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Examinations of CS and US preexposure and postexposure in conditioned taste aversion: Applications in behavioral interventions for chemotherapy anticipatory nausea and vomiting
Learning and Motivation 59 (2017) 1–10
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Examinations of CS and US preexposure and postexposure in conditioned taste aversion: Applications in behavioral interventions for chemotherapy anticipatory nausea and vomiting Ying-Chou Wanga, Hsin-Yeh Leeb, Alan Bo-Han Heb, Andrew Chih Wei Huangb, a b
MARK
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Department of Clinical Psychology, Fu-Jen Catholic University, New Taipei City 24205, Taiwan Department of Psychology, Fo-Guang University, Yilan County 26247, Taiwan
AR TI CLE I NF O
AB S T R A CT
Keywords: CS preexposure CS postexposure US preexposure US postexposure Conditioned learning Interference
Examining CS or US preexposure and postexposure to dissociate conditioned stimulus (CS)-unconditioned stimulus (US) conditioned learning and apply these findings to alleviate anticipatory nausea and vomiting are crucial for cancer chemotherapy patients. The present study utilized a conditioned taste aversion (CTA) paradigm in rats to develop a new behavioral intervention. Experiment 1 evaluated Control, Conditioning, CS preexposure, and CS postexposure groups. Experiment 2 evaluated Control, Conditioning, US preexposure, and US postexposure groups. After conditioning in both experiments, rats were given the CS alone without the US once per day over three trials, and their conditioned taste aversion was measured. The results showed that both CS preexposure and US preexposure interfered with subsequent CS-US conditioning, indicating that both induced proactive interference. Although CS postexposure interfered with prior CS-US conditioning, which indicated extinction, US postexposure did not alter CS-US conditioning. The findings should be considered for the development of new nonpharmacological clinical interventions for cancer patients with chemotherapy-induced anticipatory nausea and vomiting.
1. Introduction Theories of associative learning have provided many ways to dissociate connections between a conditioned stimulus (CS) and an unconditioned stimulus (US). In the conditioned taste aversion (CTA) paradigm, strength of the conditioned response (CR) can be modified by preexposure or postexposure to the CS or US. How the CS or US preexposure affect CS-US conditioning is an essential issue. One hypothesis suggests that CS preexposure (De la Casa & Lubow, 1995; Lipp, Siddle, & Vaitl, 1992) and US preexposure (Goddard, 2004; Matzel, Brown, & Miller, 1987) attenuate the strength of subsequent CS-US conditioning. For example, exposure to a sucrose CS solution before sucrose-illness conditioning interfered with subsequent CTA conditioning (Bakner, Strohen, Nordeen, & Riccio, 1991). In addition, frequency, duration, and amount of CS preexposure lessen conditioned suppression of CS intake during CS-US conditioning (De la Casa & Lubow, 1995). A human latent inhibition study of autonomic conditioning showed that different amounts of CS preexposure produced different degrees of latent inhibition on later CS-US conditioning, which was demonstrated by electrodermal and heart rate responses (Lipp et al., 1992). With regard to US preexposure, a study has reported that rats made fewer magazine entries when preexposed to the US (one food pellet) prior to being given three food pellets as the US (Goddard, 2004). These data show that US preexposure attenuates subsequent ⁎
Corresponding author at: Department of Psychology, Fo Guang University, No. 160, Linwei Road, Jiaosi Shiang, Yilan County 26247, Taiwan. E-mail address: [email protected] (A.C.W. Huang).
http://dx.doi.org/10.1016/j.lmot.2017.06.001 Received 27 April 2017; Received in revised form 22 June 2017; Accepted 22 June 2017 0023-9690/ © 2017 Elsevier Inc. All rights reserved.
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conditioned learning. Similarly, US preexposure has been found to interfere with conditioned lick suppression in an excitatory training context (Matzel et al., 1987). Also, US preexposure has been shown to attenuate well-trained CTA conditioning (Riley, Jacobs, & LoLordo, 1976). Therefore, the hypothesis that CS or US preexposure can attenuate CS-US conditioning in the CTA task was examined further in the present study. In regard to how CS or US postexposure affects the CS-US conditioning, each type of postexposure has shown a different result. In the case of CS postexposure, previous studies have indicated that prior CS-US conditioning can be extinguished through CS postexposure (Huang, Shyu, Hsiao, Chen, & He, 2013; Myers and Davis, 2002). The effects of US postexposure on CS-US conditioning have been inconsistent (Brookshire & Brackbill, 1976; Colby & Smith, 1977; Holman, 1976; Kawai & Nakajima, 1996; Rescorla, 1974; Riley et al., 1976; Sawa & Ishii, 2012). For example, one line of studies showed that US preexposure attenuated conditioned flavor preference (Sawa & Ishii, 2012) and CTA paradigms (Colby & Smith, 1977). Another line of studies demonstrated that US postexposure strengthened previous CS-US conditioning. For example, data from a CTA study have shown that LiCl postexposure enhanced LiClinduced taste aversion learning (Holman, 1976). A study of fear conditioning found that US footshock postexposure increased the previous fear conditioning (Rescorla, 1974). Other studies showed that US postexposure did not affect previous taste aversion learning (Riley et al., 1976) or apomorphine-induced conditioned suppression (Brookshire & Brackbill, 1976). Accordingly, how CS or US postexposure alter previous CS-US conditioning needs to be further studied. Applications of CS or US preexposure and postexposure might provide some methods to reduce the drug-induced side effects of chemotherapy, particular anticipatory nausea and vomiting (Stockhorst, Steingrueber, Enck, & Klosterhalfen, 2006). Previous studies have found that taste aversion occurred very fast, within 24 h after the first course of chemotherapy (Jacobsen et al., 1993; Mattes, Arnold, & Boraas, 1987). Such taste aversion has been explained by taste aversion learning in which daily tastants (CSs) are conditioned to the subsequent side effects of the drugs (e.g., cytotoxic drugs or USs) that are used to treat the illness. Cancer patients who undergo repeated chemotherapy, however, tend to exhibit an increase in the strength of nausea and vomiting (Bovbjerg et al., 1992; Greene & Seime, 1987; Montgomery & Bovbjerg, 1997; Montgomery et al., 1998). Anticipatory nausea and vomiting then occur as CRs when a CS is presented without the drugs (i.e., USs; Bovbjerg, 2006; Dolgin, Katz, McGinty, & Siegel, 1985). Therefore, procedures that involve CS or US preexposure or postexposure may weaken cytotoxic drug-induced side effects in cancer patients who undergo chemotherapy. Previously, how CS or US preexposure and postexposure affect LiCl-induced CTA has not been systematically investigated in the same study. Accordingly, the present study focused on two issues: (i) Whether CS or US preexposure and CS postexposure attenuate CS-US conditioned learning in the CTA paradigm, and (ii) Whether US postexposure enhances, interferes with, or does not influence CS-US conditioned learning in the CTA paradigm. The present study provides a new hypothesis to explain how CS and US exposure reduces the side effects of chemotherapy and suggests new nonpharmacological interventions. 