Taste aversions conditioned with gamma radiation: Attenuation by area postrema lesions in rats

The role of the area postrema in radiation induced taste aversions in rats was examined. One group of rats received lesions of the area postrema, another group was given sham lesions and a third group received no surgery. These three groups of rats were then given one pairing of 1 h access to a novel 0.15% sodium saccharin solution followed immediately with exposure to 200 rad gamma radiation. A fourth group of rats with area postrema lesions was given 1 h access to saccharin followed by a sham irradiation procedure. Four days later all groups were given daily two bottle preference tests (saccharin vs water) on 5 consecutive days. The groups with sham lesions or no surgery displayed a strong aversion to saccharin on all 5 test days. The two area postrema lesioned groups displayed a moderate and increasing preference for saccharin over the 5 day test period. The lesioned group given radiation treatment showed a weak but significant aversion (P < 0.05) to saccharin on the first test day, when compared to the lesioned rats not given radiation treatment. Thus, lesions of the area postrema strongly attenuated the radiation induced taste aversions, but did not completely abolish them.     

Taste aversions conditioned with intravenous copper sulfate: Attenuation by ablation of the area postrema

Borison and Wang identified the area postrema as the locus of chemoreceptors that mediate emetic reflexes elicited by blood-borne toxins. In the present experiments we have extended a systematic investigation of the afferent pathways mediating taste aversions by examining the effects of area postrema lesions on the aversions that follow either intravenous or intragastric administration of copper sulfate. Intrajugular cannulas were implanted in rats after ablation of the area postrema (Group AP-L) and in operated controls (Group AP-C). Every third day rats were offered a saccharin solution and immediately afterward were injected intravenously with 0.05 ml isotonic CuSO₄. A group of pseudo-conditioned rats (Group SAC-C) was injected with CuSO₄ approximately 24 h after ingestion of saccharin. Compared to control animals, rats with area postrema damage acquired significantly weaker aversions to saccharin when it was paired repeatedly with intravenous CuSO₄. After three conditioning trials, the rats in Group AP-L that were most resistant to acquisition of a taste aversion (Group AP-L^*) were again offered saccharin, but ingestion in this case was followed immediately by intragastric injection of CuSO₄. After a single conditioning trial rats in Group AP-L^* demonstrated a robust aversion. The results are discussed in terms of the parallels in afferent systems between emetic physiology and some instances of taste aversion conditioning.     

Paradoxical reinforcing properties of apomorphine: Effects of nucleus accumbens and area postrema lesions

Apomorphine (0.01–10.0 mg/kg, subcutaneously) paradoxically produced both dose-dependent aversive and positive reinforcing effects, as measured in conditioned taste aversion and place preference paradigms, respectively. The conditioned taste aversions produced by apomorphine were not modified in rats with bilateral 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens (producing 92% depletion of dopamine in the nucleus accumbens) nor in rats with thermal lesions of the area postrema. Both types of lesions were behaviorally verified as effective in other paradigms; the 6-OHDA lesions potentiated the facilitatory effects of apomorphine on locomotor activity in photocell cages, and the area postrema lesions attenuated the conditioned taste aversions to a novel flavor paired with scopolamine methylnitrate (1.0 mg/kg, intraperitoneally). However, 6-OHDA lesions of the nucleus accumbens did clearly potentiate the conditioned place preferences induced by apomorphine. These results suggest that both the positive reinforcing and locomotor effects of apomorphine may partially result from activation of post-synaptic dopamine receptors in the nucleus accumbens. Moreover, the dissociation of apomorphine's aversive and positive reinforcing properties revealed by the 6-OHDA lesions may provide the first step in attempts to pinpoint the different brain sites of action where apomorphine produces its opposite motivational effects.     

Area postrema: site where cholecystokinin acts to decrease food intake

Administration of cholecystokinin (CCK) reduces food intake in rats. This effect of CCK was attenuated in rats with thermal lesions of the area postrema. This result was specific to CCK, as area postrema lesions had no effect on the reduction in food intake produced by amphetamine. The effect of the lesions was not due to changes in taste sensation as the lesioned rats showed no deficits in morphine induced conditioned taste aversions. Thus, the area postrema may be the major site where CCK acts to decrease food intake.     

