparing the performance of adult dorsal hippocampal lesioned and fifteen-month-old intact rats with that of adult intact rats. In experiment 1 the conditioned blocking phenomenon was absent in the hippocampal and the aging rats. Unlike the adult intact rats, the hippocampal and aging rats were not impaired in acquiring a learned aversion to a cider vinegar solution (3 %) presented as a serial compound with a previously conditioned saccharin solution (0.1 %). In experiment 2 both the hippocampal and the aging rats developed reduced aversions to a saline solution (0.5 %) followed by an i.p. injection of lithium chloride (0.15 M; 2 % b.w.) if the taste solution was previously preexposed without consequences. This latent inhibition effect was similar to that seen in intact adult rats. In both experiments, the aging rats exhibited enhanced conventional learned taste aversions. It is concluded that aging is not a unitary process but induces both hippocampal dependent and hippocampal independent complex changes in the functioning of the neural circuits, implementing taste aversion learning.     

A DUAL TASTE FOR SACCHARIN IN THE RAT: II. Taste Change Following Alloxan Injection

It has previously been proposed that saccharin has a dual tasefor the rat, that is has both sweet and aversive componentsto its taste, and that the aversion shown to saccharin by alloxandiabetic rats might be accounted for by the diabetes reducingthe effectiveness of the sweet component. In this study it isshown that the generalization to saccharin of a conditionedaversion to glucose is reduced or eliminated following alloxantreatment suggesting that the sweet component is reduced, andthat the generalization of a conditioned aversion to quinineis enhanced suggesting that the second component of the saccharintaste is quinine-like. ^* Supported by National Research Council of Canada Grant #APO-97     

Striatal-Enriched Protein Tyrosine Phosphatase Controls Responses to Aversive Stimuli: Implication for Ethanol Drinking

The STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase whose dysregulation in expression and/or activity is associated with several neuropsychiatric disorders. We recently showed that long-term excessive consumption of ethanol induces a sustained inhibition of STEP activity in the dorsomedial striatum (DMS) of mice. We further showed that down-regulation of STEP expression in the DMS, and not in the adjacent dorsolateral striatum, increases ethanol intake, suggesting that the inactivation of STEP in the DMS contributes to the development of ethanol drinking behaviors. Here, we compared the consequence of global deletion of the STEP gene on voluntary ethanol intake to the consumption of an appetitive rewarding substance (saccharin) or an aversive solution (quinine or denatonium). Whereas saccharin intake was similar in STEP knockout (KO) and wild type (WT) littermate mice, the consumption of ethanol as well as quinine and denatonium was increased in STEP KO mice. These results suggested that the aversive taste of these substances was masked upon deletion of the STEP gene. We therefore hypothesized that STEP contributes to the physiological avoidance towards aversive stimuli. To further test this hypothesis, we measured the responses of STEP KO and WT mice to lithium-induced conditioned place aversion (CPA) and found that whereas WT mice developed lithium place aversion, STEP KO mice did not. In contrast, conditioned place preference (CPP) to ethanol was similar in both genotypes. Together, our results indicate that STEP contributes, at least in part, to the protection against the ingestion of aversive agents.     

Tests of adipsia and conditioned taste aversion following the intrahypothalamic injection of amylin.

Intrahypothalamic injection of amylin (AMY) was shown to reduce the intake of rat chow and water for 8 and 4 h, respectively, in schedule-fed rats. Amylin also reduced water intake to a much lesser degree in 24-h water-deprived rats. A test of the ability of AMY to form a conditioned taste aversion yielded no change in saccharin preference, as compared to controls treated with vehicle. These results suggest that although AMY has adipsic effects, the reduction in water is not of sufficient magnitude to cause the anorexia. In addition, the failure of AMY to support a conditioned taste aversion suggests that AMY does not cause anorexia by inducing malaise. Therefore, in addition to other metabolic effects, AMY may be involved in the control of food and water intake.     

Inhibition of protein synthesis during associative memory reactivation produces reversible or irreversible amnesia in the snail Helix lucorum

Effects of protein synthesis inhibitors on reactivation processes of food aversion conditioning were inverstigated in snail Helix lucorum. Protein synthesis inhibitor (PSI, anisomycin, 0.4 mg, or cycloheximede, 0.6 mg) was injected into snail body cavity 24 hours after 3-day training; then conditioned stimulus (banana) was presented and memory was tested. It was found that 2.5-3 hours after first reminding, associative food conditioning was suppressed, recovering of the conditioning was observed 4.5-5.5 hours after first reminding. In other group of snails, PSI injections were single (1.8 mg) or triple (0.6 mg with 2-hour interval). Reminding stimulus was presented after each injection. In this case, suppression of food aversion conditioning was also observed 2.5-3 hours after first reminding, while amnesia in this case lasted over 30 days. Repeated training of the group of snails recovered the food aversion conditioning only partially. In control snails (saline instead of PSI or 3 injections of PSI without reminding), foot aversion conditioning was detected 30 days after first training. Thus we found that PSI effects during reminding of food aversion conditioning produced two phases amnesia: (1) the easily suppressed by PSI transient phase lasted 2-3 hours, and (2) irreversible phase, its suppression by high doses of PSI-initiated amnesia lasting over 1 month. Second phase of amnesia was not recovered after repeated training. It was suggested that reminding induced reconsolidation of initial memory. Its suppression by protein synthesis inhibitors results in erasing of memory trace and disturbs repeated consolidation.     