2. Materials and methods 2.1. Animals Eighty male Wistar rats were obtained from the Laboratory Animal Center of the National Taiwan University College of Medicine in Taipei, Taiwan. The rats weighed 250–300 g and were approximately 6 weeks old at the beginning of the experiments. The rats were allowed to habituate in a temperature-controlled (20 ± 2 °C) colony room for 7 days. They were group-housed, two per cage, in a colony room on a cycle of 12 h each of light and dark (lights were on from 6:00 AM-6:00 PM), with food and water available ad libitum with the exception of specific treatments in some phases of the study. The present study was performed in compliance with the Animal Scientific Procedures Act of 1986 and received local ethics committee approval. All efforts were made to minimize animal suffering and the number of animals used. 2.2. Apparatus The present study utilized a lickometer apparatus to measure intake volume, the interlick intervals, the latency period between contacting the burette, and the number of licks. The lickometer consisted of a wire-mesh cage, a white panel, and a 25-ml burette with 0.1-ml graduations. The panel was mounted in front of the wire-mesh cage and connected to the burette. Only the intake volume was recorded in the water-deprived rats in the present study. This apparatus was also used in a previous similar study (Huang & Hsiao, 2002). 2.3. Experimental procedure Experiment 1. Effects of CS preexposure and CS postexposure on CS-US conditioning All of the rats underwent a water-deprivation regimen for 23.5 h/day for 7 days. On the final 2 days, the rats were given water in the morning for 15 min and in the afternoon 30 min after training in the lickometer apparatus. The 30-min water availability regimen each day was performed during all phases of the experiment. Experiment 1 included CS preexposure, conditioning, CS postexposure, and testing phases. An exception was that although the testing phase was administered for 3 days, rats encountered the water regimen on each of the 5 days. In the CS preexposure phase, they were assigned to four groups that were given either a 0.1% saccharin solution for a CS or water and then injected with 4 ml/kg of a 0.15 M isotonic NaCl solution (0.1% saccharin solution-0.15 M NaCl, 2
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Water-0.15 M NaCl, 0.1% saccharin solution-0.15 M NaCl, and Water-0.15 M NaCl groups). In the conditioning phase, these four groups were given the CS and then injected with 4 ml/kg of a 0.15 M NaCl or 0.15 M LiCl solution (0.1% saccharin solution-0.15 M NaCl, 0.1% saccharin solution-0.15 M LiCl, 0.1% saccharin solution-0.15 M LiCl, and 0.1% saccharin solution-0.15 M LiCl groups). In the CS postexposure phase, these four groups were exposed to the CS or water and then injected with 4 ml/kg of a 0.15 M NaCl solution (0.1% saccharin solution-0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M NaCl, and 0.1% saccharin solution-0.15 M NaCl groups). After the CS postexposure phase, all of the rats were exposed to the CS alone without any injection. Altogether, these four groups were denoted as the Control (n = 10), the Conditioning (n = 10), the CS preexposure (n = 10), and the CS postexposure (n = 10) groups (Fig. 1). Experiment 2. Effects of US preexposure and US postexposure on CS-US conditioning The protocol for Experiment 2 was similar to Experiment 1, with the exception being that CS preexposure and CS postexposure were replaced with US preexposure and US postexposure. Another exception was that testing was administered for 3 days while the other phases were conducted on each of 5 days. In the US phase, rats were assigned to four groups that were given a 0.1% saccharin solution for the CS or water and then injected with 4 ml/kg of a 0.15 M isotonic NaCl or LiCl solution (0.1% saccharin solution0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M LiCl, and Water-0.15 M NaCl groups). In the conditioning phase, these four groups were given the CS and then injected with 4 ml/kg of a 0.15 M NaCl or 0.15 M LiCl solution (0.1% saccharin solution-0.15 M NaCl, 0.1% saccharin solution-0.15 M LiCl, 0.1% saccharin solution-0.15 M LiCl, and 0.1% saccharin solution-0.15 M LiCl groups). In the US postexposure phase, these four groups were exposed to the CS or water and then injected with 4 ml/kg of a 0.15 M NaCl solution (0.1% saccharin solution-0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M NaCl, and Water-0.15 M LiCl groups). All of the rats were then exposed to the CS alone without any injections for 15 min in the test phase. Altogether, these four groups were denoted as the Control (n = 10), the US preexposure (n = 10), the Conditioning (n = 10), and the US postexposure (n = 10) groups (Fig. 1). 2.4. Drug preparation and administration Saccharin solutions and all of the chemicals for the NaCl and LiCl solution preparations were purchased from Sigma (St. Louis, MO, USA). A 0.1% concentration of the saccharin solution was dissolved in water. Both a 0.15 M NaCl isotonic solution and a 0.15 M LiCl isotonic solution were dissolved in water. The given volumes of NaCl and LiCl were both 4 ml/kg, and all of the drugs were administered intraperitoneally. 2.5. Statistical analysis A 4 × 3 two-way mixed analysis of variance (ANOVA) with repeated sessions was used to analyze the mean intake volume (ml), which was determined with the lickometer. When appropriate, Fisher’s Least Significant Difference (LSD) post hoc tests were conducted for sessions 1–3. A one-way ANOVA was also conducted to analyze the mean total intake volume (ml) for all of the sessions, followed by Fisher’s LSD post hoc tests when appropriate. Values of p < 0.05 were considered statistically significant. 3. Results 3.1. Experiment 1: CS preexposure and CS postexposure The mean ( ± SEM) intake volume over sessions 1–3 was measured in water-deprived rats in the Control, Conditioning, CS preexposure, and CS postexposure groups. This experiment tested whether CS preexposure and CS postexposure affect the strength of CS-US conditioning. A 4 × 3 two-way mixed ANOVA with repeated sessions revealed a significant effect of group (F3,36 = 21.63, p < 0.05) but no effect of session (F2,72 = 0.90, p > 0.05). A significant group × session interaction was observed (F6,72 = 4.07, p < 0.05). The post hoc Fisher’s LSD test indicated there were significant differences between the Control and Conditioning groups in sessions 1–3 (p < 0.05). Both CS preexposure and CS postexposure significantly increased intake volume, compared with the Conditioning group in sessions 1–3 (p < 0.05; Fig. 2). Upon combining all the intake volume data of sessions 1–3 for all groups, a one-way ANOVA revealed that mean total intake volume differed significantly among groups (F3,36 = 21.63, p < 0.05). The post hoc Fisher’s LSD test indicated a significant difference between the Conditioning and Control groups for mean total intake volume (p < 0.05). Moreover, significant differences occurred when the CS preexposure and CS postexposure groups were compared with the Conditioning group (p < 0.05). Therefore, CS preexposure and CS postexposure appeared to attenuate CS-US conditioning (Fig. 3). 3.2. Experiment 2: US preexposure and US postexposure All of the rats underwent the preexposure, conditioning, postexposure, and test phases (the Control, Conditioning, US preexposure, and US postexposure groups). We evaluated the mean intake volume over sessions 1–3 in water-deprived rats in these four groups in the test phase. A 4 × 3 mixed two-way ANOVA revealed significant effects on group (F3,36 = 48.73, p < 0.05) and session (F2,72 = 4.64, p < 0.05) and a significant group × session interaction (F6,72 = 3.53, p < 0.05). The post hoc Fisher’s LSD test indicated that the mean intake volume of the Conditioning group was significantly less than that of the Control group in sessions 1–3 (p < 0.05). The mean intake volume in the US preexposure group significantly increased compared to the Conditioning group in 3
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Fig. 1. A timeline of Experiment 1 and Experiment 2 on preexposure, conditioning, postexposure, and testing phases for CS or US.
