Examination of factors which might disrupt a learned association between pentobarbital and LiCl

LEARNING

AND

MOTIVATION

13, 185-199 (1982)

Examination of Factors Which Might Disrupt A Learned Association between Pentobarbital and LiCl GERARD M. MARTIN Memorial

University

injections of a sedative dose of pentobarbital (Pent) were followed 30 min later by injections of a toxic dose of lithium chloride (LiCl). As a result of these Pent +LiCl pairings, injections of Pent after consumption of saccharin solution failed to produce the usual saccharin aversion. This loss of the capacity of Pent to produce a flavor aversion is called Avfail. Experiment 1 showed that the Avfail effect was obtained with saccharin even though the rats consumed a novel vinegar solution prior to the Pent+LiCl pairings in Phase 1. This was surprising since the novel flavor was associated with the LiCl and ought to have overshadowed the association of Pent with LiCl. Experiment 2 showed that one set of PenhLiCl pairings can produce two Avfail effects in sequence: the first with a novel flavor and the second with a flavor previously paired with LiCl sickness. It also showed that insertion of Pent injections and handling cues between the Pent-LiCl and the Flavor+Pent phases did not reduce the magnitude of Avfail. Experiment 3 showed that the Avfail effect was not disrupted by the insertion of 54 saline injections between the PenhLiCl and Flavor-Pent pairings, nor by interposing 26 saline injections between each pair of Flavor-+Pent trials. This seemed to exclude an important role for injection cues. Experiment 3 also showed that 4 exposures to Pent and 50 exposures to saline between the Pent+LiCl trials and the Flavor+Pent trials and 26 exposures to saline injections between each pair of Flavor-Pent trials did not reduce the magnitude of Avfail. The same exposure to Pent and saline injections did reduce the magnitude of the saccharin aversion shown by the LiCkPent group. These data are viewed as consistent with Lett’s (Drug-drug sponse.

associations:

Evidence

for

the conditioning

of a compensatory

re-

Paper presented at a meeting of the Eastern Psychological Association, New York, 1981) suggestion that Avfail represents a learned antisickness response.

Recreational drugs such as pentobarbital, ethanol, morphine, and amphetamine produce flavor aversions at dosages that are typically selfadministered (Deneau, Yanagita, & Seevers, 1969; Cappell & LeBlanc, The author thanks Drs. Sam Revusky and Anne Storey for criticizing earlier versions of this manuscript and Elizabeth Noseworthy for technical assistance. This research was supported by Grant A7460 from the Natural Sciences and Engineering Research Council of Canada. 18.5 0023-%90/82/020185-15$02.00/O Copyright Q 1982 by Academic Press, Inc. All rights of reproduction in any form reserved.

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1976). Thus, paradoxically, the same drug seems rewarding in one context and aversive in another. Further, Revusky, Taukulis, Parker, and Coombes (1979) found that a higher-order conditioning procedure, often used to make other stimuli aversive, decreases the aversiveness of a recreational drug state in a flavor aversion situation. They expected that pairing a drug state with LiCl-induced sickness would increase the aversiveness of the drug state and thus enable the drug to produce larger flavor aversions: During Phase 1 of their experiment injections of pentobarbital (Pent) were followed by injections of LiCl (Pent+LiCI). Other groups were injected with the two drugs in the reverse order (LiCl -Pent), with Pent alone, or LiCl alone. All groups were given access to a novel 0.75% saccharin solution during Phase 2. This saccharin drinking was followed by a Pent injection except in a control group which was injected with saline. The Control group and the group with the Pent *LiCl history recovered from saccharin neophobia, but the other groups did not. In this sense, prior Pent+LiCl pairings may be said to have reduced the capacity of Pent to produce flavor aversions, although the a priori hypothesis of Revusky, Taukulis, Parker, and Coombes (1979) had been that it would increase this capacity. They called this loss of Pent’s aversive properties Avfail (aversion failure). Avfail does not occur because some unique interaction exists between Pent and LiCl. Similar effects have been obtained when ethanol (Cunningham & Linakis, 1980; Revusky, Taukulis, Parker, & Coombes, 1979), chlordiazepoxide, morphine, and amphetamine were substituted for Pent and when a high dosage of amphetamine was substituted for LiCl (Revusky, Taukulis, Parker, & Coombes, 1979). Avfail cannot be attributed simply to habituation to the physiological effects of the drugs since the effect depends on the order of drug presentation. Nor do the animals treat the flavor which precedes Pent as a Pavlovian conditioned inhibitor which predicts the absence of LiCl-induced sickness. A series of experiments showed that the flavor did not have the usual properties of a Pavlovian conditioned inhibitor (Revusky, Taukulis, & Peddle, 1979). Avfail, then, seems to depend on pairing the drug state with sickness. The following experiments examine factors which might prevent the formation and maintenance of the postulated association between the Pent and LiCI. EXPERIMENT 1 The drug stat-sickness pairings were temporally separated from fluid consumption during Phase 1 in earlier Avfail experiments (Cunningham & Linakis, 1980; Revusky, Taukulis, Parker, & Coombes, 1979; Revusky, Taukulis, & Peddle, 1979; Revusky, Taukulis, & Coombes, 1980). The investigators probably feared that fluid exposure would interfere with the formation of an association between the drug state and sickness. The

