Progesterone,estradiol, testosterone and dihydrotestosterone: Effects on rate of extinction of a conditioned taste aversion in rats

An investigation was made to determine why the prolonged rate of extinction of a conditioned taste aversion induced by testosterone is diminished when the ovarian system is intact. In the first experiment, 36 gonadectomized female rats received injections of progesterone, testosterone propionate (TP), progesterone plus TP, or sesame oil. Progesterone did not reduce the slow extinction rate induced by TP. In a second experiment, 36 gonadectomized female rats received injections of estradiol dipropionate (EP), TP, EP plus TP, or sesame oil. Estradiol dipropionate reduced the effectiveness of TP in prolonging the extinction rate. These same results (the ineffectiveness of progesterone and the effectiveness of EP in blocking TP-induced slow extinction) were also observed in male rats in a third experiment. Dihydrotestosterone, as well as testosterone, has been shown to prolong extinction: hence, in a fourth experiment 30 gonadectomized female rats received injections of EP, TP, dihydrotestosterone propionate (DHTP), EP plus DHTP, or sesame oil. Estradiol dipropionate reduced the DHTP-induced slow extinction. All the above data are consistent with the hypothesis that it is estradiol from the ovaries that diminishes the effect of testosterone on the rate of extinction of a conditioned taste aversion in intact females.     

Sensitivity of male, female, and androgenized female rats to testosterone during extinction of a conditioned taste aversion

Experiment 1 tested the hypothesis that male and female rats differ in the amount of testosterone (T) required to prolong extinction of a conditioned taste aversion. Gonadectomized male and female rats were implanted with empty or 30-, 60-, or 120-mm T-filled capsules. The males had slower extinction rates than females when both were implanted with 30-mm and 60-mm capsules but not when implanted with 120-mm capsules. The dimorphic sensitivity was not due to differences in plasma T levels: the levels for males and females were not different. Experiment 2 tested the hypothesis that the presence of T during the perinatal period results in a greater sensitivity to T in adulthood. Females exposed to T during the perinatal period showed prolonged extinction when given a 30-mm T-filled capsule as an adult, whereas unexposed females did not. These results support the hypothesis that the amount of T required to activate the prolonged extinction in an adult depends on perinatal exposure to T.     

The role of conditioned taste aversion in the suppression of food intake by estradiol

In three experiments, ovariectomized rats were given a familiar or novel diet prior to treatment with a brain-enhanced estradiol-chemical delivery system (E2-CDS, 1 mg/kg). Experiment 1 showed that food intake was suppressed in subjects receiving either diet, but animals given a novel diet initially showed a profound anorexia which eventually recovered to the moderate suppression of animals given the familiar diet. In Experiment 2, rats showed an aversion to a novel diet paired with the E2-CDS in a two-choice preference test given on Day 2 after the injection, indicating that the initial large reduction in intake was mediated by a conditioned taste aversion. However, no aversion was observed seven days after the E2-CDS, suggesting that the residual intake suppression was mediated by unconditioned aversion or appetite suppression. Experiment 3 showed that lengthening the postovariectomy time resulted in a taste aversion that persisted for a longer duration.     

Pseudo-castration effects of social isolation on extinction of a taste aversion

The effects of social isolation on the slow rate of extinction of a conditioned taste aversion exhibited by male rats were investigated. When the males were isolated for six weeks prior to poisoning, they showed a nontypical, rapid rate of extinction from the conditioned taste aversion. The isolation had no effect on the already rapid rate of extinction exhibited by the females. Behaviorally, the change in the rate of extinction in the male following social isolation is identical to the change in rate that occurs following castration of the male. It was therefore proposed that isolation increased the rate of extinction in the male by decreasing the availability of testosterone. This proposal was supported by the finding that socially isolated males had lower plasma testosterone levels than did non-isolated males.     

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.     

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.     

Rapid extinction of a conditioned taste aversion following unreinforced intraperitoneal injection of the fluid CS

After drinking a novel, saccharin-cyclamate solution, two groups of rats were poisoned with LiCl injection in order to establish a conditioned taste aversion, while a control group was not poisoned. Eighteen hours later, one of the poisoned groups of rats received differential unreinforced exposure to the sweet solution via an intraperitoneal injection. The group injected with the concentrated form of the saccharin-cyclamate solution showed subsequent rapid extinction of the conditioned taste aversion. An analogy was made to the technique of flooding (response prevention) used to hasten extinction of active, shock-motivated avoidance behavior.     

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.     

Effects of midazolam on acquisition and extinction of conditioned taste aversion memory in rats

Some intravenous anesthetic agents such as midazolam are known to induce anterograde and retrograde amnesia. We analyzed the effect of midazolam by the conditioned taste aversion (CTA) acquisition and retention. After the rats were offered 0.1% sodium saccharin (Sac) as conditioned stimulus (CS), an intraperitoneal (i.p.) injection of several concentrations (5–30 mg/kg) of midazolam was followed by an i.p. injection of 0.15 M LiCl (2% of body weight) as unconditioned stimulus (US). The rats, which acquired CTA by every CS–US paradigm, strongly avoided Sac on the 1st test day after conditioning and maintained the avoidance for 3 days. We have already reported that Sac intake abruptly increased on the 2nd test day and the almost complete extinction occurred on the 3rd test day after conditioning by injection of subhypnotic dose of propofol before LiCl-injection. In contrast, we found that subhypnotic dose of midazolam suppressed not only CTA acquisition, but also CTA retention. On the other hand, an α2-adrenergic blocker, yohimbin (1 mg/kg) suppressed only the CTA retention. These results suggest that the subhypnotic doses of midazolam firstly affect the acquisition mechanism of the CTA memory (CTAM), resulting the suppression of the retention of CTAM.     