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Fig. 2. Mean ( ± SEM) intake volume (ml) in the Control (n = 10), Conditioning (n = 10), CS preexposure (n = 10), and CS postexposure (n = 10) groups. The Control, Conditioning, and CS postexposure groups were not exposed to the CS in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the CS postexposure group was exposed to the CS, and the other groups did not receive any CS exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference between the Control, Conditioning, CS preexposure, and CS postexposure groups. The CS was a 0.1% saccharin solution. The US was lithium chloride (LiCl).
sessions 1–3 (p < 0.05). No difference was found between the Conditioning and US postexposure groups in sessions 1–3 (p > 0.05; Fig. 4). A one-way ANOVA of the mean total intake volumes in all of the sessions revealed a significant effect of group (F3,36 = 48.73, p < 0.05). The post hoc Fisher’s LSD test indicated a significant difference between the Conditioning and Control groups (p < 0.05). There was also a significant difference between the US preexposure and Conditioning groups (p < 0.05). However, the US postexposure group did not demonstrate a significant difference from the Conditioning group (p > 0.05; Fig. 5). Conditioning was attenuated in the US preexposure group but not in the US postexposure group. However, the US postexposure group might have reached the ceiling for differences between the Conditioning and US postexposure groups. 4. Discussion In the present study, rats underwent both CS and US preexposure and postexposure to investigate how they affect CS-US conditioned learning. The present study results revealed some crucial findings. In the CS exposure experiment, the preexposure and postexposure groups both exhibited attenuation of CS-US conditioning. The CS preexposure attenuated the LiCl-induced CTA effect, indicating proactive interference or latent inhibition. The CS postexposure also reduced the CTA effect, suggesting extinction. Translation of these CS preexposure and postexposure effects with rats to humans suggests ways in which the side effects of tastantsillness conditioning for cancer patients who undergo chemotherapy may be reduced. Use of these two procedures might reduce anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Similarly, US preexposure has been revealed to attenuate CS-US conditioning, indicating a proactive interference effect. This finding suggests that administration of chemotherapy drugs before the tastants-illness conditioning might reduce the aversive side effects. Chemotherapy-induced side effects of anticipatory nausea and vomiting might be attenuated by preexposure to the tastant CS or by postexposure to the drug US. However, our results showed that US postexposure did not interfere with LiCl-induced CTA conditioning. This finding suggests that chemotherapy drugs might not influence the tastant-illness conditioning when they are given after tastant-illness conditioning. Therefore, different procedures of CS or US preexposure and postexposure may have to be developed to treat chemotherapy-induced anticipatory nausea and vomiting in cancer patients who undergo chemotherapy (Table 1). 4.1. Possible hypotheses for proactive and retroactive interference: the learning interference hypothesis of CS and US exposures in behavioral mechanisms In the present study, both CS and US preexposure proactively interfered with later CS-US conditioning. In regard to the interfering 5
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Fig. 3. Mean ( ± SEM) total intake volume (ml) in the Control (n = 10), Conditioning (n = 10), CS preexposure (n = 10), and CS postexposure (n = 10) groups over all sessions. The Control, Conditioning, and CS postexposure groups were not exposed to the CS in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the CS postexposure group was exposed to the CS, and the other groups did not receive any CS exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl).
effect of CS preexposure, the present results corroborate prior evidence of latent inhibition in conditioned learning in healthy subjects (Fouquet, Oberling, & Sandner, 2001; Hall & Channell, 1986). To explain the interfering effect of CS preexposure (i.e., latent inhibition), three hypotheses have been proposed. First, an attentional mechanism may account for latent inhibition in which the salience of the CS was diminished, thus decreasing the formation of CS-US conditioning (Lubow, 1973). Second, a cognitive mechanism was offered in which the CS is learned to be irrelevant to the US during the preexposure phase (Bonardi & Ong, 2003; Dess & Overmier, 1989). Third, an associative learning mechanism was suggested in which the CS is conditioned to no-US and subsequently blocks CS-US learning (Bouton, 1993). The above three hypotheses are based on behavioral and cognitive mechanisms. However, which neural mechanism can clearly explain the CS preexposure effect on conditioning remains unclear and awaits discovery in further studies. In regard to an explanation of the effect of CS postexposure on LiCl-induced CTA, two different hypotheses (i.e., unlearning hypothesis and interference hypothesis) may explain the extinction effect. The unlearning hypothesis posits that CS-US association weakens without US presentation, suggesting that extinction is equal to forgetting (Pavlov, 1927; Rescorla & Wagner, 1972). The interference hypothesis (Mensink & Raaijmakers, 1988) attributes the decrease in memory retrieval to retroactive interference between new learning and the original learning (Bouton, 1993, 2002, 2004), which has been termed associative competition (Bills, Dopheide, Pineno, & Schachtman, 2006; Miller & Escobar, 2002). The interference hypothesis is supported by four behavioral mechanisms: spontaneous recovery, the renewal effect, reinstatement, and rapid reacquisition. Spontaneous recovery means that CS-US conditioning is recovered again when a CS is tested alone after a long period of time following extinction (Myers & Davis, 2007). The time factor is hypothesized to be crucial for testing the interference hypothesis versus the unlearning hypothesis (Escobar, Arcediano, Platt, & Miller, 2004; Myers, Ressler, & Davis, 2006). The renewal effect occurs when the CS is conditioned in context A and extinguished in context B. The CR then reappears when the CS is presented in context A but not in context B (Bouton, Westbrook, Corcoran, & Maren, 2006; Crombag, Bossert, Koya, & Shaham, 2008). Reinstatement also supports the interference hypothesis. Following CS extinction, the US is repeatedly presented in the same context as extinction. The CS-US conditioning is then recovered in a retention test (Bouton & Bolles, 1979). Rapid acquisition also supports the interference hypothesis. When CS-US conditioning is tested following CS extinction, the CR conditions more rapidly than during initial conditioning. Therefore, a trace of the CS is assumed to be retained during extinction and can then be rapidly associated with the US (Bouton, 2004). Research on latent inhibition, however, has generated conflicting results. For example, when the time interval between preexposure and conditioning is longer, rats showed a weakened latent inhibition effect. The authors explained that the characteristics of the CS might be erased or forgotten, and that the data supported the unlearning hypothesis (Metzger & Riccio, 2009). Issues that have emerged are how the CS postexposure produces retroactive interference with CS-US conditioning and whether CS postexposure causes forgetting or interference. With regard to interference by US preexposure, two hypotheses may be suggested. One hypothesis comes from an associative 6
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Fig. 4. Mean ( ± SEM) intake volume (ml) in the Control (n = 10), Conditioning (n = 10), US preexposure (n = 10), and US postexposure (n = 10) groups. The Control, Conditioning, and US postexposure groups were not exposed to the US in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the US postexposure group was exposed to the US, and the other groups did not receive any US exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference among the Control, Conditioning, US preexposure, and US postexposure groups. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl).