EXAMINATION

OF

AVFAIL

187

flavor of the fluid might become associated with sickness and would overshadow the drug stat-sickness association. The present experiment directly tested this possibility. Animals were exposed to a novel vinegar solution prior to the pairing of Pent with LiCl (Vin*Pent+LiCl). The control groups were either exposed to the Pent and LiCl in the other order (Vin-*LiCl+Pent) or received the injections without being exposed to the novel flavor (Pent-LiCl or LiCl*Pent). One would expect the Avfail effect to be weakened when vinegar is consumed prior to the Pent+LiCl pairings if the Vinegar+LiCl associations were capable of overshadowing the Pent+LiCl association. Method Subjects

Forty-eight male Sprague-Dawley rats which weighed 200-250 g prior to the experiment were housed in wire cages. Food pellets were available continuously and fluids were provided when indicated. Apparatus

and Procedure

Phase 1, Days 1 to 10. All rats were maintained on a thirst cycle of 24 hr water separated by 48 hr without water. The rats were 24 hr thirsty on Days 1,4,7, and 10when the experimental manipulations were carried out. Twenty-four rats were not given any fluid on these days. The other 24 animals were given IO-min access to a 2.0% (v/v) vinegar solution (Vin). Two milliliters of vinegar was passed over the rat’s tongue if its consumption of vinegar did not exceed 2 ml during the lo-min presentation. This “passive infusion” ensured that each rat in the Vin group was exposed to the flavor on occasions when a learned aversion might prevent exposure. Half the rats in the Vin group and half the rats.which were not exposed to a solution were subjected to an intraperitoneal (i.p.) injection of Pent (5 mg in 0.5 ml of physiological saline) followed 30 min later by an i.p. injection of LiCl (2.5 ml of 2.0% (w/v) LiCl). The other 12 rats in each group were injected with the same two substances in the reverse order. The first injection was immediately after fluid consumption for the groups that were exposed to vinegar. The four groups were designated Vin+Pent+LiCl, Vin+LiCl+Pent, Pent+LiCl, and LiCl+Pent. Phase 2, Days 11 to 33. All rats were maintained on lo-min access to water per day, On Days 25, 29, and 33 the water was flavored with 0.75% (w/v) sodium saccharin. The rat were injected with 5 mg of Pent in 0.5 ml of saline 10 min after the saccharin was removed. Statistical

Analysis

In this and all subsequent experiments in this series, flavored water scores were converted to suppression ratios (Flavored water/Flavored

