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High doses of vasopressin delay the onset of extinction and strengthen acquisition of LiCl-induced conditioned taste avoidance
Physiology & Behavior 84 (2005) 625 – 633
High doses of vasopressin delay the onset of extinction and strengthen acquisition of LiCl-induced conditioned taste avoidance UnJa L. Hayesa,T, Kathleen C. Chambersb a
Center for Neuroendocrine Studies, University of Massachusetts, Tobin Hall, Amherst, MA 01003, United States b Department of Psychology, University of Southern California, Los Angeles, CA 90089, United States Received 8 June 2004; received in revised form 5 January 2005; accepted 10 February 2005
Abstract When low doses of vasopressin are given 50 min after pairing sucrose consumption with a high dose of LiCl, extinction of the LiClinduced conditioned taste avoidance is accelerated. These low doses of vasopressin do not themselves induce conditioned taste avoidance when paired with sucrose consumption. Predicated on previous studies administering two avoidance-inducing agents after sucrose consumption, studies were designed to determine whether high doses of vasopressin capable of inducing conditioned taste avoidance would (1) delay rather than accelerate extinction of a conditioned taste avoidance induced by a high dose of LiCl and (2) strengthen acquisition of a conditioned taste avoidance induced by a low dose of LiCl. The results of three studies showed that doses of 9 and 18 Ag/kg of vasopressin induced a conditioned taste avoidance when injected 50 min after sucrose consumption, delayed the onset of extinction when injected 50 min after pairing sucrose consumption with a high dose of LiCl, and strengthened acquisition of a conditioned taste avoidance when injected 50 min after pairing sucrose consumption with a low dose of LiCl. Taken together, these data suggest that the delay in onset of extinction is due to a strengthening of acquisition. It has been suggested that vasopressin is a mnemonic neuropeptide that delays extinction of learned tasks. However, for conditioned taste avoidance, the evidence for the effects of low doses of vasopressin on extinction do not support this hypothesis and the evidence for high doses of vasopressin can be accounted for by the avoidance-inducing properties of vasopressin. D 2005 Elsevier Inc. All rights reserved. Keywords: Conditioned taste aversion; LiCl
1. Introduction The neuropeptide, vasopressin, has been implicated in both physiological responses (e.g., antidiuresis, cardiovascular regulation, and thermoregulation) and behavioral responses (e.g., eating, defensive behaviors, aggression, and parental behavior) [1–6]. In addition, it modulates performance in a number of different kinds of learning situations, including appetitive, spatial, social, and aversive situations [7–17]. The most commonly reported effects of vasopressin in learning situations are facilitation of retention, enhanced performance, and delay in extinction. These
T Corresponding author. Tel.: +1 413 545 0794; fax: +1 413 545 0996. E-mail address: [email protected] (U.L. Hayes). 0031-9384/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2005.02.012
effects of vasopressin in learning and memory tasks have led investigators to hypothesize that vasopressin acts as a mnemonic neuropeptide [13,18–21]. Although a number of different learning tasks have been used to study the effects of vasopressin in memory, most studies have used active (e.g., shuttle box and polejumping) and passive (e.g., step-through) shock avoidance paradigms. The delaying effect of vasopressin on extinction of shock avoidance behaviors has been reported 1) in both active and passive shock avoidance tasks, 2) with peripheral as well as central administration of the neuropeptide, and 3) when treatment occurred at different times during acquisition and/or extinction testing, e.g., before or after the last acquisition trial, before or after the first extinction trial, or before each acquisition or extinction trial [22–36].
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However, not all of the evidence is consistent with a simple mnemonic hypothesis. Individual and strain differences within the shock avoidance paradigm and timedependent differences within other learning paradigms have been found. For shock avoidance, several studies have reported that vasopressin produces bimodal effects, that is, it maintains the avoidance behavior in most animals but disrupts it in some [37,38]. Additionally, acquisition of a two-way shuttle box task is accelerated in one strain of inbred mice and disrupted in another strain [39]. For other learning paradigms, there is evidence that vasopressin can differentially modulate learned behaviors depending on whether it is present during the initial or later stages of the learning process [40]. Infusion of vasopressin into the ventral hippocampus after the first learning session of an appetitive visual discrimination task, slightly delays performance during subsequent testing, but enhances performance when infused after the second learning session. Similar inconsistencies have been found when the effects of vasopressin on conditioned taste avoidance have been examined. While earlier studies reported that vasopressin prolonged extinction [41,42], more recent research has found that this neuropeptide can produce the opposite effect, namely an acceleration of extinction [43,44]. Peripheral administration of vasopressin shortly before acquisition or extinction, or before both acquisition and extinction tests resulted in a delayed extinction of conditioned taste avoidance induced by LiCl or amphetamine and intracerebroventricular infusion of vasopressin increased the number of animals to show a delay in extinction of a LiCl-induced conditioned taste avoidance [41,42,44]. On the other hand, both peripheral and intracerebroventricular administration of vasopressin shortly after acquisition of a LiCl-induced conditioned taste avoidance accelerated extinction [43,44]. These findings suggest that the direction of the effect of vasopressin on extinction of conditioned taste avoidance is dependent upon when during the learning or testing process vasopressin is administered [44]. Another factor that might influence the direction of the effect of vasopressin on extinction of conditioned taste avoidance is dose. The doses of arginine vasopressin and DG–LVP that were administered before or after acquisition do not themselves induce conditioned taste avoidance [43,45–47]. However, higher doses of vasopressin can induce conditioned taste avoidance [47]. The issue of whether vasopressin can induce conditioned taste avoidance is important because agents that are capable of inducing a conditioned taste avoidance can weaken acquisition of a conditioned taste avoidance when administered before acquisition and strengthen acquisition when administered after acquisition [48–50]. For example, when LiCl is given 1 day or 30 min before pairing saccharin with LiCl, the subsequent conditioned taste avoidance is attenuated [51– 53]. On the other hand, the avoidance induced by one agent
can be strengthened by administration of a second agent that is capable of inducing conditioned taste avoidance [48,54– 57]. For example, administration of both estradiol and LiCl or radiation and LiCl immediately after sucrose consumption reduces the amount of sucrose consumed during the first few days of extinction [48,54]. In addition, a stronger conditioned taste avoidance is produced when two separate doses of 1.5 mEq/kg LiCl are injected immediately and 35 or 70 min after sucrose consumption than when a single dose of 3.0 mEq/kg LiCl is injected immediately after consumption [57]. These data suggest that doses of vasopressin that can themselves induce conditioned taste avoidance could weaken a LiCl-induced conditioned taste avoidance when administered before acquisition and strengthen this type of avoidance when administered after acquisition. As indicated above, doses of vasopressin that do not themselves induce conditioned taste avoidance accelerate extinction when given 50 min after pairing consumption of a sucrose solution with injection of a moderate dose of LiCl [43,44]. The following experiments were designed to test the hypothesis that a dose of vasopressin capable of inducing conditioned taste avoidance would strengthen acquisition when administered after acquisition of a LiClinduced conditioned taste avoidance. Strength of acquisition was assessed in two ways. In experiment 2, doses of vasopressin capable of inducing conditioned taste avoidance were administered peripherally 50 min after pairing consumption of a sucrose solution with a moderate dose of LiCl. This dose of LiCl produces a relatively strong avoidance after one pairing with sucrose consumption. If vasopressin strengthens acquisition, one would expect to see a stronger acquisition expressed as a delay in the onset of extinction. In experiment 3, a dose of vasopressin capable of inducing conditioned taste avoidance was administered peripherally 50 min after pairing consumption of a sucrose solution with a weak dose of LiCl. This dose of LiCl requires several pairings with sucrose consumption to produce a strong avoidance. If vasopressin strengthens acquisition, one would expect fewer pairings to produce a strong avoidance. Before conducting these two experiments, it was important to determine a peripheral dose of vasopressin that could itself induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution. Experiment 1 was designed to identify such a dose of vasopressin.