viewpoint, which presumes that the US is associated with contextual stimuli in the preexposure phase. The association between the US and contextual stimuli then interferes with subsequent CS-US conditioning. Another nonassociative hypothesis proposes that the reduction of the ability of the US to associate with the CS is attributable to central habituation of the US or peripheral sensory adaptation of the US with repeated US exposure (Randich & LoLordo, 1979). Unfortunately, these two hypotheses do not provide neural mechanisms, and which hypothesis can account for US preexposure’s interference with CS-US conditioning is unclear. Importantly, the present data found that US postexposure did not affect CTA conditioning (Brookshire & Brackbill, 1976; Riley et al., 1976). However, it is still unknown whether different doses and strengths of US postexposure might have effects on conditioning learning. For example, Kawai and Nakajima (1996) used different concentrations of US postexposure to affect conditioned flavor preference. These authors suggested that a lower concentration of US postexposure did not affect conditioned flavor preference, a middle concentration of US postexposure attenuated conditioned flavor preference, and a higher concentration of US postexposure enhanced conditioned flavor preference (Kawai & Nakajima, 1996). Obviously, the strengths of US agents might be essential for change in the subsequent CS-US conditioning. To achieve an intersection of all of the explanations above, the learning interference hypothesis might be the most suitable explanation for the effects of preexposure and postexposure of CS and US. Therefore, the learning interference hypothesis of CS and US exposures in behavioral mechanisms may explain why CS preexposure and postexposure and US preexposure decreased LiClinduced CTA effects. The novel hypothesis is based on the learning interference viewpoint that either the CS or the US was associated with one kind of stimulus and proactively interfered with subsequent CTA conditioning. Moreover, a specified CS in the postexposure phase was also associated with a change in the environment or context to form retroactive interference with the LiCl-induced CTA conditioning. In conclusion, the learning interference hypothesis of CS and US exposures in behavioral mechanisms can be applied to treat chemotherapy-induced side effects in anticipatory nausea and vomiting. Regardless of whether proactive or retroactive interference is applied, the process of learning interference may be used to attenuate tastant-illness conditioning for cancer patients who undergo chemotherapy.
4.2. Clinical implications: behavioral interventions for cancer chemotherapy-induced anticipatory nausea and vomiting Pharmacological interventions (e.g., benzodiazepines and serotonin-3 receptor antagonists) and nonpharmacological interventions (e.g., behavioral interventions) have been considered for the relief of chemotherapy-induced anticipatory nausea and vomiting 7
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Fig. 5. Mean ( ± SEM) total intake volume (ml) in the Control (n = 10), Conditioning (n = 10), US preexposure (n = 10), and US postexposure (n = 10) groups over all sessions. The Control, Conditioning, and US postexposure groups were not exposed to the US in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the US postexposure group was exposed to the US, and the other groups did not receive any US exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl). Table 1 The effects of CS or US preexposure and postexposure on CTA conditioning in the conditioned taste aversion learning task.
CS US
Preexposure
Postexposure
CTA ↓ (proactive interference) CTA ↓ (proactive interference)
CTA ↓ (retroactive interference) ––
Note that CS: conditioned stimulus; US: unconditioned stimulus; –: nonsignificant differences; ↓: decrease.
(Kamen et al., 2014). With regard to behavioral interventions, systematic desensitization (Aapro, Molassiotis, & Olver, 2005), muscle relaxation training and guided imagery (Burish, Carey, Krozely, & Greco, 1987), hypnosis (Redd, Montgomery, & DuHamel, 2001), and overshadowing (Stockhorst, Klosterhalfen, Klosterhalfen, Winkelmann, & Steingrueber, 1993; Stockhorst et al., 1998) have been suggested for the clinical treatment of chemotherapy-induced anticipatory nausea and vomiting. In the present study, we found that the CS and US preexposure proactively interfered with CS-US conditioning, and CS postexposure retroactively interfered with CS-US conditioning. The present findings may suggest alternative possible behavioral interventions to decrease cancer chemotherapy-induced anticipatory nausea and vomiting. The CS preexposure, CS postexposure, and US preexposure may be utilized to develop novel nonpharmacological interventions. In doing so, patients could be exposed to either a CS tastant or a US prior to any subsequent CS-US conditioning, thus preventing further cancer chemotherapy-induced anticipatory nausea and vomiting. The CS and US preexposure procedures can be viewed as similar to systematic desensitization. This means that exposure to the CS tastant can be repeatedly performed after CS-US conditioning to reduce such side effects of chemotherapy. The CS preexposure procedure is also equivalent to extinction procedures. Our data showed that US postexposure did not change CS-US conditioning, implying that US postexposure may not affect cancer chemotherapy-induced anticipatory nausea and vomiting. However, different doses and strengths of US might exhibit different effects of US postexposure on CS-US conditioning (Kawai & Nakajima, 1996). Therefore, the use of different parameters of US postexposure to alter nausea or vomiting after undergoing cancer chemotherapy should be investigated. 4.3. Further studies Previous studies indicated that the insular cortex is involved in the effects of CS preexposure (Quintero et al., 2014). Specifically, injection cues have been shown to mediate the inhibitory effect of US preexposure on LiCl-induced CTA (Riley & Freeman, 2004). One study reported that proactive interference and retroactive interference occur because of underlying damage in the perirhinal and 8
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postrhinal cortices (Bartko, Cowell, Winters, Bussey, & Saksida, 2010). Nonetheless, the following questions remain to be answered by further studies: Which neural mechanisms mediate the influence of CS preexposure, US preexposure, CS postexposure, and US postexposure on CS-US conditioned learning? Do proactive interference and retroactive interference share identical neural mechanisms? 5. Conclusions The CS and US preexposure proactively interfered with subsequent CS-US conditioning. While the US postexposure did not affect CS-US conditioning, the CS postexposure caused retroactive interference. In addition, the US postexposure may be attributed to a ceiling effect, thereby causing retroactive enhancement, although the data of US postexposure groups were not significantly different when compared with the Conditioning group. However, many hypotheses have sought to explain the interference that is caused by CS or US preexposure and postexposure. The learning interference hypothesis of CS and US exposures can be applied in examining chemotherapy-induced side effects in anticipatory nausea and vomiting. Conflict of interest The authors of this paper do not have any commercial associations or financial interests that might pose a conflict of interest in connection with the results or interpretations of this study. Acknowledgements This research was supported by funding from the National Research Council of the Republic of China (NSC 102-2410-H-431-005MY3) and from the Ministry of Science and Technology of the Republic of China (MOST 104-2410-H-030-014-MY2 and MOST 1052410-H-431-005). References Aapro, M. S., Molassiotis, A., & Olver, I. (2005). Anticipatory nausea and vomiting. Supportive Care in Cancer, 13(2), 117–121. Bakner, L., Strohen, K., Nordeen, M., & Riccio, D. C. (1991). Postconditioning recovery from the latent inhibition effect in conditioned taste aversion. Physiology & Behavior, 50(6), 1269–1272. Bartko, S. 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(1976). The effect of drug habituation before and after taste aversion learning in rats. Animal Learning & Behavior, 4, 329–332. Huang, A. C., & Hsiao, S. (2002). Haloperidol attenuates rewarding and aversively conditioned suppression of saccharin solution intake: Reevaluation of the anhedonia hypothesis of dopamine blocking. Behavioral Neuroscience, 116, 646–650. Huang, A. C., Shyu, B. C., Hsiao, S., Chen, T. C., & He, A. B. (2013). Neural substrates of fear conditioning, extinction, and spontaneous recovery in passive avoidance learning: A c-fos study in rats. Behavioural Brain Research, 237, 23–31. Jacobsen, P. B., Bovbjerg, D. H., Schwartz, M. D., Andrykowski, M. A., Futterman, A. D., Gilewski, T., et al. (1993). Formation of food aversions in cancer patients receiving repeated infusions of chemotherapy. Behaviour Research & Therapy, 31(8), 739–748. Kamen, C., Tejani, M. A., Chandwani, K., Janelsins, M., Peoples, A. R., Roscoe, J. A., et al. (2014). 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Contents lists available at ScienceDirect