188

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water + Previous day’s tap water consumption) after it was shown with ANOVAs that the groups’ tap water consumption did not differ. A score of 0.50 indicates equal flavored water and tap water consumption, a score above 0.50 indicates greater flavored than tap water consumption, and a score below 0.50 indicates less flavored than tap water consumption. Two-way ANOVAs (Groups x Days) were used to analyze the suppression ratios. The simple main effects were calculated and a Newman-Keuls test was performed on the results when a significant interaction was obtained. In all statistical tests, the criterion for rejection of the null hypothesis was P < .05. Results and Discussion A 2 x 4 ANOVA (Groups x Days) of vinegar suppression ratios during Phase 1 revealed that the only significant difference was over days [F(3, 66) = 29.771. This indicated that the rats in the Vin+Pent*LiCl and Vin+LiCl*Pent groups had acquired equally strong vinegar aversions. These data are not shown since the occurrence of a learned flavor aversion is not surprising given the high dosage of LiCl which was used. A 2 x 2 x 3 ANOVA (Vinegar x Drug Order x Days) showed Avfail in the Vin+Pent+LiCl and the Pent*LiCl groups. The combined Pent+LiCl groups differed from the combined LiCl+Pent groups [F(I, 44) = 32.341 and there was an interaction between the order of drug presentation and the three days [F(2, 88) = 50.671. These two findings are reflected in Fig. 1 by the higher suppression ratios observed in the two Pent+LiCl groups relative to the LiCl*Pent groups during the second and third presentations of saccharin. The ANOVA also indicates a Days effect [F(2, 88) = 24.431, which reflects the recovery from saccharin neophobia by the Pent-+LiCl groups in Fig. 1. These findings support the conclusion of Revusky, Taukulis, Parker, & Coombes (1979) and Cunningham and Linakis (1980) that pairing a drug state with induced sickness reduces the aversiveness of the druginduced state. The comparable Avfail effect in the Pent-+LiCl and Vin+Pent+LiCl groups is contrary to predictions based on Pavlovian overshadowing (Pavlov, 1927; Revusky, 1971). The Flavor*Sickness association might be expected to prevent the Pent+Sickness association from occurring according to a Pavlovian analysis. The absence of overshadowing suggests that either the two associations can be formed in parallel or that Avfail is not due to an association between Pent and LiCl . EXPERIMENT 2 Revusky, Taukulis, Parker, and Coombes (1979) illustrated the robustness of Avfail when they showed that it lasted through at least I3 Flavor-Pent pairings. The differences between the Pent+LiCl group and the control groups might reflect the effects produced during the early

EXAMINATION

OF AVFAIL

I TR:ALS

189

I 3

FIG. 1. Mean saccharin suppression ratios for groups that were injected with Pent after saccharin removal.

Flavor-Pent pairings rather than some change in the animals’ treatment of Pent which lasted over the 13 Flavor+Pent pairings. The following experiment tested this possibility by pairing a second novel flavor with a Pent injection. One would not expect to obtain Avfail with the second flavor if the effect of Pent+LiCl pairings was limited to a single flavor or to a few Flavor+Pent trials. This experiment also provided preliminary data on the question of whether exposure to Pent alone or to handling cues, prior to the Flavor+Pent pairings, reduced the magnitude of Avfail. Animals are typically not handled between the Pent-+LiCl and the Flavor-Pent phase of Avfail experiments. The absence of any manipulations may reflect a fear that handling will disrupt the Avfail effect. Such disruption was noted by Cunningham and Linakis (1980) who used ethanol instead of Pent. An LiCl-based aversion to 2.0% vinegar was produced in the first phase of the experiment. Rats were then exposed to either Pent*LiCl, LiCl+Pent pairings, or a combination of exposures. Some animals in the Pent*LiCl group were then given either eight injections of saline or eight injections of Pent. The existence of Avfail was shown by pairing consumption of a 0.75% saccharin solution with an injection of Pent. The saccharin exposure phase was followed by another phase in which 2.0% vinegar was paired with an injection of Pent. Method Subjects and Apparatus

The sixty male Sprague-Dawley rats weighed between 205 and 256 g at the start of the experiment. The concentrations and volumes of all solutions were the same as those employed in the previous experiment.

190

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Procedure

A summary of the experimental treatments is presented in Table 1. Phase 1, Days 1 to 7. Rats were adapted to 10 min per day access to tap water and were given ad lib access to food. A 2.0% vinegar solution was substituted for tap water on Day 5. All animals were injected with LiCl immediately after the vinegar was removed. Phase 2, Days 8 to Z4. Rats were injected on Days 8, 10, 12, and 14. Thirty-six rats received Pent+LiCl injections, 12 rats received LiCkPent injections, and the remaining 12 rats (Control) received two Pent*LiCl and two LiCl+Pent injections in varying orders. All rats were given 60min access to tap water on noninjection days. Phase 3, Days 15 to 39. The Pent-*LiCl group was subdivided; 12 were injected with saline (Pent+LiCl/Sal) and 12were injected with Pent (Pent+LiCl/Pent) on Days 18, 21, 24, 27, 30, 33, 36, and 39. These animals were given IO-min accessto tap water on noninjection days. The remaining animals were maintained on lo-min access to tap water per day throughout this phase. Phase 4, Days 40 to 52. All animals were maintained on IO-min access to tap water per day. A 0.75% saccharin solution was substituted for tap water on Days 43, 46, 49, and 52. After saccharin removal, animals in the experimental groups were injected with Pent and Control group animals were injected with saline. Phase 5, Days 53 to 63. The 10 min/day drinking schedule was continued. The vinegar solution was substituted for tap water on Days 55, 58, 61, and 63. Animals in the experimental groups were injected with Pent and the Control group was injected with saline immediately after vinegar removal. Results and Discussion