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.     

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.     

The effect of androgen on the retention of extinction memory after conditioned taste aversion in mice

Conditioned taste aversion (CTA) induced by the application of a novel taste such as sodium saccharin (Sac) as the conditioned stimulus (CS) and a malaise-inducing agent as the unconditioned stimulus (US), results in acquisition of CTA memory to Sac. In contrast, CTA is extinguished by repeated presentations of the CS without the US, resulting in acquisition of the extinction memory. We examined the effects of androgenic hormones on acquisition and retention of extinction memory in mice. We gonadectomized sexually immature mice and continuously administered androgens to these animals. After sexual maturation, the mice underwent a conditioning period followed by an extinction period. Retrieval tests revealed that the androgen-treated group showed significantly greater retention of extinction memory than the non-treated group 5 weeks later, whereas such significant difference was not observed in acquisition of extinction memory. These results demonstrate the enhancing effect of androgens on retention of extinction memory.     

Conditioned taste aversion induced by estradiol pellets.

In two experiments, ovariectomized rats were given a novel diet prior to the implantation of a fused pellet of estradiol (E2 pellet). In short-term (3 weeks) ovariectomized rats, the suppression of food intake induced by estrogen was not affected by the introduction of the novel diet. However, a sensitive two-choice preference test revealed that subjects implanted with the E2 pellet had a lesser preference for the novel diet than controls implanted with the vehicle pellet. In long-term (18 weeks) ovariectomized rats, implantation of the E2 pellet had a large effect on the consumption of the novel diet. Intake was reduced to less than 1 g in all subjects on Days 3-7 after E2 pellet implantation. A subsequent two-choice preference test indicated the presence of a strong aversion to the novel diet in the estradiol-treated rats relative to the controls. These experiments show that estradiol can induce conditioned taste aversions that have either no effect on intake or totally suppress food intake, depending upon postovariectomy time.     

Forebrain structures specifically activated by conditioned taste aversion

This study investigates which forebrain structures show Fos protein expression during conditioned taste aversion (CTA) acquisition and whether Fos expression depends on the aversion strength. A novel taste paired with an intraperitoneal injection of a low dose of the malaise-inducing agent lithium chloride (LiCl) induced a weak CTA, whereas associating this novel taste with a high dose of LiCl induced a strong CTA. Increasing the strength of the gastric malaise alone enhanced Fos expression in central, basal, and lateral amygdala nuclei and decreased Fos expression in the nucleus accumbens core. Taste-malaise association induced specific Fos activation in the insular cortex (with both the low and the high doses of LiCl) and the nucleus accumbens shell (with the high LiCl dose only). No significant variation of Fos expression was measured in the perirhinal cortex. Several forebrain areas may be sites of taste-malaise convergence during CTA acquisition depending on the strength of the aversion.     

Estradiol-induced conditioned taste aversion and place aversion in rats: sex- and dose-dependent effects.

Effects of various doses (0-250 micrograms/kg, SC) of estradiol-17 beta (E2) in a two-bottle choice conditioned taste aversion and a two-compartment conditioned place preference procedure were studied in male and female rats. Dose-dependent taste aversion and place aversion effects of E2 were established, and the conditioned taste aversion procedure was found to be more sensitive in detecting aversive properties of E2 than the conditioned place preference procedure. Although aversive properties of E2 were found in both sexes, the effects were clearly more prominent in males as compared to females. From this study, it was concluded that E2 acts as an unconditioned aversive stimulus in both male and female rats capable of gaining control over different types of behavior by associative learning.     

The anterograde effect of ECS on the acquisition, retrieval and extinction of conditioned taste aversion.

Conditioned taste aversion was established in rats by spontaneous or forced drinking of saccharin (0.1%, CS) followed after 30 min by poisoning (0.15 M LiCl, 2% body weight, US) and retention was tested by offering the animals saccharin 1 or 2 days later. ECS (50 Hz, 50 mA, 0.5 s) applied 120, 60, 30 or 15 min before saccharin administration elicited an increasing disruption of CTA acquisition which was complete with the 15-min ECS-CS interval. On the other hand, ECS applied 2, 15 or 30 min after saccharin drinking caused either no or only moderate CTA disruption. ECS applied 30 min before retention testing reduced the fluid intake but did not prevent CTA retrieval. Forced feeding saccharin to rats with a strong CTA, established by repeated saccharin-LiCl pairing, caused CTA extinction which was only slightly decreased by ECS applied 10 or 60 min before the extinction trial. The proactive ECS effects prevent formation of the short-term gustatory trace but do not seriously disrupt the gustatory trace-poisioning association and leave the CTA retrival and extinction unaffected. In this respect ECS resembles other procedures that differentially interfere with CTA acquisition and retrieval, particularly the effect of paradoxical sleep deprivation.     

Early learning and retention of a conditioned taste aversion

Weanling rats were trained on a taste aversion task and tested 60 days later using the single bottle and preference methods for assessing the retention of a taste aversion, and a competitive situation in which the CS was eventually substituted for plain water. Only the competitive situation showed the effects of the early taste aversion training. The results are discussed in terms of the conditioning and reactivation of adrenocortical steroid elevations and how these might affect subsequent retrieval.