Learning and Motivation journal homepage: www.elsevier.com/locate/l&m
Examinations of CS and US preexposure and postexposure in conditioned taste aversion: Applications in behavioral interventions for chemotherapy anticipatory nausea and vomiting Ying-Chou Wanga, Hsin-Yeh Leeb, Alan Bo-Han Heb, Andrew Chih Wei Huangb, a b
MARK
⁎
Department of Clinical Psychology, Fu-Jen Catholic University, New Taipei City 24205, Taiwan Department of Psychology, Fo-Guang University, Yilan County 26247, Taiwan
AR TI CLE I NF O
AB S T R A CT
Keywords: CS preexposure CS postexposure US preexposure US postexposure Conditioned learning Interference
Examining CS or US preexposure and postexposure to dissociate conditioned stimulus (CS)-unconditioned stimulus (US) conditioned learning and apply these findings to alleviate anticipatory nausea and vomiting are crucial for cancer chemotherapy patients. The present study utilized a conditioned taste aversion (CTA) paradigm in rats to develop a new behavioral intervention. Experiment 1 evaluated Control, Conditioning, CS preexposure, and CS postexposure groups. Experiment 2 evaluated Control, Conditioning, US preexposure, and US postexposure groups. After conditioning in both experiments, rats were given the CS alone without the US once per day over three trials, and their conditioned taste aversion was measured. The results showed that both CS preexposure and US preexposure interfered with subsequent CS-US conditioning, indicating that both induced proactive interference. Although CS postexposure interfered with prior CS-US conditioning, which indicated extinction, US postexposure did not alter CS-US conditioning. The findings should be considered for the development of new nonpharmacological clinical interventions for cancer patients with chemotherapy-induced anticipatory nausea and vomiting.
1. Introduction Theories of associative learning have provided many ways to dissociate connections between a conditioned stimulus (CS) and an unconditioned stimulus (US). In the conditioned taste aversion (CTA) paradigm, strength of the conditioned response (CR) can be modified by preexposure or postexposure to the CS or US. How the CS or US preexposure affect CS-US conditioning is an essential issue. One hypothesis suggests that CS preexposure (De la Casa & Lubow, 1995; Lipp, Siddle, & Vaitl, 1992) and US preexposure (Goddard, 2004; Matzel, Brown, & Miller, 1987) attenuate the strength of subsequent CS-US conditioning. For example, exposure to a sucrose CS solution before sucrose-illness conditioning interfered with subsequent CTA conditioning (Bakner, Strohen, Nordeen, & Riccio, 1991). In addition, frequency, duration, and amount of CS preexposure lessen conditioned suppression of CS intake during CS-US conditioning (De la Casa & Lubow, 1995). A human latent inhibition study of autonomic conditioning showed that different amounts of CS preexposure produced different degrees of latent inhibition on later CS-US conditioning, which was demonstrated by electrodermal and heart rate responses (Lipp et al., 1992). With regard to US preexposure, a study has reported that rats made fewer magazine entries when preexposed to the US (one food pellet) prior to being given three food pellets as the US (Goddard, 2004). These data show that US preexposure attenuates subsequent ⁎
Corresponding author at: Department of Psychology, Fo Guang University, No. 160, Linwei Road, Jiaosi Shiang, Yilan County 26247, Taiwan. E-mail address: [email protected] (A.C.W. Huang).
http://dx.doi.org/10.1016/j.lmot.2017.06.001 Received 27 April 2017; Received in revised form 22 June 2017; Accepted 22 June 2017 0023-9690/ © 2017 Elsevier Inc. All rights reserved.
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conditioned learning. Similarly, US preexposure has been found to interfere with conditioned lick suppression in an excitatory training context (Matzel et al., 1987). Also, US preexposure has been shown to attenuate well-trained CTA conditioning (Riley, Jacobs, & LoLordo, 1976). Therefore, the hypothesis that CS or US preexposure can attenuate CS-US conditioning in the CTA task was examined further in the present study. In regard to how CS or US postexposure affects the CS-US conditioning, each type of postexposure has shown a different result. In the case of CS postexposure, previous studies have indicated that prior CS-US conditioning can be extinguished through CS postexposure (Huang, Shyu, Hsiao, Chen, & He, 2013; Myers and Davis, 2002). The effects of US postexposure on CS-US conditioning have been inconsistent (Brookshire & Brackbill, 1976; Colby & Smith, 1977; Holman, 1976; Kawai & Nakajima, 1996; Rescorla, 1974; Riley et al., 1976; Sawa & Ishii, 2012). For example, one line of studies showed that US preexposure attenuated conditioned flavor preference (Sawa & Ishii, 2012) and CTA paradigms (Colby & Smith, 1977). Another line of studies demonstrated that US postexposure strengthened previous CS-US conditioning. For example, data from a CTA study have shown that LiCl postexposure enhanced LiClinduced taste aversion learning (Holman, 1976). A study of fear conditioning found that US footshock postexposure increased the previous fear conditioning (Rescorla, 1974). Other studies showed that US postexposure did not affect previous taste aversion learning (Riley et al., 1976) or apomorphine-induced conditioned suppression (Brookshire & Brackbill, 1976). Accordingly, how CS or US postexposure alter previous CS-US conditioning needs to be further studied. Applications of CS or US preexposure and postexposure might provide some methods to reduce the drug-induced side effects of chemotherapy, particular anticipatory nausea and vomiting (Stockhorst, Steingrueber, Enck, & Klosterhalfen, 2006). Previous studies have found that taste aversion occurred very fast, within 24 h after the first course of chemotherapy (Jacobsen et al., 1993; Mattes, Arnold, & Boraas, 1987). Such taste aversion has been explained by taste aversion learning in which daily tastants (CSs) are conditioned to the subsequent side effects of the drugs (e.g., cytotoxic drugs or USs) that are used to treat the illness. Cancer patients who undergo repeated chemotherapy, however, tend to exhibit an increase in the strength of nausea and vomiting (Bovbjerg et al., 1992; Greene & Seime, 1987; Montgomery & Bovbjerg, 1997; Montgomery et al., 1998). Anticipatory nausea and vomiting then occur as CRs when a CS is presented without the drugs (i.e., USs; Bovbjerg, 2006; Dolgin, Katz, McGinty, & Siegel, 1985). Therefore, procedures that involve CS or US preexposure or postexposure may weaken cytotoxic drug-induced side effects in cancer patients who undergo chemotherapy. Previously, how CS or US preexposure and postexposure affect LiCl-induced CTA has not been systematically investigated in the same study. Accordingly, the present study focused on two issues: (i) Whether CS or US preexposure and CS postexposure attenuate CS-US conditioned learning in the CTA paradigm, and (ii) Whether US postexposure enhances, interferes with, or does not influence CS-US conditioned learning in the CTA paradigm. The present study provides a new hypothesis to explain how CS and US exposure reduces the side effects of chemotherapy and suggests new nonpharmacological interventions. 