A 5 x 4 ANOVA (Groups x Days) of the saccharin suppression ratios revealed a difference between groups [F(4, 55) = 11.231,over days [F(3, 165) = 45.111 and a Groups x Days interaction [F(12,165) = 2.351. The left side of Fig. 2 shows that these differences reflect the recovery from saccharin neophobia by all the groups relative to the LiCl+Pent group. A Newman-Keuls test on the means of the simple effects supports this conclusion. All groups differed from the LiCl-*Pent group on trials 2, 3, and 4. These findings indicate that exposure to injection cues did not attenuate the Avfail effect. The Pent+LiCl groups never differed from the saline Control group though 29 days intervened between the Pent-tLiCl phase of the experiment and the Sac-Pent phase of the experiment. This finding suggests that Avfail does not dissipate with the passage of time. A reduction in the magnitude of Avfail might have been expected after a 29-day interval if the effect tended to disappear with time.

+ + + -+ + -+

Pent/Pent/Pent Pent/Sal LiCl/LiCliPent LiCYSal

Pent LiCl LiCl LiCl LiCl Pent Pent Pent

Vin Vin Vin Vin

-+ + -+ + * + + -+

+ + + +

LiCl Pent Pent Pent Pent LiCl LiCl LiCl

LiCl LiCl LiCl LiCl

Vin + LiCl

Phase 1

-

-+ + -+ + + --,

LiCl Pent Pent LiCl LiCl LiCl

Pent & Sal Pent & Sal Sal Pent & Sal Sal

Pent LiCl LiCl Pent Pent Pent

Phase 2

a Vin-Vinegar solution, LiCl-Lithium Chloride injection, Pent-Pentobarbital solution. * Animals in Control groups were exposed to all experimental conditions.

LiCl LiCl LiCl Pent Pent Pent

Experiment Control

3

Pent LiCVLiWPent LiCYSal

LiCl Pent Pent Pent

-+ + + +

2”

Experiment Controlb

Group

Sac Sac Sac Sac Sac Sac

Pent Pent Pent Pent Pent Pent

injection,

+ + + + + -+

Sac -9 Sal

Sal-Physiological

& Sal t Sal

& Sal & Sal

Phase 3 Sal & Pent Pent SZil

TABLE 1 Groups and Treatments

+ -+ + +

Pent Pent Pent Pent

Saline injection,

Sac Sac Sac Sac

Sac + Sal

Phase 4

+ -+ + -+

Pent Pent Pent Pent

Sac-Saccharin

Vin Vin Vin Vin

Vin + Sal

Phase 5

z F

g *

$

E g 5 5

192

GERARD M. MARTIN I U M I O---O &--A

CONTROL Pent-LiCI/LiCI-Pent / Pent-LiCVPent Pent-LICI/Sollne

I

I

I

050

-

i 0.40 22i a I- 0.30 ?+ 5% g 020 z > 040

I

4 &lnl.~

0

I

4 :RlnL?3

FIG. 2. Mean saccharin (left) and vinegar (right) suppression ratios of groups that were injected with Pent after saccharin removal during the first half of the experiment and vinegar removal during the second half of the experiment. The Control animals were injected with physiological saline. One Pent-LiCI group was exposed to eight Pent injections prior to the Flavor-Pent pairings. Another Pent-LiCI group was exposed to eight saline injections.

A 5 x 4 (Groups x Days) ANOVA of the vinegar suppression ratios showed that the groups differed [F(4,55) = 4.651, that there was a Days effect [F(3, 165) = 135.111, and that there was a Groups x Days interaction [F(12, 165) = 2.461. A Newman-Keuls test of the simple main effects showed that the groups did not differ on the first vinegar day and that all groups had higher suppression ratios than the LiCl*Pent group on all the subsequent vinegar days. These findings indicate that the Pent+LiCl pairings had an effect which lasted for more than one flavor. The demonstration of Avfail with the vinegar solution also indicates that Avfail is not limited to an interaction between novel flavors and the druginduced state. Flavors which have been paired with LiCl-induced sickness can also be used to demonstrate Avfail. Further, the findings show that exposure to the handling cues did not have any effect on the demonstration of Avfail with a second flavor. These findings, in addition to Revusky, Taukulis, Parker, and Coombes’ (1979) demonstration that