2. General methods 2.1. Subjects Male Sprague–Dawley rats (Simonsen Laboratory, Gilroy, CA), which weighed approximately 300 g at the beginning of the experiments, were used in these experiments. They were housed two per cage in a room that was
U.L. Hayes, K.C. Chambers / Physiology & Behavior 84 (2005) 625–633
temperature (21–22 8C), humidity (51%), and light controlled (a 12 h light:12 h dark cycle with lights on at 1000 and lights off at 2200 hours). Each cage measured 58 38 cm and had a solid bottom that was covered with wood chips. A stainless steel divider was placed in the middle of each cage to separate each pair of rats during behavioral testing. The rats were allowed at least 1 week to adapt to their living conditions before the experiments were initiated. Rats had ad libitum access to rat chow and tap water before behavioral testing began. During conditioned taste avoidance testing, water was available 23 h a day. In previous studies, we found that rats given similar drinking schedules are essentially nondeprived [58–61]. The experiments were conducted according to the standards set by the National Institutes of Health Guide for the Care and Use of Laboratory Animals (DHEW Publication 80-23, Revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda MD) and the institutional guidelines of the University of Southern California.
3. Drugs 3.1. Vasopressin Arginine vasopressin (AVP; Sigma-Aldrich, St. Louis, MO) was dissolved in sterile, normal saline (0.9% NaCl). Peripheral administration consisted of subcutaneous injection at the nape of the neck in the amount of 9 or 18 Ag/kg. The injection amount was 0.2 ml. The control animals received the same amount of the saline vehicle. 3.2. Lithium chloride Lithium chloride (LiCl; Sigma-Aldrich, Inc., St. Louis, MO) was dissolved in distilled water to make a 0.15 M solution. The doses of LiCl were either 1.5 mEq/kg (10 ml/ kg) in experiment 2 or 0.075 mEq/kg (0.5 ml/kg) in experiment 3. In each study, the vehicle was saline, the volume of vehicle and LiCl administered was the same, and both vehicle and LiCl were injected intraperitoneally.
4. Conditioned taste avoidance The experimental testing procedure was divided into the following four periods: preconditioning, acquisition testing, post-acquisition recovery, and post-acquisition or extinction testing. All solutions used during testing were stored under refrigeration for 24 h before use and they were given to the rats at the beginning of the dark portion of the light/dark cycle. During preconditioning, the water bottle of each rat was replaced with one cylinder containing refrigerated tap water at the onset of the dark cycle. After 1 h, the cylinders were replaced with the regular water bottles. Preconditioning rats
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with cold water just after the lights switch off increases the likelihood that nondeprived rats will drink the novel sucrose solution used for conditioning. During acquisition testing, the water bottle of each rat was replaced with 1 cylinder containing a 10% (w/v) sucrose solution. One hour later, the amount of sucrose consumed was recorded, the cylinder was removed, and the regular water bottle was returned. The post-acquisition or extinction tests were conducted in the same manner as the acquisition tests except neither LiCl nor vasopressin was administered. The number of acquisition and post-acquisition tests given and the type of agent injected after sucrose consumption varied with each experiment.
5. Experimental design 5.1. Experiment 1: doses of vasopressin that induce conditioned taste avoidance Previous studies have determined that even after 2 pairings a 6 Ag/kg dose of vasopressin does not induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution [44]. This experiment was designed to determine whether higher doses would produce the stimulus effects necessary to significantly condition a decrease in sucrose consumption. Twenty-nine rats were randomly assigned to one of three groups: injections of saline (n = 9), 9 Ag/kg AVP (n = 10), or 18 Ag/kg AVP (n = 10) given 50 min after consumption of sucrose on each of 2 acquisition tests. The acquisition tests were given every other day and a post-acquisition test was given two days after the last acquisition test. 5.2. Experiment 2: vasopressin and extinction of LiCl-induced conditioned taste avoidance In a previous study, a 6 Ag/kg dose of vasopressin, which does not produce a conditioned taste avoidance, accelerated extinction of a conditioned taste avoidance induced by a 1.5 mEq/kg dose of LiCl when it was administered 50 min after LiCl injection [44]. This experiment was designed to determine whether using higher doses of vasopressin, which are capable of producing conditioned taste avoidance, will strengthen acquisition as evidenced by a delay in the onset of the extinction of a LiCl-induced conditioned taste avoidance. Forty-two rats were randomly assigned to one of six groups: injection of saline (n = 3), 9 Ag/kg AVP (n = 9), or 18 Ag/kg AVP (n = 9) given 25 min after the LiCl injection on acquisition day and injection of saline (n = 3), 9 Ag/kg AVP (n = 9), or 18 Ag/kg AVP (n = 9) given 50 min after the LiCl. All rats were injected with 1.5 mEq/kg of LiCl immediately after access to a sucrose solution for 1 h and then 25 or 50 min later, they received an injection of vasopressin or saline. Starting two days later, the animals were given 1 extinction test per day for 9 days.
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5.3. Experiment 3: vasopressin and acquisition of LiCl-induced conditioned taste avoidance In previous studies using our methodology, a 1.5 mEq/ kg dose of LiCl produced a substantial decrease in consumption after pairing it with a sucrose solution [43,44]. Consumption levels dropped from a mean of 12 ml to a mean of 3 ml. Because the consumption levels drop so low, it is likely that any further decrease in consumption that might occur if a high dose of vasopressin as well as LiCl were paired with sucrose consumption would be masked by a floor effect. This possibility could be circumvented by reducing the dose of LiCl. The following experiment was designed to determine whether acquisition of a conditioned taste avoidance induced by a low dose of LiCl could be strengthened by administering a high dose of vasopressin 50 min after LiCl injection. Thirty-two rats were randomly assigned to one of four groups (n = 8/group): saline plus saline, LiCl plus saline, saline plus vasopressin, and LiCl plus vasopressin. Rats were injected with 0.075 mEq/kg of LiCl or saline immediately after access to a sucrose solution for 1 h and then 50 min later, they received an injection of vasopressin (18 Ag/kg) or saline. All rats were given two acquisition tests every other day and one post-acquisition test was given one day after the last acquisition test.
6. Statistical analysis An alpha level of p b 0.05 was used for determination of significance in all statistical tests. For experiments 1 and 3, a two-factor (groups by tests) analysis of variance (ANOVA) with repeated measures on tests was used to analyze sucrose consumption across all of the tests (2 acquisition tests and 1 post-acquisition test). In the case of a significant interaction, a dependent t test was used to analyze sucrose consumption for each group across the two acquisition tests and a onefactor (tests) ANOVA with repeated measures on tests was used for analyses across the acquisition and post-acquisition tests. A one-factor ANOVA and a Tukey HSD test (unequal n in experiment 1 and equal n in experiment 3) were used to determine group differences for each of the tests. For experiment 2, a two-factor (groups by tests) ANOVA with repeated measures on tests was used for all analyses of sucrose consumption. First, the sucrose consumption of the control animals administered saline 25 and 50 min after LiCl injection were compared. Because there were no differences in sucrose consumption for these two groups, their data were combined for subsequent analyses. Sucrose consumption across the acquisition and first extinction test, across the first 3 extinction tests, and across all 9 extinction tests was analyzed. Analyses of both the first 3 extinction tests and all 9 extinction tests were done because previous studies have shown that vasopressin influences the completion of extinction rather than the initiation of extinction
[41,43]. In the case of significant interaction when the consumption of all groups was analyzed, paired comparisons were made.