2. Materials and methods 2.1. Animals Eighty male Wistar rats were obtained from the Laboratory Animal Center of the National Taiwan University College of Medicine in Taipei, Taiwan. The rats weighed 250–300 g and were approximately 6 weeks old at the beginning of the experiments. The rats were allowed to habituate in a temperature-controlled (20 ± 2 °C) colony room for 7 days. They were group-housed, two per cage, in a colony room on a cycle of 12 h each of light and dark (lights were on from 6:00 AM-6:00 PM), with food and water available ad libitum with the exception of specific treatments in some phases of the study. The present study was performed in compliance with the Animal Scientific Procedures Act of 1986 and received local ethics committee approval. All efforts were made to minimize animal suffering and the number of animals used. 2.2. Apparatus The present study utilized a lickometer apparatus to measure intake volume, the interlick intervals, the latency period between contacting the burette, and the number of licks. The lickometer consisted of a wire-mesh cage, a white panel, and a 25-ml burette with 0.1-ml graduations. The panel was mounted in front of the wire-mesh cage and connected to the burette. Only the intake volume was recorded in the water-deprived rats in the present study. This apparatus was also used in a previous similar study (Huang & Hsiao, 2002). 2.3. Experimental procedure Experiment 1. Effects of CS preexposure and CS postexposure on CS-US conditioning All of the rats underwent a water-deprivation regimen for 23.5 h/day for 7 days. On the final 2 days, the rats were given water in the morning for 15 min and in the afternoon 30 min after training in the lickometer apparatus. The 30-min water availability regimen each day was performed during all phases of the experiment. Experiment 1 included CS preexposure, conditioning, CS postexposure, and testing phases. An exception was that although the testing phase was administered for 3 days, rats encountered the water regimen on each of the 5 days. In the CS preexposure phase, they were assigned to four groups that were given either a 0.1% saccharin solution for a CS or water and then injected with 4 ml/kg of a 0.15 M isotonic NaCl solution (0.1% saccharin solution-0.15 M NaCl, 2
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Water-0.15 M NaCl, 0.1% saccharin solution-0.15 M NaCl, and Water-0.15 M NaCl groups). In the conditioning phase, these four groups were given the CS and then injected with 4 ml/kg of a 0.15 M NaCl or 0.15 M LiCl solution (0.1% saccharin solution-0.15 M NaCl, 0.1% saccharin solution-0.15 M LiCl, 0.1% saccharin solution-0.15 M LiCl, and 0.1% saccharin solution-0.15 M LiCl groups). In the CS postexposure phase, these four groups were exposed to the CS or water and then injected with 4 ml/kg of a 0.15 M NaCl solution (0.1% saccharin solution-0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M NaCl, and 0.1% saccharin solution-0.15 M NaCl groups). After the CS postexposure phase, all of the rats were exposed to the CS alone without any injection. Altogether, these four groups were denoted as the Control (n = 10), the Conditioning (n = 10), the CS preexposure (n = 10), and the CS postexposure (n = 10) groups (Fig. 1). Experiment 2. Effects of US preexposure and US postexposure on CS-US conditioning The protocol for Experiment 2 was similar to Experiment 1, with the exception being that CS preexposure and CS postexposure were replaced with US preexposure and US postexposure. Another exception was that testing was administered for 3 days while the other phases were conducted on each of 5 days. In the US phase, rats were assigned to four groups that were given a 0.1% saccharin solution for the CS or water and then injected with 4 ml/kg of a 0.15 M isotonic NaCl or LiCl solution (0.1% saccharin solution0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M LiCl, and Water-0.15 M NaCl groups). In the conditioning phase, these four groups were given the CS and then injected with 4 ml/kg of a 0.15 M NaCl or 0.15 M LiCl solution (0.1% saccharin solution-0.15 M NaCl, 0.1% saccharin solution-0.15 M LiCl, 0.1% saccharin solution-0.15 M LiCl, and 0.1% saccharin solution-0.15 M LiCl groups). In the US postexposure phase, these four groups were exposed to the CS or water and then injected with 4 ml/kg of a 0.15 M NaCl solution (0.1% saccharin solution-0.15 M NaCl, Water-0.15 M NaCl, Water-0.15 M NaCl, and Water-0.15 M LiCl groups). All of the rats were then exposed to the CS alone without any injections for 15 min in the test phase. Altogether, these four groups were denoted as the Control (n = 10), the US preexposure (n = 10), the Conditioning (n = 10), and the US postexposure (n = 10) groups (Fig. 1). 2.4. Drug preparation and administration Saccharin solutions and all of the chemicals for the NaCl and LiCl solution preparations were purchased from Sigma (St. Louis, MO, USA). A 0.1% concentration of the saccharin solution was dissolved in water. Both a 0.15 M NaCl isotonic solution and a 0.15 M LiCl isotonic solution were dissolved in water. The given volumes of NaCl and LiCl were both 4 ml/kg, and all of the drugs were administered intraperitoneally. 2.5. Statistical analysis A 4 × 3 two-way mixed analysis of variance (ANOVA) with repeated sessions was used to analyze the mean intake volume (ml), which was determined with the lickometer. When appropriate, Fisher’s Least Significant Difference (LSD) post hoc tests were conducted for sessions 1–3. A one-way ANOVA was also conducted to analyze the mean total intake volume (ml) for all of the sessions, followed by Fisher’s LSD post hoc tests when appropriate. Values of p < 0.05 were considered statistically significant. 3. Results 3.1. Experiment 1: CS preexposure and CS postexposure The mean ( ± SEM) intake volume over sessions 1–3 was measured in water-deprived rats in the Control, Conditioning, CS preexposure, and CS postexposure groups. This experiment tested whether CS preexposure and CS postexposure affect the strength of CS-US conditioning. A 4 × 3 two-way mixed ANOVA with repeated sessions revealed a significant effect of group (F3,36 = 21.63, p < 0.05) but no effect of session (F2,72 = 0.90, p > 0.05). A significant group × session interaction was observed (F6,72 = 4.07, p < 0.05). The post hoc Fisher’s LSD test indicated there were significant differences between the Control and Conditioning groups in sessions 1–3 (p < 0.05). Both CS preexposure and CS postexposure significantly increased intake volume, compared with the Conditioning group in sessions 1–3 (p < 0.05; Fig. 2). Upon combining all the intake volume data of sessions 1–3 for all groups, a one-way ANOVA revealed that mean total intake volume differed significantly among groups (F3,36 = 21.63, p < 0.05). The post hoc Fisher’s LSD test indicated a significant difference between the Conditioning and Control groups for mean total intake volume (p < 0.05). Moreover, significant differences occurred when the CS preexposure and CS postexposure groups were compared with the Conditioning group (p < 0.05). Therefore, CS preexposure and CS postexposure appeared to attenuate CS-US conditioning (Fig. 3). 3.2. Experiment 2: US preexposure and US postexposure All of the rats underwent the preexposure, conditioning, postexposure, and test phases (the Control, Conditioning, US preexposure, and US postexposure groups). We evaluated the mean intake volume over sessions 1–3 in water-deprived rats in these four groups in the test phase. A 4 × 3 mixed two-way ANOVA revealed significant effects on group (F3,36 = 48.73, p < 0.05) and session (F2,72 = 4.64, p < 0.05) and a significant group × session interaction (F6,72 = 3.53, p < 0.05). The post hoc Fisher’s LSD test indicated that the mean intake volume of the Conditioning group was significantly less than that of the Control group in sessions 1–3 (p < 0.05). The mean intake volume in the US preexposure group significantly increased compared to the Conditioning group in 3
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Fig. 1. A timeline of Experiment 1 and Experiment 2 on preexposure, conditioning, postexposure, and testing phases for CS or US.