Lipopolysaccharide inhibits the simultaneous establishment of LiCl-induced anticipatory nausea and intravascularly conditioned taste avoidance in the rat

This study examined the effects of the bacterial endotoxin, lipopolysaccharide (LPS), on the establishment of anticipatory nausea and conditioned taste avoidance in a simultaneous conditioning paradigm using an intravascular/intraperitoneal saccharin taste. 83 na?ve adult male Long-Evans rats were injected (intraperitoneal) with either 200 μg/kg LPS or 0.9% saline (NaCl), 90 min prior to ip treatment with either 64 mg/kg LiCl, 64 mg/kg LiCl+2.0% saccharin, 0.9% NaCl, or 0.9% NaCl+2.0% saccharin, and immediately placed into a distinctive context for 30 min (repeated over 4 conditioning days, spaced 72 h apart). 72 h following the final conditioning day, each animal was re-exposed to the context on a drug-free test day where orofacial responding was recorded. The next day, animals received a 24 h 2-bottle preference test with a choice between water and a palatable 0.2% saccharin solution. Results showed that LPS exposure, prior to LiCl or LiCl+Saccharin treatment, inhibited the establishment of anticipatory nausea, as evidenced by significantly lower conditioned gaping frequencies relative to animals pre-treated with NaCl followed by LiCl or LiCl+Saccharin. LPS pre-treatment also inhibited the formation of LiCl-induced taste avoidance, as evidence by significantly higher saccharin preferences in Group LPS-LiCl+Saccharin relative to Group NaCl-LiCl+Saccharin. The results of the current study provide additional evidence for the deleterious effects of LPS on learning and memory in aversive conditioning.     

Area postrema mediation of physiological and behavioral effects of lithium chloride in the rat.

The area postrema (AP), a chemoreceptor trigger zone for nausea and vomiting, has been implicated in taste aversion conditioning with LiCl. In addition to taste aversion acquisition, the present studies indicate that a number of other responses to LiCl administration are eliminated by lesions of the AP. These include a behavioral response, 'lying-on-belly' as well as two physiological responses, delayed stomach emptying and hypothermia. These findings suggest that the area postrema is critically involved in the detection of LiCl and in a wide range of responses to this toxin. They also provide strong evidence that the failure to acquire conditioned taste aversions to LiCl-paired flavors after AP lesions can be attributed to the absence of a significant 'illness' response in lesioned animals.     

Effects of metabotropic glutamate receptor 5 on latent inhibition in conditioned taste aversion

Latent inhibition (LI) is a phenomenon by which pre-exposure of a conditioned stimulus (CS) prior to the CS-unconditioned stimulus (US) pairings retards conditioned responding (CR). LI has been demonstrated in a variety of learning tasks including conditioned taste aversion (CTA). Earlier work has shown that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 (mGlu5) antagonist, is able to disrupt classical conditioning in CTA. The present study investigated the involvement of mGlu5 receptors in LI using a CTA procedure. In the first experiment, rats received either water (non-pre-exposed, NPE) or a saccharin solution (pre-exposed, PE) on 2 consecutive days. The animals then received conditioning in which a fixed amount of saccharin was paired with lithium chloride and then the CR to the taste was tested. Either MPEP (3, 6, 12 mg/kg) or vehicle was injected intraperitoneally prior to taste pre-exposure or testing. Animals in the vehicle control groups displayed LI. MPEP injections before pre-exposure trials attenuated LI but also reduced consumption during pre-exposure, which obscured interpretation of the LI effect. The second experiment used four pre-exposure trials and controlled access to fixed amount of the solutions during the pre-exposure as well as the conditioning trials. Rats were injected before pre-exposure trials but not before the test trial. The results found that MPEP attenuates latent inhibition suggesting that the mGlu5 receptor exerts an influence on the processes that underlie the effects of taste pre-exposure on conditioning.     

Conditioned taste aversion and c-Fos expression in cholestatic rats

Rats in which a ligation of the bile duct (BDL) was paired with a saccharin taste developed a persistent conditioned taste aversion in both preference and taste reactivity tests. All BDL animals regardless of pairing had increased c-Fos-like immunoreactivity (FLI) in the area postrema and the nucleus of the solitary tract. This FLI may reflect the illness associated with BDL, but there was no evidence of conditioned FLI.     