7. Results 7.1. Experiment 1: doses of vasopressin that induce conditioned taste avoidance Both vasopressin groups acquired conditioned taste avoidance after two acquisition tests when injections occurred 50 min after sucrose consumption (see Fig. 1). The consumption of the vasopressin groups decreased significantly across the acquisition and post-acquisition tests but the consumption of the saline group did not change ( F(4,52) = 4.12, p = 0.006 for interaction effect; oneway ANOVA: for 18 Ag/kg VP, F(2,18) = 11.35, p = 0.001; for 9 Ag/kg VP, F(2, 18) = 7.74, p = 0.004; for saline, F(2,16) = 0.36, p = 0.701). For both vasopressin groups, a decrease in sucrose consumption was not evident until after the second acquisition test and the sucrose consumption of these groups was significantly different from that of the saline group only during the post-acquisition test ( F(2,26) = 6.97, p = 0.0038 and Tukey HSD p b 0.001). No differences in sucrose consumption were found for the two vasopressin groups. 7.2. Experiment 2: vasopressin and extinction of LiCl-induced conditioned taste avoidance Both doses of vasopressin delayed the onset of extinction of a LiCl-induced conditioned taste avoidance when given 50 min after LiCl injection but only the highest dose delayed onset when given 25 min after LiCl (see Fig. 2). No differences in sucrose consumption were found when consumption across the acquisition and first post-acquisition tests and across the 9 extinction tests was analyzed. However, the 5 groups differed in the amount of sucrose consumed across the first 3 extinction tests and in the rate of increase in consumption ( F(4,38) = 3.63, p = 0.013 for group main effect; F(8,76) = 2.55, p = 0.016 for interaction effect). Less sucrose was consumed across the first 3 extinction tests by the groups given 9 and 18 Ag/kg of vasopressin 50 min after LiCl injection than the groups given saline ( F(1,13) = 5.67, p = 0.033 and F(1,14) = 4.93, p = 0.043, respectively). However, when vasopressin was injected 25 min after LiCl, only the group given 18 Ag/kg of vasopressin consumed less sucrose than the group given saline ( F(1,13) = 6.43, p = 0.025). 7.3. Experiment 3: vasopressin and acquisition of LiCl-induced conditioned taste avoidance All rats injected with LiCl and/or vasopressin acquired a conditioned taste avoidance but the rats given both LiCl
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20 Saline 9 µg/kg AVP
Mean (+SE) Sucrose Consumption (ml)
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18 µg/kg AVP
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8
* *
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0 Acq 1
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Test Days Fig. 1. Mean (FSE) sucrose consumption (ml) during two acquisition tests (Acq 1–Acq 2) and one post-acquisition test (Post-Acq) for rats injected with saline or 9 or 18 Ag/kg of arginine vasopressin (AVP). For each acquisition test, subcutaneous injections were given 50 min after access to a sucrose solution. *Significant decrease in sucrose consumption across the acquisition and post-acquisition tests and significantly lower consumption than the saline group during the post-acquisition test, p b 0.001.
and vasopressin acquired a stronger avoidance (see Fig. 3). The rats injected with LiCl plus saline, saline plus vasopressin, and LiCl plus vasopressin showed a decrease in sucrose consumption across the two acquisition and one post-acquisition tests but the rats injected with saline plus saline did not ( F(6,56) = 6.19, p b 0.001; one-way ANOVA: for LiCl plus saline, F(2,14) = 11.86, p = 0.001; for saline 16
Mean ( SE) Sucrose Consumption (ml)
Saline
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plus vasopressin, F(2,14) = 12.77, p = 0.001; for LiCl plus vasopressin, F(2, 14) = 28.64, p b 0.001; for saline plus saline, F(2,14) = 0.81, p = 0.47). Each of the groups injected with LiCl and/or vasopressin consumed significantly less sucrose during the post-acquisition test than the saline group ( F(3,28) = 12.92, p b 0.001 and Tukey HSD p b 0.027). Comparisons of the three groups injected with
9 µg/kg: 25 Min
18 µg/kg: 25 Min*
9 µg/kg: 50 Min*
18 µg/kg: 50 Min*
12 10 8 6 4 2 0 ACQ
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Tests Fig. 2. Mean (FSE) amount of sucrose consumed by male rats during acquisition (Acq) and extinction (E1–E9) of a conditioned taste avoidance. On acquisition day, intraperitoneal injections of 1.5 mEq/kg of LiCl were given immediately after consumption of a sucrose solution and subcutaneous injections of saline or 9 or 18 Ag/kg of arginine vasopressin (AVP). *Significantly lower sucrose consumption than the saline group across the first 3 extinction tests, p b 0.05.
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20
Mean ( SE) Sucrose Consumption (ml)
Saline+Saline
LiCl+Saline
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16 12 8
**
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* ** 0 Acq1
Acq2
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Tests Fig. 3. Mean (F SE) sucrose consumption (ml) during two acquisition tests (Acq 1–Acq 2) and one post-acquisition test (Post-Acq). For each acquisition test, rats were injected with 0.075 mEq/kg of LiCl or saline immediately after access to a sucrose solution for 1 h and then 50 min later, they received an injection of arginine vasopressin (18 Ag/kg AVP) or saline. *Significant decrease in sucrose consumption across the acquisition and post-acquisition tests and significantly lower consumption than the saline + saline group during the post-acquisition test, p b 0.001. **Significantly lower consumption than the LiCl + saline or saline + AVP groups during the post-acquisition test, p b 0.001.
LiCl and/or vasopressin revealed that the sucrose consumption of the LiCl plus vasopressin group was significantly lower than that of the LiCl plus saline and saline plus vasopressin groups during the post-acquisition test ( F(2,21) = 7.89, p = 0.0028, Tukey HSD p b 0.016).
8. General discussion In a previous study, when a 6 Ag/kg dose of vasopressin was administered 50 min after pairing LiCl with sucrose consumption, extinction of the LiCl-induced conditioned taste avoidance was accelerated [44]. However, when a 9 or 18 Ag/kg dose of vasopressin was administered 50 min after pairing LiCl with sucrose consumption in experiment 2, the initiation of extinction was delayed as evidenced by reduced sucrose consumption during the first 3 extinction tests. The only procedural difference between the previous study and the present study was the dose of vasopressin used. The stimulus effects of the 6 Ag/kg dose and the 9 and 18 Ag/kg doses of vasopressin are different. The results of experiment 1 demonstrated that in the absence of LiCl, the higher doses of vasopressin could induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution. However, subcutaneous administration of a 6 Ag/kg dose of vasopressin 50 min after consumption of a sucrose solution failed to induce a conditioned taste avoidance even after two acquisition tests [44]. These results suggest that the stimulus effects produced by different doses of vasopressin play an important role in determining the kind of effect vasopressin will have on extinction when administered after acquisition of a LiCl-induced conditioned taste avoidance.
This is in contrast to what has been found for passive and active shock avoidance. Vasopressin consistently facilitates retention and delays extinction across a wide range of doses. In studies using passive shock avoidance tasks, vasopressin in amounts ranging from 4 to 21.4 Ag/kg facilitated retention and similar amounts (e.g., 1.2–21.4 Ag/kg) delayed extinction [23–26,35,62,63]. In studies using the active avoidance task pole-jumping, animals receiving injections in amounts ranging from 1.2 to 21.4 Ag/kg exhibited delayed extinction [64,65]. The lower levels of consumption exhibited by the animals treated with 9 or 18 Ag/kg of vasopressin during the first few extinction tests are characteristic of what is found when the dose of LiCl is increased [66]. Increasing the dose of a 0.15 M LiCl solution from 1.5 to 3.0 mEq/kg, produces a significant decrease in the amount of sucrose consumed during the first four extinction tests. Taken together, these results suggest that in experiment 2, administering 9 or 18 Ag/kg of vasopressin 50 min after injecting the 1.5 mEq/kg dose of LiCl, in effect, increased the dose of LiCl and that the delay in the initiation of extinction represents a strengthening of the acquisition process. This suggestion is supported by the results of experiment 3. There is a substantial decrease in consumption of a sucrose solution after a 1.5 mEq/kg dose of LiCl has been paired with consumption of this solution. Thus, a lower dose of LiCl was used in experiment 3 so that animals would show a gradual decrease in sucrose consumption after repeated pairings of sucrose with LiCl and therefore the effects of vasopressin on acquisition of a LiCl-induced conditioned taste avoidance could more easily be assessed [43,44]. The results of this experiment demonstrated that when 18 Ag/kg vasopressin was administered 50 min after pairing a 0.075 mEq/kg dose of LiCl with a sucrose solution, the decrease in consumption after two acquisition tests was greater than when only vasopressin or LiCl were injected. Thus, acquisition of a LiCl-induced conditioned taste avoidance was strengthened when vasopressin was administered 50 min after LiCl injection. We have suggested that when doses of vasopressin, which do not induce conditioned taste avoidance, are administered after LiCl injection, they act on the acquisition process by reducing the illness-inducing effects produced by LiCl and thereby accelerate extinction [43,44]. Responses produced by illness-inducing agents can be reduced by vasopressin. Social exploration of conspecific juveniles by adult animals is a behavioral response that decreases when exposed to illness-inducing agents [67]. The cytokine interleukin-1 (IL-1) reduces this response and infusion of vasopressin into the lateral ventricle attenuates this reduction. If subsequent research supports this hypothesis, then this would mean that the stimulus properties of low doses of vasopressin, which do not induce conditioned taste avoidance, are subtractive with respect to the stimulus properties of LiCl while high doses of vasopressin, which do induce conditioned taste avoidance, are additive.