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Fig. 2. Mean ( ± SEM) intake volume (ml) in the Control (n = 10), Conditioning (n = 10), CS preexposure (n = 10), and CS postexposure (n = 10) groups. The Control, Conditioning, and CS postexposure groups were not exposed to the CS in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the CS postexposure group was exposed to the CS, and the other groups did not receive any CS exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference between the Control, Conditioning, CS preexposure, and CS postexposure groups. The CS was a 0.1% saccharin solution. The US was lithium chloride (LiCl).
sessions 1–3 (p < 0.05). No difference was found between the Conditioning and US postexposure groups in sessions 1–3 (p > 0.05; Fig. 4). A one-way ANOVA of the mean total intake volumes in all of the sessions revealed a significant effect of group (F3,36 = 48.73, p < 0.05). The post hoc Fisher’s LSD test indicated a significant difference between the Conditioning and Control groups (p < 0.05). There was also a significant difference between the US preexposure and Conditioning groups (p < 0.05). However, the US postexposure group did not demonstrate a significant difference from the Conditioning group (p > 0.05; Fig. 5). Conditioning was attenuated in the US preexposure group but not in the US postexposure group. However, the US postexposure group might have reached the ceiling for differences between the Conditioning and US postexposure groups. 4. Discussion In the present study, rats underwent both CS and US preexposure and postexposure to investigate how they affect CS-US conditioned learning. The present study results revealed some crucial findings. In the CS exposure experiment, the preexposure and postexposure groups both exhibited attenuation of CS-US conditioning. The CS preexposure attenuated the LiCl-induced CTA effect, indicating proactive interference or latent inhibition. The CS postexposure also reduced the CTA effect, suggesting extinction. Translation of these CS preexposure and postexposure effects with rats to humans suggests ways in which the side effects of tastantsillness conditioning for cancer patients who undergo chemotherapy may be reduced. Use of these two procedures might reduce anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Similarly, US preexposure has been revealed to attenuate CS-US conditioning, indicating a proactive interference effect. This finding suggests that administration of chemotherapy drugs before the tastants-illness conditioning might reduce the aversive side effects. Chemotherapy-induced side effects of anticipatory nausea and vomiting might be attenuated by preexposure to the tastant CS or by postexposure to the drug US. However, our results showed that US postexposure did not interfere with LiCl-induced CTA conditioning. This finding suggests that chemotherapy drugs might not influence the tastant-illness conditioning when they are given after tastant-illness conditioning. Therefore, different procedures of CS or US preexposure and postexposure may have to be developed to treat chemotherapy-induced anticipatory nausea and vomiting in cancer patients who undergo chemotherapy (Table 1). 4.1. Possible hypotheses for proactive and retroactive interference: the learning interference hypothesis of CS and US exposures in behavioral mechanisms In the present study, both CS and US preexposure proactively interfered with later CS-US conditioning. In regard to the interfering 5
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Fig. 3. Mean ( ± SEM) total intake volume (ml) in the Control (n = 10), Conditioning (n = 10), CS preexposure (n = 10), and CS postexposure (n = 10) groups over all sessions. The Control, Conditioning, and CS postexposure groups were not exposed to the CS in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the CS postexposure group was exposed to the CS, and the other groups did not receive any CS exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl).
effect of CS preexposure, the present results corroborate prior evidence of latent inhibition in conditioned learning in healthy subjects (Fouquet, Oberling, & Sandner, 2001; Hall & Channell, 1986). To explain the interfering effect of CS preexposure (i.e., latent inhibition), three hypotheses have been proposed. First, an attentional mechanism may account for latent inhibition in which the salience of the CS was diminished, thus decreasing the formation of CS-US conditioning (Lubow, 1973). Second, a cognitive mechanism was offered in which the CS is learned to be irrelevant to the US during the preexposure phase (Bonardi & Ong, 2003; Dess & Overmier, 1989). Third, an associative learning mechanism was suggested in which the CS is conditioned to no-US and subsequently blocks CS-US learning (Bouton, 1993). The above three hypotheses are based on behavioral and cognitive mechanisms. However, which neural mechanism can clearly explain the CS preexposure effect on conditioning remains unclear and awaits discovery in further studies. In regard to an explanation of the effect of CS postexposure on LiCl-induced CTA, two different hypotheses (i.e., unlearning hypothesis and interference hypothesis) may explain the extinction effect. The unlearning hypothesis posits that CS-US association weakens without US presentation, suggesting that extinction is equal to forgetting (Pavlov, 1927; Rescorla & Wagner, 1972). The interference hypothesis (Mensink & Raaijmakers, 1988) attributes the decrease in memory retrieval to retroactive interference between new learning and the original learning (Bouton, 1993, 2002, 2004), which has been termed associative competition (Bills, Dopheide, Pineno, & Schachtman, 2006; Miller & Escobar, 2002). The interference hypothesis is supported by four behavioral mechanisms: spontaneous recovery, the renewal effect, reinstatement, and rapid reacquisition. Spontaneous recovery means that CS-US conditioning is recovered again when a CS is tested alone after a long period of time following extinction (Myers & Davis, 2007). The time factor is hypothesized to be crucial for testing the interference hypothesis versus the unlearning hypothesis (Escobar, Arcediano, Platt, & Miller, 2004; Myers, Ressler, & Davis, 2006). The renewal effect occurs when the CS is conditioned in context A and extinguished in context B. The CR then reappears when the CS is presented in context A but not in context B (Bouton, Westbrook, Corcoran, & Maren, 2006; Crombag, Bossert, Koya, & Shaham, 2008). Reinstatement also supports the interference hypothesis. Following CS extinction, the US is repeatedly presented in the same context as extinction. The CS-US conditioning is then recovered in a retention test (Bouton & Bolles, 1979). Rapid acquisition also supports the interference hypothesis. When CS-US conditioning is tested following CS extinction, the CR conditions more rapidly than during initial conditioning. Therefore, a trace of the CS is assumed to be retained during extinction and can then be rapidly associated with the US (Bouton, 2004). Research on latent inhibition, however, has generated conflicting results. For example, when the time interval between preexposure and conditioning is longer, rats showed a weakened latent inhibition effect. The authors explained that the characteristics of the CS might be erased or forgotten, and that the data supported the unlearning hypothesis (Metzger & Riccio, 2009). Issues that have emerged are how the CS postexposure produces retroactive interference with CS-US conditioning and whether CS postexposure causes forgetting or interference. With regard to interference by US preexposure, two hypotheses may be suggested. One hypothesis comes from an associative 6
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Fig. 4. Mean ( ± SEM) intake volume (ml) in the Control (n = 10), Conditioning (n = 10), US preexposure (n = 10), and US postexposure (n = 10) groups. The Control, Conditioning, and US postexposure groups were not exposed to the US in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the US postexposure group was exposed to the US, and the other groups did not receive any US exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference among the Control, Conditioning, US preexposure, and US postexposure groups. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl).