The effect of elevated blood cortisol levels on the extinction of a conditioned stress response in rainbow trout

Following previously published observations that a conditioned response (CR) was lost more quickly by rainbow trout (Oncorhynchus mykiss) exhibiting a high responsiveness to stressors than by low responding individuals this study was designed to investigate the effects of exogenous cortisol on the retention of a CR in unselected rainbow trout. Fish held in isolation were conditioned over a 10-day period by pairing an innocuous signal (conditioned stimulus, CS: a water jet played on the surface of the tank water) with a mild stressor (unconditioned stimulus, US: 30 min of confinement). This resulted in a brief elevation of plasma cortisol levels (the CR) when the fish was exposed to the CS only. The effect of exogenous cortisol on the retention of the CR was evaluated by comparing the performance of fish that received cortisol-containing slow-release intraperitoneal implants, with fish receiving vehicle-only implants. Retention of the CR was assessed at intervals up to 35 days after conditioning ceased. The CR was considered to be evident when 30 min following presentation of the CS, mean plasma cortisol levels were significantly higher in conditioned than untrained fish. On day 1 both cortisol-implanted and vehicle-implanted conditioned fish exhibited a CR. However, from day 5 onwards the CR was observed only in the vehicle-implanted and conditioned group. This finding indicates that administration of cortisol accelerated the extinction of the CR in the cortisol-implanted fish, suggesting that elevated plasma cortisol levels can impair memory processes in rainbow trout.     

A time contraction effect of acute tail-pinch stress on the associative learning of rats

The effect of tail-pinch stress interpolated between the saccharin conditioned stimulus (CS) and the illness-inducing unconditioned stimulus (US) during long-trace taste-aversion conditioning was examined in young- and old adult rats with a two-cylinder (saccharin versus water) test. A 2 x 2 x 4 factorial ANOVA was performed on percent-preference-for-saccharin data, with age (young, old), stress condition (stressed, non-stressed), and CS-US interval (22.5-, 45-, 90-, and 180-min) being the factors under consideration. The ANOVA yielded only significant main effects of stress condition and CS-US interval. These findings indicate that stress weakens the CS-US association as evidenced by a higher percent preference for saccharin in the stressed rats than in non-stressed rats at all CS-US intervals. A comparison of the stressed and non-stressed conditioned rats with pseudo-conditioned controls showed that the non-stressed rats formed strong aversions up to the 45-min CS-US interval whereas the stressed rats showed no conditioning beyond the 22.5 min CS-US interval, indicating that stress decreases the effective CS-US interval. Results were interpreted in terms of time-contraction and an internal biological countdown timer hypothesized to govern processes involved in associative learning over long delays.     

Is glycine "sweet" to mice? Mouse strain differences in perception of glycine taste

Glycine is an amino acid tasting sweet to humans. In 2-bottle tests, C57BL/6ByJ (B6) mice strongly prefer glycine solutions, whereas 129P3/J (129) mice do not, suggesting that they differ in perception of glycine taste. We examined this question using the conditioned taste aversion (CTA) generalization technique. CTA was achieved by injecting LiCl after drinking glycine, and next its generalization to 10 taste solutions (glycine, sucrose, saccharin, D-tryptophan, L-tryptophan, L-alanine, L-proline, L-glutamine, NaCl, and HCl) was examined by video recording licking behavior. Both B6 and 129 mice generalized the aversion to sucrose, saccharin, L-alanine, and L-proline and did not generalize it to NaCl, HCl, and L-tryptophan. This indicates that both B6 and 129 mice perceive the sweetness (i.e., a sucrose-like taste) of glycine. Thus, the lack of a glycine preference by 129 mice cannot be explained by their inability to perceive its sweetness. Strain differences were observed for CTA generalization to 2 amino acids: 129 mice generalized aversion to L-glutamine but not D-tryptophan, whereas B6 mice generalized it to D-tryptophan but not L-glutamine. 129.B6-Tas1r3 congenic mice with 2 genotypes of the Tas1r3 locus (B6/129 heterozygotes and 129/129 homozygotes) did not differ in aversion generalization, suggesting that the differences between 129 and B6 strains are not attributed to the Tas1r3 allelic variants and that other, yet unknown, genes are involved in taste perception of amino acids.