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Whether the doses of vasopressin are low or high, the findings demonstrate that there is an optimal time during which vasopressin modulates extinction when it is administered after LiCl injection. Vasopressin is most effective in producing an effect when it is administered 50 min after LiCl injection. In our previous study, 6 Ag/kg of vasopressin was effective in accelerating extinction when given 50 min after the injection of LiCl but not when given 25 min after injection [44]. In experiment 2 of the present study, both the 9 and 18 Ag/kg doses of vasopressin were effective in delaying the onset of extinction when administered 50 min after LiCl injection but only the 18 Ag/kg dose of vasopressin delayed the onset when given 25 min after LiCl. Although the 25 min findings were not significant in both of the above studies, vasopressin did produce a trend similar to what was reported after the 50 min latency. This temporal factor may be a function of the time course of the increase in the blood levels of LiCl after injection and consequently, the acquisition process. For four different concentrations of LiCl (2.5, 5.0, 10.0, and 20.0 mEq/kg), the blood levels of LiCl gradually increase and peak approximately 30 min after injection regardless of dose, although the height of the peak is positively correlated with the dose [68]. The levels of LiCl remain elevated for 0.5–1.5 h before slowly dissipating [68,69]. Some of the behavioral effects of LiCl, such as decreased ingestive and increased aversive taste reactions to a novel sucrose solution, have been observed 15 and 20 min, respectively, after injection of a 3.0 mEq/kg dose of LiCl [70]. It has been suggested that the acquisition process begins at this time and it probably continues at least as long as LiCl is producing aversive stimulus effects. This means that when vasopressin is given 25 min after acquisition it is present during the early stages of the acquisition process but when it is given 50 min after the acquisition test it is present during the later stages of the acquisition process. Perhaps the ability of vasopressin to modulate extinction is more effective during the later stages of the acquisition process. Depending on time of administration, vasopressin in doses that do not induce conditioned taste avoidance produce contradictory effects. It delays extinction when given before pairing a sweet taste solution with LiCl and accelerates extinction when given after such a pairing [41– 44]. Depending on the dose used, vasopressin can delay or accelerate extinction when given after pairing a sucrose solution with LiCl. A simple mnemonic hypothesis cannot account for these contradictory findings. There are other explanations that can explain these findings. First, the delay in extinction when vasopressin is present before acquisition could be the result of an alteration in the acquisition process. There is evidence that intracerebroventricular infusion of vasopressin in unconditioned mice increases fos-like protein immunoreactivity in areas of the brain that are involved in acquisition of conditioned taste avoidance [71]. This suggests that vasopressin treatment before acquisition could result in neural changes that alter subsequent processing of
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taste-illness information. Second, as indicated above, the acceleration of extinction when a low dose of vasopressin is given after pairing a sucrose solution with LiCl could be accounted for by a vasopressin-induced reduction in the illness-inducing effects of LiCl. Third, the delay in extinction when a high dose of vasopressin is given after pairing sucrose with LiCl can be explained by the aversive properties of vasopressin. The pattern of results found in experiments 2 and 3 are similar to what is found for other agents with aversive properties [48,51–57]. That the delay in extinction when a high dose of vasopressin is given after LiCl involves the initiation of extinction while the delay in extinction when a low dose of vasopressin is given before acquisition involves the completion of extinction suggests that the reason for the delay in each case is different [43,44].
Acknowledgement The research described in this article was part of a doctoral dissertation submitted by UnJa L. Hayes to the University of Southern California. It was supported by BNRF and Sigma Xi GIAR.
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[35] Kovacs GL, Veldhuis HD, Versteeg DHG, DeWied D. Facilitation of avoidance behavior by vasopressin fragments microinjected into limbic–midbrain structures. Brain Res 1986;371(1):17 – 24. [36] Koob GF, LeMoal M, Gaffori O, Manning M, Sawyer WH, Rivier J, et al. Arginine vasopressin and a vasopressin antagonist peptide: opposite effects on extinction of active avoidance in rats. Regul Pept 1981;2:153 – 63. [37] Sahgal A, Wright C. A comparison of the effects of vasopressin and oxytocin with amphetamine and chlordiazepoxide on passive avoidance behaviour in rats. Psychopharmacology 1983;80(3):88 – 92. [38] Sahgal A, Wright C, Edwardson JA. Failure of vasopressin to enhance memory in a passive avoidance task in rats. Neurosci Lett 1982;28: 87 – 92. [39] Hamburger R, Sela A, Belmaker RH. Differences in learning and extinction in response to vasopressin in sex inbred mouse strains. Psychopharmacology 1985;87:124 – 5. [40] Alescio-Lautier B, Soumireu-Mourat B. Role of vasopressin in learning and memory in the hippocampus. Prog Brain Res 1998; 119:501 – 21. [41] Vawter MP, Green KF. Effects of desglycinamide–lysine vasopressin on a conditioned taste aversion in rats. Physiol Behav 1980;25(6):851 – 4. [42] Cooper RL, McNamara MC, Thompson WG. Vasopressin and conditioned flavor aversion in aged rats. Neurobiol Aging 1980; 1(1):53 – 7. [43] Hayes U, Chambers KC. Central infusion of vasopressin in male rats accelerates extinction of conditioned taste avoidance induced by LiCl. Brain Res Bull 2002;57:727 – 33. [44] Hayes UL, Chambers KC. Peripheral vasopressin accelerates extinction of conditioned taste avoidance. Physiol Behav 2005;84:147 – 56. [45] Ettenberg A, van der Kooy D, LeMoal M, Koob GF, Bloom FE. Can aversive properties of peripherally injected vasopressin account for its putative role in memory? Behav Brain Res 1983;7:331 – 50. [46] Bluthe RM, Dantzer R, Mormede P, LeMoal M. Specificity of aversive stimulus properties of vasopressin. Psychopharmacol 1985; 87:238 – 41. [47] Chambers KC, Hayes UL. The role of vasopressin in behaviours associated with aversive stimuli. In: Steckler T, Reul H, Kalin N. (eds.), Handbook of Stress and the Brain, Part I: The Neurobiology of Stress. Amsterdam: Elsevier Science; 2005. pp. 231–61. [48] Chambers KC, Hayes UL. Exposure to estradiol before but not during acquisition of LiCl-induced conditioned taste avoidance accelerates extinction. Horm Behav 2002;41(3):297 – 305. [49] Yuan DL, Chambers KC. Estradiol accelerates extinction of a conditioned taste aversion in female and male rats. Horm Behav 1999;36:1 – 16. [50] Yuan DL, Chambers KC. Estradiol accelerates extinction of lithium chloride-induced conditioned taste aversions through its illnessassociated properties. Horm Behav 1999;36:287 – 98. [51] Cannon DS, Berman RF, Baker TB, Atkins CA. Effect of preconditioning unconditioned stimulus experience on learned taste aversions. J Exp Psychol Anim Behav Process 1975;1(3):270 – 84. [52] Domjan M. Effects of proximal unconditioned stimulus preexposure on ingestional aversions learned as a result of taste presentation following drug treatment. Anim Learn Behav 1978;6:133 – 42. [53] Domjan M, Best MR. Paradoxical effects of proximal unconditioned stimulus preexposure: interference with and conditioning of a taste aversion. J Exp Psychol Anim Behav Proc 1977;3:310 – 21. [54] Rabin BM, Hunt WA, Lee J. Taste aversion learning produced by combined treatment with subthreshold radiation and lithium chloride. Pharmacol Biochem Behav 1987;27(4):671 – 5. [55] Rabin BM, Hunt WA, Lee J. Interactions between radiation and amphetamine in taste aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions. Pharmacol Biochem Behav 1987;27(4):677 – 83. [56] Kusnecov AW, King MG, Husband AJ. Synergism of a compound unconditioned stimulus in taste aversion conditioning. Physiol Behav 1987;39:531 – 3.