viewpoint, which presumes that the US is associated with contextual stimuli in the preexposure phase. The association between the US and contextual stimuli then interferes with subsequent CS-US conditioning. Another nonassociative hypothesis proposes that the reduction of the ability of the US to associate with the CS is attributable to central habituation of the US or peripheral sensory adaptation of the US with repeated US exposure (Randich & LoLordo, 1979). Unfortunately, these two hypotheses do not provide neural mechanisms, and which hypothesis can account for US preexposure’s interference with CS-US conditioning is unclear. Importantly, the present data found that US postexposure did not affect CTA conditioning (Brookshire & Brackbill, 1976; Riley et al., 1976). However, it is still unknown whether different doses and strengths of US postexposure might have effects on conditioning learning. For example, Kawai and Nakajima (1996) used different concentrations of US postexposure to affect conditioned flavor preference. These authors suggested that a lower concentration of US postexposure did not affect conditioned flavor preference, a middle concentration of US postexposure attenuated conditioned flavor preference, and a higher concentration of US postexposure enhanced conditioned flavor preference (Kawai & Nakajima, 1996). Obviously, the strengths of US agents might be essential for change in the subsequent CS-US conditioning. To achieve an intersection of all of the explanations above, the learning interference hypothesis might be the most suitable explanation for the effects of preexposure and postexposure of CS and US. Therefore, the learning interference hypothesis of CS and US exposures in behavioral mechanisms may explain why CS preexposure and postexposure and US preexposure decreased LiClinduced CTA effects. The novel hypothesis is based on the learning interference viewpoint that either the CS or the US was associated with one kind of stimulus and proactively interfered with subsequent CTA conditioning. Moreover, a specified CS in the postexposure phase was also associated with a change in the environment or context to form retroactive interference with the LiCl-induced CTA conditioning. In conclusion, the learning interference hypothesis of CS and US exposures in behavioral mechanisms can be applied to treat chemotherapy-induced side effects in anticipatory nausea and vomiting. Regardless of whether proactive or retroactive interference is applied, the process of learning interference may be used to attenuate tastant-illness conditioning for cancer patients who undergo chemotherapy.
4.2. Clinical implications: behavioral interventions for cancer chemotherapy-induced anticipatory nausea and vomiting Pharmacological interventions (e.g., benzodiazepines and serotonin-3 receptor antagonists) and nonpharmacological interventions (e.g., behavioral interventions) have been considered for the relief of chemotherapy-induced anticipatory nausea and vomiting 7
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Fig. 5. Mean ( ± SEM) total intake volume (ml) in the Control (n = 10), Conditioning (n = 10), US preexposure (n = 10), and US postexposure (n = 10) groups over all sessions. The Control, Conditioning, and US postexposure groups were not exposed to the US in the preexposure phase. All four groups were then subjected to CS-US conditioned learning. In the postexposure phase, the US postexposure group was exposed to the US, and the other groups did not receive any US exposure. In the test phase, all of the rats were exposed to the CS in three trials to assess CS-US conditioning in sessions 1–3. The p value (p < 0.05) revealed a significant difference. The CS was a 0.1% saccharin solution and the US was lithium chloride (LiCl). Table 1 The effects of CS or US preexposure and postexposure on CTA conditioning in the conditioned taste aversion learning task.
CS US
Preexposure
Postexposure
CTA ↓ (proactive interference) CTA ↓ (proactive interference)
CTA ↓ (retroactive interference) ––
Note that CS: conditioned stimulus; US: unconditioned stimulus; –: nonsignificant differences; ↓: decrease.
(Kamen et al., 2014). With regard to behavioral interventions, systematic desensitization (Aapro, Molassiotis, & Olver, 2005), muscle relaxation training and guided imagery (Burish, Carey, Krozely, & Greco, 1987), hypnosis (Redd, Montgomery, & DuHamel, 2001), and overshadowing (Stockhorst, Klosterhalfen, Klosterhalfen, Winkelmann, & Steingrueber, 1993; Stockhorst et al., 1998) have been suggested for the clinical treatment of chemotherapy-induced anticipatory nausea and vomiting. In the present study, we found that the CS and US preexposure proactively interfered with CS-US conditioning, and CS postexposure retroactively interfered with CS-US conditioning. The present findings may suggest alternative possible behavioral interventions to decrease cancer chemotherapy-induced anticipatory nausea and vomiting. The CS preexposure, CS postexposure, and US preexposure may be utilized to develop novel nonpharmacological interventions. In doing so, patients could be exposed to either a CS tastant or a US prior to any subsequent CS-US conditioning, thus preventing further cancer chemotherapy-induced anticipatory nausea and vomiting. The CS and US preexposure procedures can be viewed as similar to systematic desensitization. This means that exposure to the CS tastant can be repeatedly performed after CS-US conditioning to reduce such side effects of chemotherapy. The CS preexposure procedure is also equivalent to extinction procedures. Our data showed that US postexposure did not change CS-US conditioning, implying that US postexposure may not affect cancer chemotherapy-induced anticipatory nausea and vomiting. However, different doses and strengths of US might exhibit different effects of US postexposure on CS-US conditioning (Kawai & Nakajima, 1996). Therefore, the use of different parameters of US postexposure to alter nausea or vomiting after undergoing cancer chemotherapy should be investigated. 4.3. Further studies Previous studies indicated that the insular cortex is involved in the effects of CS preexposure (Quintero et al., 2014). Specifically, injection cues have been shown to mediate the inhibitory effect of US preexposure on LiCl-induced CTA (Riley & Freeman, 2004). One study reported that proactive interference and retroactive interference occur because of underlying damage in the perirhinal and 8
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postrhinal cortices (Bartko, Cowell, Winters, Bussey, & Saksida, 2010). Nonetheless, the following questions remain to be answered by further studies: Which neural mechanisms mediate the influence of CS preexposure, US preexposure, CS postexposure, and US postexposure on CS-US conditioned learning? Do proactive interference and retroactive interference share identical neural mechanisms? 5. Conclusions The CS and US preexposure proactively interfered with subsequent CS-US conditioning. While the US postexposure did not affect CS-US conditioning, the CS postexposure caused retroactive interference. In addition, the US postexposure may be attributed to a ceiling effect, thereby causing retroactive enhancement, although the data of US postexposure groups were not significantly different when compared with the Conditioning group. However, many hypotheses have sought to explain the interference that is caused by CS or US preexposure and postexposure. 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