The effects of trimethyltin chloride on the acquisition of long delay conditioned taste aversion learning in the rat

Naive rats injected with LiCl at various times following consumption of a novel saccharin solution subsequently avoided the ingestion of saccharin with the degree of the aversion related to the interval between ingestion and LiCl administration. Although a similar relationship was also evident in animals which had received a single intragastric administration of trimethyltin chloride 21 days prior to the pairing of saccharin and LiCl, the trimethyltin-pretreated subjects receiving delayed injections of LiCl displayed weaker taste aversions than those not exposed to trimethyltin. This disruption in the acquisition of taste aversions over long delays is consistent with other work suggesting that trimethyltin disrupts tasks involving short-term memory. The utility of the conditioned taste aversion paradigm in detecting and characterizing drug toxicity was discussed.     

Effects of insular cortex lesions on conditioned taste aversion and latent inhibition in the rat

The present study tested the hypothesis that lesions of the insular cortex of the rat retard the acquisition of conditioned taste aversions (CTAs) because of an impairment in the detection of the novelty of taste stimuli. Demonstrating the expected latent inhibition effect, nonlesioned control subjects acquired CTAs more rapidly when the conditioned stimulus (0.15% sodium saccharin) was novel rather than familiar (achieved by pre-exposure to the to-be-conditioned taste cue). However, rats with insular cortex lesions acquired taste aversions at the same slow rate regardless of whether the saccharin was novel or familiar. The pattern of behavioural deficits obtained cannot be interpreted as disruptions of taste detection or stimulus intensity, but is consistent with the view that insular cortex lesions disrupt taste neophobia, a dysfunction that consequently retards CTA acquisition because of a latent inhibition-like effect.     

Partial recovery of gustatory function after neurol tissue transplantation to the lesioned gustatory neocortex

The ability of homotypic cortical tissue grafts to induce recovery of function after a gustatory neocortex (GN) lesion was studied using the conditioned taste aversion (CTA) paradigm. On acquisition day, 26 GN-lesioned and 8 sham-lesioned rats were presented with a saccharin solution, followed by an injection of the illness-inducing agent lithium chloride (LiCl). On the test day, 2 days later, saccharin was presented again. The GN-lesioned rats showed significantly less aversion to saccharin on the test day, indicating that the lesion impaired their ability to form taste-illness association. Nine of the lesioned rats were then bilaterally transplanted with fetal GN tissue. Nine weeks after the transplantation, the rats were presented with a LiCl solution, which served as both a tastant and an illness-inducing agent. An NaCl solution, which tasted very similar to the LiCl solution, was used to test the CTA to salt 3 days later. The nontransplanted rats consumed significantly more LiCl than the transplanted and sham-operated rats on the acquisition day, but both transplanted and nontransplanted rats consumed more NaCl than sham-operated rats on the test day. Nissl and Golgi stainings showed numerous somata and extensive arborization of neurons within the grafts. The results indicate that fetal GN grafts can restore the ability to integrate gustatory and visceral inputs but not to form long-lasting taste-illness associations.     

Lateral parabrachial nucleus lesions in the rat: neophobia and conditioned taste aversion

The present study investigated the hypothesis that the conditioned taste aversion (CTA) deficit consequent to lesions of the lateral parabrachial nucleus (LPBN) may be due to a disruption of neophobia. In Experiment 1, subjects were tested with one of three taste stimuli (alanine, saccharin, or quinine) and two nontaste stimuli (capsaicin and almond odor). Ibotenic acid lesions of the LPBN eliminated neophobia to alanine and saccharin but had no influence on the neophobic response to quinine, capsaicin, or almond odor. In Experiment 2, all the LPBN-lesioned (LPBNX) rats failed to develop a CTA. These results do not support the experimental hypothesis. Not only was the lesion-induced disruption of neophobia restricted to taste stimuli, the deficit was selective within that category. It is already known that LPBNX rats are unable to acquire conditioned aversions to capsaicin as well as alanine. Thus, the absence of a conditioned ingestional aversion in LPBNX rats is not predicated upon the absence of a neophobic response to the target stimulus. The present results, although exposing a stimulus selective disruption of neophobia, suggest that this deficit is independent of, rather than responsible for, the absence of conditioned ingestional aversions in rats with LPBN lesions.     