U.L. Hayes, K.C. Chambers / Physiology & Behavior 84 (2005) 625–633 [57] Domjan M, Foster K, Gillan DJ. Effects of distribution of the drug unconditioned stimulus on taste-aversion learning. Physiol Behav 1979;23:931 – 8. [58] Brownson EA, Sengstake CB, Chambers KC. The role of serum testosterone in the accelerated extinction of a conditioned taste aversion in fluid deprived male rats. Physiol Behav 1994;55:273 – 8. [59] Chambers KC, Sengstake CB, Brownson EA, Westfahl PK. Decreased testosterone levels and accelerated extinction of a conditioned taste aversion in fluid deprived male rats. Behav Neurosci 1993;107(2): 299 – 305. [60] Sengstake CB, Chambers KC. Differential effects of fluid deprivation on the acquisition and extinction phases of a conditioned taste aversion. Bull Psychon Soc 1979;14:85 – 7. [61] Sengstake CB, Chambers KC, Thrower JH. Interactive effects of fluid deprivation and testosterone on the expression of a sexually dimorphic conditioned taste aversion. J Comp Physiol Psychol 1978;92:1150 – 5. [62] Lebrun C, Le Moal M, Dantzer R, Bloom FE, Koob GF. Hyptertonic saline mimics the effects of vasopressin on inhibitory avoidance in the rat. Behav Neural Biol 1987;47(2):130 – 7. [63] DeWied D, Gaffori O, Burbach JPH, Kovacs GL, van Ree JM. Structure activity relationship studies with C-terminal fragments of vasopressin and oxytocin on avoidance behaviors in rats. J Pharmacol Exp Ther 1987;241:268 – 74. [64] DeWied D. Behavioral effects of intraventricularly administered vasopressin and vasopressin fragments. Life Sci 1976;19:685 – 90.
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[65] Van Wimersma Greidanus TB, Croiset G, Schuiling GA. Fornix transection: discrimination between neuropeptide effects on attention and memory. Brain Res Bull 1979;4(5):625 – 9. [66] Chambers KC, Wang Y. Role of the lateral parabrachial nucleus in apomorphine-induced conditioned consumption reduction: cooling lesions and relationship of c-Fos-like immunoreactivity to strength of conditioning. Behav Neurosci 2004;118:199 – 213. [67] Dantzer R, Bluthe RM, Kelly KW. Androgen-dependent vasopressinergic neurotransmission attenuates interleukin-1-induced sickness behavior. Brain Res 1991;557(1–2):115 – 20. [68] Morrison JM, Pritchard HD, Braude ML, D’Aguanno W. Plasma and brain lithium levels after lithium carbonate and lithium chloride administration by different routes in rats. Proc Soc Exp Biol Med 1971;137:889 – 92. [69] Sterner RT. Plasma lithium as a marker of lithium chloride in wild Norway rats (R. norvegicus). Physiol Behav 1990;47:1013 – 35. [70] Spector AC, Breslin P, Grill HJ. Taste reactivity as a dependent measure of the rapid formation of conditioned taste aversion: a tool for the neural analysis of taste-visceral associations. Behav Neurosci 1988;102(6):942 – 52. [71] Paban V, Alescio-Lautier B, Devigne C, Soumireu-Mourat B. Fos protein expression induced by intracerebroventricular injection of vasopressin in unconditioned and conditioned mice. Brain Res 1999; 825(1–2):115 – 31.
High doses of vasopressin delay the onset of extinction and strengthen acquisition of LiCl-induced conditioned taste avoidance UnJa L. Hayesa,T, Kathleen C. Chambersb a
Center for Neuroendocrine Studies, University of Massachusetts, Tobin Hall, Amherst, MA 01003, United States b Department of Psychology, University of Southern California, Los Angeles, CA 90089, United States Received 8 June 2004; received in revised form 5 January 2005; accepted 10 February 2005
Abstract When low doses of vasopressin are given 50 min after pairing sucrose consumption with a high dose of LiCl, extinction of the LiClinduced conditioned taste avoidance is accelerated. These low doses of vasopressin do not themselves induce conditioned taste avoidance when paired with sucrose consumption. Predicated on previous studies administering two avoidance-inducing agents after sucrose consumption, studies were designed to determine whether high doses of vasopressin capable of inducing conditioned taste avoidance would (1) delay rather than accelerate extinction of a conditioned taste avoidance induced by a high dose of LiCl and (2) strengthen acquisition of a conditioned taste avoidance induced by a low dose of LiCl. The results of three studies showed that doses of 9 and 18 Ag/kg of vasopressin induced a conditioned taste avoidance when injected 50 min after sucrose consumption, delayed the onset of extinction when injected 50 min after pairing sucrose consumption with a high dose of LiCl, and strengthened acquisition of a conditioned taste avoidance when injected 50 min after pairing sucrose consumption with a low dose of LiCl. Taken together, these data suggest that the delay in onset of extinction is due to a strengthening of acquisition. It has been suggested that vasopressin is a mnemonic neuropeptide that delays extinction of learned tasks. However, for conditioned taste avoidance, the evidence for the effects of low doses of vasopressin on extinction do not support this hypothesis and the evidence for high doses of vasopressin can be accounted for by the avoidance-inducing properties of vasopressin. D 2005 Elsevier Inc. All rights reserved. Keywords: Conditioned taste aversion; LiCl
1. Introduction The neuropeptide, vasopressin, has been implicated in both physiological responses (e.g., antidiuresis, cardiovascular regulation, and thermoregulation) and behavioral responses (e.g., eating, defensive behaviors, aggression, and parental behavior) [1–6]. In addition, it modulates performance in a number of different kinds of learning situations, including appetitive, spatial, social, and aversive situations [7–17]. The most commonly reported effects of vasopressin in learning situations are facilitation of retention, enhanced performance, and delay in extinction. These
T Corresponding author. Tel.: +1 413 545 0794; fax: +1 413 545 0996. E-mail address: [email protected] (U.L. Hayes). 0031-9384/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2005.02.012
effects of vasopressin in learning and memory tasks have led investigators to hypothesize that vasopressin acts as a mnemonic neuropeptide [13,18–21]. Although a number of different learning tasks have been used to study the effects of vasopressin in memory, most studies have used active (e.g., shuttle box and polejumping) and passive (e.g., step-through) shock avoidance paradigms. The delaying effect of vasopressin on extinction of shock avoidance behaviors has been reported 1) in both active and passive shock avoidance tasks, 2) with peripheral as well as central administration of the neuropeptide, and 3) when treatment occurred at different times during acquisition and/or extinction testing, e.g., before or after the last acquisition trial, before or after the first extinction trial, or before each acquisition or extinction trial [22–36].
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However, not all of the evidence is consistent with a simple mnemonic hypothesis. Individual and strain differences within the shock avoidance paradigm and timedependent differences within other learning paradigms have been found. For shock avoidance, several studies have reported that vasopressin produces bimodal effects, that is, it maintains the avoidance behavior in most animals but disrupts it in some [37,38]. Additionally, acquisition of a two-way shuttle box task is accelerated in one strain of inbred mice and disrupted in another strain [39]. For other learning paradigms, there is evidence that vasopressin can differentially modulate learned behaviors depending on whether it is present during the initial or later stages of the learning process [40]. Infusion of vasopressin into the ventral hippocampus after the first learning session of an appetitive visual discrimination task, slightly delays performance during subsequent testing, but enhances performance when infused after the second learning session. Similar inconsistencies have been found when the effects of vasopressin on conditioned taste avoidance have been examined. While earlier studies reported that vasopressin prolonged extinction [41,42], more recent research has found that this neuropeptide can produce the opposite effect, namely an acceleration of extinction [43,44]. Peripheral administration of vasopressin shortly before acquisition or extinction, or before both acquisition and extinction tests resulted in a delayed extinction of conditioned taste avoidance induced by LiCl or amphetamine and intracerebroventricular infusion of vasopressin increased the number of animals to show a delay in extinction of a LiCl-induced conditioned taste avoidance [41,42,44]. On the other hand, both peripheral and intracerebroventricular administration of vasopressin shortly after acquisition of a LiCl-induced conditioned taste avoidance accelerated extinction [43,44]. These findings suggest that the direction of the effect of vasopressin on extinction of conditioned taste avoidance is dependent upon when during the learning or testing process vasopressin is administered [44]. Another factor that might influence the direction of the effect of vasopressin on extinction of conditioned taste avoidance is dose. The doses of arginine vasopressin and DG–LVP that were administered before or after acquisition do not themselves induce conditioned taste avoidance [43,45–47]. However, higher doses of vasopressin can induce conditioned taste avoidance [47]. The issue of whether vasopressin can induce conditioned taste avoidance is important because agents that are capable of inducing a conditioned taste avoidance can weaken acquisition of a conditioned taste avoidance when administered before acquisition and strengthen acquisition when administered after acquisition [48–50]. For example, when LiCl is given 1 day or 30 min before pairing saccharin with LiCl, the subsequent conditioned taste avoidance is attenuated [51– 53]. On the other hand, the avoidance induced by one agent
can be strengthened by administration of a second agent that is capable of inducing conditioned taste avoidance [48,54– 57]. For example, administration of both estradiol and LiCl or radiation and LiCl immediately after sucrose consumption reduces the amount of sucrose consumed during the first few days of extinction [48,54]. In addition, a stronger conditioned taste avoidance is produced when two separate doses of 1.5 mEq/kg LiCl are injected immediately and 35 or 70 min after sucrose consumption than when a single dose of 3.0 mEq/kg LiCl is injected immediately after consumption [57]. These data suggest that doses of vasopressin that can themselves induce conditioned taste avoidance could weaken a LiCl-induced conditioned taste avoidance when administered before acquisition and strengthen this type of avoidance when administered after acquisition. As indicated above, doses of vasopressin that do not themselves induce conditioned taste avoidance accelerate extinction when given 50 min after pairing consumption of a sucrose solution with injection of a moderate dose of LiCl [43,44]. The following experiments were designed to test the hypothesis that a dose of vasopressin capable of inducing conditioned taste avoidance would strengthen acquisition when administered after acquisition of a LiClinduced conditioned taste avoidance. Strength of acquisition was assessed in two ways. In experiment 2, doses of vasopressin capable of inducing conditioned taste avoidance were administered peripherally 50 min after pairing consumption of a sucrose solution with a moderate dose of LiCl. This dose of LiCl produces a relatively strong avoidance after one pairing with sucrose consumption. If vasopressin strengthens acquisition, one would expect to see a stronger acquisition expressed as a delay in the onset of extinction. In experiment 3, a dose of vasopressin capable of inducing conditioned taste avoidance was administered peripherally 50 min after pairing consumption of a sucrose solution with a weak dose of LiCl. This dose of LiCl requires several pairings with sucrose consumption to produce a strong avoidance. If vasopressin strengthens acquisition, one would expect fewer pairings to produce a strong avoidance. Before conducting these two experiments, it was important to determine a peripheral dose of vasopressin that could itself induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution. Experiment 1 was designed to identify such a dose of vasopressin.
2. General methods 2.1. Subjects Male Sprague–Dawley rats (Simonsen Laboratory, Gilroy, CA), which weighed approximately 300 g at the beginning of the experiments, were used in these experiments. They were housed two per cage in a room that was
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temperature (21–22 8C), humidity (51%), and light controlled (a 12 h light:12 h dark cycle with lights on at 1000 and lights off at 2200 hours). Each cage measured 58 38 cm and had a solid bottom that was covered with wood chips. A stainless steel divider was placed in the middle of each cage to separate each pair of rats during behavioral testing. The rats were allowed at least 1 week to adapt to their living conditions before the experiments were initiated. Rats had ad libitum access to rat chow and tap water before behavioral testing began. During conditioned taste avoidance testing, water was available 23 h a day. In previous studies, we found that rats given similar drinking schedules are essentially nondeprived [58–61]. The experiments were conducted according to the standards set by the National Institutes of Health Guide for the Care and Use of Laboratory Animals (DHEW Publication 80-23, Revised 1985, Office of Science and Health Reports, DRR/NIH, Bethesda MD) and the institutional guidelines of the University of Southern California.
3. Drugs 3.1. Vasopressin Arginine vasopressin (AVP; Sigma-Aldrich, St. Louis, MO) was dissolved in sterile, normal saline (0.9% NaCl). Peripheral administration consisted of subcutaneous injection at the nape of the neck in the amount of 9 or 18 Ag/kg. The injection amount was 0.2 ml. The control animals received the same amount of the saline vehicle. 3.2. Lithium chloride Lithium chloride (LiCl; Sigma-Aldrich, Inc., St. Louis, MO) was dissolved in distilled water to make a 0.15 M solution. The doses of LiCl were either 1.5 mEq/kg (10 ml/ kg) in experiment 2 or 0.075 mEq/kg (0.5 ml/kg) in experiment 3. In each study, the vehicle was saline, the volume of vehicle and LiCl administered was the same, and both vehicle and LiCl were injected intraperitoneally.
4. Conditioned taste avoidance The experimental testing procedure was divided into the following four periods: preconditioning, acquisition testing, post-acquisition recovery, and post-acquisition or extinction testing. All solutions used during testing were stored under refrigeration for 24 h before use and they were given to the rats at the beginning of the dark portion of the light/dark cycle. During preconditioning, the water bottle of each rat was replaced with one cylinder containing refrigerated tap water at the onset of the dark cycle. After 1 h, the cylinders were replaced with the regular water bottles. Preconditioning rats
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with cold water just after the lights switch off increases the likelihood that nondeprived rats will drink the novel sucrose solution used for conditioning. During acquisition testing, the water bottle of each rat was replaced with 1 cylinder containing a 10% (w/v) sucrose solution. One hour later, the amount of sucrose consumed was recorded, the cylinder was removed, and the regular water bottle was returned. The post-acquisition or extinction tests were conducted in the same manner as the acquisition tests except neither LiCl nor vasopressin was administered. The number of acquisition and post-acquisition tests given and the type of agent injected after sucrose consumption varied with each experiment.