Systemic treatment with the enteric bacterial fermentation product, propionic acid, produces both conditioned taste avoidance and conditioned place avoidance in rats

Propionic acid, an enteric bacterial fermentation product, has received recent attention in regards to satiety and obesity in humans. The possibility that propionic acid might produce internal aversive cues was investigated in two experiments using conditioned taste avoidance and place avoidance procedures to index the potential aversive nature of systemic treatment with propionic acid in male rats. Experiment 1 examined the effect of systemic treatment with propionic acid (500 mg/kg), LiCl (95 mg/kg) or vehicle (all corrected to pH 7.5) on the formation of conditioned taste avoidance using a lickometer procedure. On 3 acquisition days three groups of rats were injected with propionic acid, LiCl or vehicle, following 30 min access to 0.3 M sucrose solution. Both the Propionic acid group and the LiCl group evidenced a conditioned taste avoidance by the end of the acquisition period. During a drug free extinction phase the Propionic acid group showed extinction of the taste avoidance whereas the LiCl group did not. Experiment 2 involved place preference conditioning with propionic acid treatment associated with one novel context and vehicle with a different novel context on 6 conditioning trials for each type of injection. Place avoidance was assessed on two drug free extinction trials. Multi-variable assessment of the unconditioned (Acquisition Trials) and conditioned effects (Extinction Trials) of propionic acid on locomotor activity was quantified as was chamber choice time on the extinction trials. Propionic acid induced a significant place avoidance and significantly reduced locomotor activity on some acquisition trials. During the extinction trials rats exhibited enhanced locomotor activity levels in the propionic acid associated chamber, likely due to the conditioned aversive nature of this chamber.     

Hippocampus, aging, and segregating memories

Rats use time-of-day cues to modulate learned taste aversion memories. If adult rats are accustomed to drinking saline in the evening and they receive a lithium chloride injection after drinking saline in the morning, they form a stronger aversion to saline than rats that were conditioned after drinking saline at the familiar time. The difference indicated that the rats formed segregated representations of saline taste and the time of day the saline was consumed. This was inferred because the modulation of learning by time of day was observed when the aversions were tested at the familiar evening drinking time. If the rats had formed a compound representation of saline taste and the time of day it was consumed, the opposite pattern of differences would be expected. We used this modulation of learning by time of day to assay whether aged rats have an impaired ability to form segregated representations of experience. We find that aged rats had similar saline aversions if they were conditioned at either the familiar or the unfamiliar time of day. Furthermore, dorsal hippocampal lesions affecting also the overlying parietal cortex in the aged rats caused greater saline aversions if the rats were conditioned after drinking saline at the familiar time of day. This indicated that aged rats are aware of the time of day but after the lesion, they act as if they do not segregate saline taste from the time of day it was consumed. The results suggest that the ability to form segregated representations of a complex experience is impaired in aging and abolished by hippocampal lesions.     

Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone

1. 1. Water-deprived male rats were given access to water, or to a 0.005M sodium saccharin solution, or to a 0.9% sodium chloride solution, during a 30 min test period.

2. 2. Naloxone (0.01–10.0 mg/kg) produced dose-dependent reductions in the consumption of each fluid. Saccharin-drinking was significantly reduced by 0.01 mg/kg naloxone, and water- and saline-drinking by 0.1 mg/kg naloxone. Quaternary naloxone (0.01–10.0 mg/kg) had no effect on drinking under any condition.

3. 3. Access to the saline solution resulted in hyperdipsia, due to a prolongation of the initial bout of avid drinking in the thirsty rats. Naloxone, in small doses, completely abolished this hyperdipsia. Since the quaternary compound had no effect, it was concluded that opiate antagonist suppression of saline-induced hyperdipsia was probably mediated at central opiate receptors.

Conditioned taste aversion and c-Fos expression in cholestatic rats.

Rats in which a ligation of the bile duct (BDL) was paired with a saccharin taste developed a persistent conditioned taste aversion in both preference and taste reactivity tests. All BDL animals regardless of pairing had increased c-Fos-like immunoreactivity (FLI) in the area postrema and the nucleus of the solitary tract. This FLI may reflect the illness associated with BDL, but there was no evidence of conditioned FLI.     

c-Fos-like immunoreactivity in the brainstem following gastric loads of various chemical solutions in rats