5. Experimental design 5.1. Experiment 1: doses of vasopressin that induce conditioned taste avoidance Previous studies have determined that even after 2 pairings a 6 Ag/kg dose of vasopressin does not induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution [44]. This experiment was designed to determine whether higher doses would produce the stimulus effects necessary to significantly condition a decrease in sucrose consumption. Twenty-nine rats were randomly assigned to one of three groups: injections of saline (n = 9), 9 Ag/kg AVP (n = 10), or 18 Ag/kg AVP (n = 10) given 50 min after consumption of sucrose on each of 2 acquisition tests. The acquisition tests were given every other day and a post-acquisition test was given two days after the last acquisition test. 5.2. Experiment 2: vasopressin and extinction of LiCl-induced conditioned taste avoidance In a previous study, a 6 Ag/kg dose of vasopressin, which does not produce a conditioned taste avoidance, accelerated extinction of a conditioned taste avoidance induced by a 1.5 mEq/kg dose of LiCl when it was administered 50 min after LiCl injection [44]. This experiment was designed to determine whether using higher doses of vasopressin, which are capable of producing conditioned taste avoidance, will strengthen acquisition as evidenced by a delay in the onset of the extinction of a LiCl-induced conditioned taste avoidance. Forty-two rats were randomly assigned to one of six groups: injection of saline (n = 3), 9 Ag/kg AVP (n = 9), or 18 Ag/kg AVP (n = 9) given 25 min after the LiCl injection on acquisition day and injection of saline (n = 3), 9 Ag/kg AVP (n = 9), or 18 Ag/kg AVP (n = 9) given 50 min after the LiCl. All rats were injected with 1.5 mEq/kg of LiCl immediately after access to a sucrose solution for 1 h and then 25 or 50 min later, they received an injection of vasopressin or saline. Starting two days later, the animals were given 1 extinction test per day for 9 days.
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5.3. Experiment 3: vasopressin and acquisition of LiCl-induced conditioned taste avoidance In previous studies using our methodology, a 1.5 mEq/ kg dose of LiCl produced a substantial decrease in consumption after pairing it with a sucrose solution [43,44]. Consumption levels dropped from a mean of 12 ml to a mean of 3 ml. Because the consumption levels drop so low, it is likely that any further decrease in consumption that might occur if a high dose of vasopressin as well as LiCl were paired with sucrose consumption would be masked by a floor effect. This possibility could be circumvented by reducing the dose of LiCl. The following experiment was designed to determine whether acquisition of a conditioned taste avoidance induced by a low dose of LiCl could be strengthened by administering a high dose of vasopressin 50 min after LiCl injection. Thirty-two rats were randomly assigned to one of four groups (n = 8/group): saline plus saline, LiCl plus saline, saline plus vasopressin, and LiCl plus vasopressin. Rats were injected with 0.075 mEq/kg of LiCl or saline immediately after access to a sucrose solution for 1 h and then 50 min later, they received an injection of vasopressin (18 Ag/kg) or saline. All rats were given two acquisition tests every other day and one post-acquisition test was given one day after the last acquisition test.
6. Statistical analysis An alpha level of p b 0.05 was used for determination of significance in all statistical tests. For experiments 1 and 3, a two-factor (groups by tests) analysis of variance (ANOVA) with repeated measures on tests was used to analyze sucrose consumption across all of the tests (2 acquisition tests and 1 post-acquisition test). In the case of a significant interaction, a dependent t test was used to analyze sucrose consumption for each group across the two acquisition tests and a onefactor (tests) ANOVA with repeated measures on tests was used for analyses across the acquisition and post-acquisition tests. A one-factor ANOVA and a Tukey HSD test (unequal n in experiment 1 and equal n in experiment 3) were used to determine group differences for each of the tests. For experiment 2, a two-factor (groups by tests) ANOVA with repeated measures on tests was used for all analyses of sucrose consumption. First, the sucrose consumption of the control animals administered saline 25 and 50 min after LiCl injection were compared. Because there were no differences in sucrose consumption for these two groups, their data were combined for subsequent analyses. Sucrose consumption across the acquisition and first extinction test, across the first 3 extinction tests, and across all 9 extinction tests was analyzed. Analyses of both the first 3 extinction tests and all 9 extinction tests were done because previous studies have shown that vasopressin influences the completion of extinction rather than the initiation of extinction
[41,43]. In the case of significant interaction when the consumption of all groups was analyzed, paired comparisons were made.
7. Results 7.1. Experiment 1: doses of vasopressin that induce conditioned taste avoidance Both vasopressin groups acquired conditioned taste avoidance after two acquisition tests when injections occurred 50 min after sucrose consumption (see Fig. 1). The consumption of the vasopressin groups decreased significantly across the acquisition and post-acquisition tests but the consumption of the saline group did not change ( F(4,52) = 4.12, p = 0.006 for interaction effect; oneway ANOVA: for 18 Ag/kg VP, F(2,18) = 11.35, p = 0.001; for 9 Ag/kg VP, F(2, 18) = 7.74, p = 0.004; for saline, F(2,16) = 0.36, p = 0.701). For both vasopressin groups, a decrease in sucrose consumption was not evident until after the second acquisition test and the sucrose consumption of these groups was significantly different from that of the saline group only during the post-acquisition test ( F(2,26) = 6.97, p = 0.0038 and Tukey HSD p b 0.001). No differences in sucrose consumption were found for the two vasopressin groups. 7.2. Experiment 2: vasopressin and extinction of LiCl-induced conditioned taste avoidance Both doses of vasopressin delayed the onset of extinction of a LiCl-induced conditioned taste avoidance when given 50 min after LiCl injection but only the highest dose delayed onset when given 25 min after LiCl (see Fig. 2). No differences in sucrose consumption were found when consumption across the acquisition and first post-acquisition tests and across the 9 extinction tests was analyzed. However, the 5 groups differed in the amount of sucrose consumed across the first 3 extinction tests and in the rate of increase in consumption ( F(4,38) = 3.63, p = 0.013 for group main effect; F(8,76) = 2.55, p = 0.016 for interaction effect). Less sucrose was consumed across the first 3 extinction tests by the groups given 9 and 18 Ag/kg of vasopressin 50 min after LiCl injection than the groups given saline ( F(1,13) = 5.67, p = 0.033 and F(1,14) = 4.93, p = 0.043, respectively). However, when vasopressin was injected 25 min after LiCl, only the group given 18 Ag/kg of vasopressin consumed less sucrose than the group given saline ( F(1,13) = 6.43, p = 0.025). 7.3. Experiment 3: vasopressin and acquisition of LiCl-induced conditioned taste avoidance All rats injected with LiCl and/or vasopressin acquired a conditioned taste avoidance but the rats given both LiCl
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and vasopressin acquired a stronger avoidance (see Fig. 3). The rats injected with LiCl plus saline, saline plus vasopressin, and LiCl plus vasopressin showed a decrease in sucrose consumption across the two acquisition and one post-acquisition tests but the rats injected with saline plus saline did not ( F(6,56) = 6.19, p b 0.001; one-way ANOVA: for LiCl plus saline, F(2,14) = 11.86, p = 0.001; for saline 16
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plus vasopressin, F(2,14) = 12.77, p = 0.001; for LiCl plus vasopressin, F(2, 14) = 28.64, p b 0.001; for saline plus saline, F(2,14) = 0.81, p = 0.47). Each of the groups injected with LiCl and/or vasopressin consumed significantly less sucrose during the post-acquisition test than the saline group ( F(3,28) = 12.92, p b 0.001 and Tukey HSD p b 0.027). Comparisons of the three groups injected with
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Tests Fig. 2. Mean (FSE) amount of sucrose consumed by male rats during acquisition (Acq) and extinction (E1–E9) of a conditioned taste avoidance. On acquisition day, intraperitoneal injections of 1.5 mEq/kg of LiCl were given immediately after consumption of a sucrose solution and subcutaneous injections of saline or 9 or 18 Ag/kg of arginine vasopressin (AVP). *Significantly lower sucrose consumption than the saline group across the first 3 extinction tests, p b 0.05.
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20
Mean ( SE) Sucrose Consumption (ml)
Saline+Saline
LiCl+Saline
LiCl+AVP
Saline+AVP
16 12 8
**
4
* ** 0 Acq1
Acq2
Post-Acq
Tests Fig. 3. Mean (F SE) sucrose consumption (ml) during two acquisition tests (Acq 1–Acq 2) and one post-acquisition test (Post-Acq). For each acquisition test, rats were injected with 0.075 mEq/kg of LiCl or saline immediately after access to a sucrose solution for 1 h and then 50 min later, they received an injection of arginine vasopressin (18 Ag/kg AVP) or saline. *Significant decrease in sucrose consumption across the acquisition and post-acquisition tests and significantly lower consumption than the saline + saline group during the post-acquisition test, p b 0.001. **Significantly lower consumption than the LiCl + saline or saline + AVP groups during the post-acquisition test, p b 0.001.