The distribution of c-Fos-like immunoreactivity (c-FLI) in the lower brainstem especially in the area postrema (AP), nucleus of the tractus solitarius (NTS) and parabrachial nucleus (PBN) was examined following gastric loads of various chemical solutions in rats. An aliquot of 7.5 ml of each stimulus was intragastrically infused, and c-FLI was detected. The most remarkable c-FLI was induced by LiCl, lactose and ethanol which are known to be effective unconditioned stimuli in conditioned taste aversions. Polycose and disaccharides such as sucrose and maltose induced more c-FLI than monosaccharides such as glucose, fructose and galactose. Relatively low levels of c-FLI were observed for other sweeteners such as saccharin, glycine and alanine, and other basic taste stimuli such as NaCl, HCl, quinine and umami substances. Each stimulus induced a similar proportion of c-FLI among the subnuclei of the NTS, but not in the PBN, where chemicals effective in inducing conditioned taste aversions elicited stronger c-FLI in the external lateral subnucleus, and those in inducing conditioned taste preferences such as Polycose and glucose elicited stronger c-FLI in the dorsal lateral subnucleus. Vagotomy reduced c-FLI to about 50% for LiCl stimulation and to about 30% for sucrose stimulation, suggesting that LiCl has a larger proportion of extravagal inputs than sucrose.     

Lateral parabrachial nucleus lesions in the rat: aversive and appetitive gustatory conditioning

Previous research involving tests of innate preferences and aversions shows that bilateral ibotenic acid lesions of the visceral neurons located in the lateral parabrachial nucleus of the pons selectively disrupt consumption of those gustatory stimuli whose intake is augmented or restricted by their postoral consequences. The present study examined the performance of the same experimental subjects in learned preference and aversion tasks. The lesioned rats failed to develop a conditioned taste aversion (Experiment 1), a conditioned flavor preference (Experiment 2), and a conditioned aversion to the oral trigeminal stimulus, capsaicin (Experiment 3). The pattern of results from both types of taste-guided behaviors (innate and learned) suggests that excitotoxic lesions of the lateral parabrachial nucleus diminish sensitivity to gastrointestinal feedback which, in the present experiments, precludes aversive and appetitive associative learning.     

Modulation of brain and pituitary dopamine receptors by estrogens and prolactin

1. Ovariectomized rats were treated for 2 weeks with 17β-estradiol (0.0002–100 μg/day). [³H] spiperone striatal dopamine receptor binding was maximally increased by 30% after 0.05 μg/day of 17β-estradiol and a similar increase is observed at higher doses. By contrast, plasma prolactin concentrations of these rats are unchanged after 0.05 μg/day and increased after 100 μg/day. A chronic estradiol treatment at very low doses (0.0002–0.001 μg/day) leads to increases in pituitary dopamine receptor binding while plasma prolactin levels are unchanged. At higher doses (1–100 μg/day) binding is decreased and plasma prolactin concentrations are elevated.

2. [³H]spiperone striatal dopamine receptor binding is elevated in lactating female rats compared to intact or ovariectomized female rats.

3. Anterior pituitary dopamine receptor concentrations fluctuate during the estrous cycle while striatal dopamine receptors are unchanged.

4. An injection of 30 ng of estradiol, which reproduces the estradiol proestrus surge, leads as in proestrus, to a decrease of anterior pituitary dopamine receptors.     

Deficits in conditioned heart rate and taste aversion in area postrema-lesioned rats

Previous studies have shown that area postrema (AP) lesions cause deficits in conditioned taste aversion in the rat. They also lead to chronically lowered heart rate which can be reversed by the animals' increased appetite for and ingestion of hypertonic saline. Although not previously examined in conditioned taste aversion, changes in autonomic nervous system activity as reflected in heart rate may be an important aspect of conditioning. The present study investigated the effects of AP lesions on heart rate conditioned responses (CRs) and unconditioned responses (UCRs). Two groups of AP lesioned and sham-operated rats, one that did and one that did not drink saline solution to raise heart rate, were studied. Both LiCl and scopolamine, which have opposite effects on heart rate, were the unconditioned stimulus (UCS) agents in two separate studies. In intact rats, LiCl-mediated conditioned taste aversion was associated with decreased conditioned stimulus (CS) intake and decreased heart rate Both effects were blunted by AP lesions, although all rats displayed heart rate UCRs to LiCl. The AP rats that drank saline behaved like intact rats exhibiting both a conditioned taste aversion and conditioned heart rate responses to the CS. Although CS intake decreased, no heart rate CRs developed with scopolamine. Scopolamine-mediated conditioned taste aversion was attenuated in both saline and non-saline drinking AP-lesioned groups. Thus, when conditioned taste aversion was associated with heart rate CRs, the AP lesion-induced deficit was counteracted by saline ingestion. Conversely, when there were no heart rate CRs, conditioned taste aversion was disrupted by the lesion regardless of saline ingestion.