LiCl and/or vasopressin revealed that the sucrose consumption of the LiCl plus vasopressin group was significantly lower than that of the LiCl plus saline and saline plus vasopressin groups during the post-acquisition test ( F(2,21) = 7.89, p = 0.0028, Tukey HSD p b 0.016).
8. General discussion In a previous study, when a 6 Ag/kg dose of vasopressin was administered 50 min after pairing LiCl with sucrose consumption, extinction of the LiCl-induced conditioned taste avoidance was accelerated [44]. However, when a 9 or 18 Ag/kg dose of vasopressin was administered 50 min after pairing LiCl with sucrose consumption in experiment 2, the initiation of extinction was delayed as evidenced by reduced sucrose consumption during the first 3 extinction tests. The only procedural difference between the previous study and the present study was the dose of vasopressin used. The stimulus effects of the 6 Ag/kg dose and the 9 and 18 Ag/kg doses of vasopressin are different. The results of experiment 1 demonstrated that in the absence of LiCl, the higher doses of vasopressin could induce a conditioned taste avoidance when administered 50 min after consumption of a sucrose solution. However, subcutaneous administration of a 6 Ag/kg dose of vasopressin 50 min after consumption of a sucrose solution failed to induce a conditioned taste avoidance even after two acquisition tests [44]. These results suggest that the stimulus effects produced by different doses of vasopressin play an important role in determining the kind of effect vasopressin will have on extinction when administered after acquisition of a LiCl-induced conditioned taste avoidance.
This is in contrast to what has been found for passive and active shock avoidance. Vasopressin consistently facilitates retention and delays extinction across a wide range of doses. In studies using passive shock avoidance tasks, vasopressin in amounts ranging from 4 to 21.4 Ag/kg facilitated retention and similar amounts (e.g., 1.2–21.4 Ag/kg) delayed extinction [23–26,35,62,63]. In studies using the active avoidance task pole-jumping, animals receiving injections in amounts ranging from 1.2 to 21.4 Ag/kg exhibited delayed extinction [64,65]. The lower levels of consumption exhibited by the animals treated with 9 or 18 Ag/kg of vasopressin during the first few extinction tests are characteristic of what is found when the dose of LiCl is increased [66]. Increasing the dose of a 0.15 M LiCl solution from 1.5 to 3.0 mEq/kg, produces a significant decrease in the amount of sucrose consumed during the first four extinction tests. Taken together, these results suggest that in experiment 2, administering 9 or 18 Ag/kg of vasopressin 50 min after injecting the 1.5 mEq/kg dose of LiCl, in effect, increased the dose of LiCl and that the delay in the initiation of extinction represents a strengthening of the acquisition process. This suggestion is supported by the results of experiment 3. There is a substantial decrease in consumption of a sucrose solution after a 1.5 mEq/kg dose of LiCl has been paired with consumption of this solution. Thus, a lower dose of LiCl was used in experiment 3 so that animals would show a gradual decrease in sucrose consumption after repeated pairings of sucrose with LiCl and therefore the effects of vasopressin on acquisition of a LiCl-induced conditioned taste avoidance could more easily be assessed [43,44]. The results of this experiment demonstrated that when 18 Ag/kg vasopressin was administered 50 min after pairing a 0.075 mEq/kg dose of LiCl with a sucrose solution, the decrease in consumption after two acquisition tests was greater than when only vasopressin or LiCl were injected. Thus, acquisition of a LiCl-induced conditioned taste avoidance was strengthened when vasopressin was administered 50 min after LiCl injection. We have suggested that when doses of vasopressin, which do not induce conditioned taste avoidance, are administered after LiCl injection, they act on the acquisition process by reducing the illness-inducing effects produced by LiCl and thereby accelerate extinction [43,44]. Responses produced by illness-inducing agents can be reduced by vasopressin. Social exploration of conspecific juveniles by adult animals is a behavioral response that decreases when exposed to illness-inducing agents [67]. The cytokine interleukin-1 (IL-1) reduces this response and infusion of vasopressin into the lateral ventricle attenuates this reduction. If subsequent research supports this hypothesis, then this would mean that the stimulus properties of low doses of vasopressin, which do not induce conditioned taste avoidance, are subtractive with respect to the stimulus properties of LiCl while high doses of vasopressin, which do induce conditioned taste avoidance, are additive.
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Whether the doses of vasopressin are low or high, the findings demonstrate that there is an optimal time during which vasopressin modulates extinction when it is administered after LiCl injection. Vasopressin is most effective in producing an effect when it is administered 50 min after LiCl injection. In our previous study, 6 Ag/kg of vasopressin was effective in accelerating extinction when given 50 min after the injection of LiCl but not when given 25 min after injection [44]. In experiment 2 of the present study, both the 9 and 18 Ag/kg doses of vasopressin were effective in delaying the onset of extinction when administered 50 min after LiCl injection but only the 18 Ag/kg dose of vasopressin delayed the onset when given 25 min after LiCl. Although the 25 min findings were not significant in both of the above studies, vasopressin did produce a trend similar to what was reported after the 50 min latency. This temporal factor may be a function of the time course of the increase in the blood levels of LiCl after injection and consequently, the acquisition process. For four different concentrations of LiCl (2.5, 5.0, 10.0, and 20.0 mEq/kg), the blood levels of LiCl gradually increase and peak approximately 30 min after injection regardless of dose, although the height of the peak is positively correlated with the dose [68]. The levels of LiCl remain elevated for 0.5–1.5 h before slowly dissipating [68,69]. Some of the behavioral effects of LiCl, such as decreased ingestive and increased aversive taste reactions to a novel sucrose solution, have been observed 15 and 20 min, respectively, after injection of a 3.0 mEq/kg dose of LiCl [70]. It has been suggested that the acquisition process begins at this time and it probably continues at least as long as LiCl is producing aversive stimulus effects. This means that when vasopressin is given 25 min after acquisition it is present during the early stages of the acquisition process but when it is given 50 min after the acquisition test it is present during the later stages of the acquisition process. Perhaps the ability of vasopressin to modulate extinction is more effective during the later stages of the acquisition process. Depending on time of administration, vasopressin in doses that do not induce conditioned taste avoidance produce contradictory effects. It delays extinction when given before pairing a sweet taste solution with LiCl and accelerates extinction when given after such a pairing [41– 44]. Depending on the dose used, vasopressin can delay or accelerate extinction when given after pairing a sucrose solution with LiCl. A simple mnemonic hypothesis cannot account for these contradictory findings. There are other explanations that can explain these findings. First, the delay in extinction when vasopressin is present before acquisition could be the result of an alteration in the acquisition process. There is evidence that intracerebroventricular infusion of vasopressin in unconditioned mice increases fos-like protein immunoreactivity in areas of the brain that are involved in acquisition of conditioned taste avoidance [71]. This suggests that vasopressin treatment before acquisition could result in neural changes that alter subsequent processing of
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taste-illness information. Second, as indicated above, the acceleration of extinction when a low dose of vasopressin is given after pairing a sucrose solution with LiCl could be accounted for by a vasopressin-induced reduction in the illness-inducing effects of LiCl. Third, the delay in extinction when a high dose of vasopressin is given after pairing sucrose with LiCl can be explained by the aversive properties of vasopressin. The pattern of results found in experiments 2 and 3 are similar to what is found for other agents with aversive properties [48,51–57]. That the delay in extinction when a high dose of vasopressin is given after LiCl involves the initiation of extinction while the delay in extinction when a low dose of vasopressin is given before acquisition involves the completion of extinction suggests that the reason for the delay in each case is different [43,44].
Acknowledgement The research described in this article was part of a doctoral dissertation submitted by UnJa L. Hayes to the University of Southern California. It was supported by BNRF and Sigma Xi GIAR.
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