EXAMINATION

OF AVFAIL

Avfail lasts through 13 Flavor+Pent pairings, with sickness produces a robust effect. EXPERIMENT

193 indicate that pairing Pent

3

Eight saline injections between the PenteLiCl and the Flavor-*Pent phase may not be enough to extinguish the postulated association between handling cues and the injection of Pent. Cunningham and Linakis gave their rats a total of 26 injections prior to the first Flavor-*Drug trial and gave another 22 injections between each Flavor+Drug trial. Consequently, the findings from Experiment 2, which included 8 exposures, are not comparable to those of Cunningham and Linakis. The present experiment corrected this defect. One group of animals from the PenteLiCl group and another from the LiCl*Pent group were given a total of 54 saline injections prior to the first Flavor-Pent pairing. An additional 26 saline injections were given prior to each additional Flavor-Pent pairing. It was expected that the Avfail effect would disappear if the role of handling cues was important. Eight exposures to Pent prior to the Flavor-Pent pairings also did not have any measurable effect on the magnitude of Avfail in the previous experiment. This negative result is difficult to interpret since apparent maintenance of Avfail could represent habituation to the effects of Pent after 12 exposures. All other groups in Experiment 2 received only four exposures to Pent prior to the Sac+Pent pairings. Consequently they were not comparable to the Pent-*LiCl/Pent group. This problem was addressed by including both a Pent*LiCl/Pent and a LiCl*Pent/Pent group in the present experiment. Both groups had four Pent exposures interposed between the Drug-Drug trials and the Flavor+Pent trials. It was hoped that the four Pent exposures would extinguish the Pent+LiCl association without producing too much physiological tolerance to the Pent. Both the Pent+LiCl/Pent and the LiCl+Pent/Pent groups also received 50 saline injections after the Drug+Drug pairings and prior to the Flavor-Pent phase of the experiment. In addition, they received 26 saline injections between each Flavor+Pent trial. These saline injections were carried out in order to reduce the likelihood that the animal would associate handling cues with an injection of Pent. Such an association could prevent the animals from associating the Pent with the consumption of saccharin. Three days were interposed between the last injection of Pent and the first Flavor-Pent day. This ensured that the earlier injections of Pent did not influence the animals’ fluid consumption. These four experimental groups were compared to Pent+LiCl and a LiClhPent groups which did not have handling or injections interposed between the Drug+Drug and the Flavor+Pent phases of the experiment. A Flavor-tSaline control group was also included. The saline control condition consisted of animals from each of the six experimental conditions.

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Method Subjects

and Apparatus

One hundred and nineteen male Sprague-Dawley rats which weighed 320-390 g prior to the experiment were housed in wire cages. Food pellets were available continuously and fluids were provided when indicated. The concentration of Pent was increased from 5 mg/rat to 8 mg/ rat since these rats were larger than those used in earlier experiments. All other materials remained unchanged. Procedure

Animals were adapted to lo-min accessto tap water per day for 7 days prior to the beginning of Phase 1. A summary of the experimental manipulations is presented in Table 1. Phase I, Days 8 to 29. Animals were injected on days 8, 11, 14, 17. Fifty-one animals were injected with Pent followed 30 min later by an injection of LiCl (Pent+LiCl). Another 51 rats were injected with LiCl followed 30 min by an injection of Pent (LiCl-+Pent). The remaining 17 animals (Control) were subdivided such that 8 received Pent+LiCl and 9 received LiCl+Pent pairings. Tap water was provided for 60 min on noninjection days. Phase 2, Days 20 to 25. Both the Pent+LiCl and the LiCl+Pent groups were subdivided into three further groups with 17 animals per group. The Pent+LiCl/Sal and the LiCl+Pent/Sal groups were injected with physiological saline 9 times on each day for a total of 54 saline injections during phase 2. On each day two injections of 0.5 ml of saline, which were spaced 10 min apart, were given at 1000, 1130, 1430, and 1600hr. Another injection of saline was given at 1300hr, after the animals had received their lo-min accessto tap water. The Pent+LiCl/Pent and LiCl*Pent/Pent groups were maintained on the same regimen with the exception that Pent was substituted for physiological saline during the second injection at 1600 hr during the first four days of phase 2. Hence, these two groups received 50 saline injections and 4 Pent injections during phase 2. The Pent+LiCl and LiCl+Pent groups were also given IO-min accessto water at 1300hr but were not handled or injected during this phase of the experiment. The animals in the Control group were assigned to one of the three conditions. Phase 3, Days 26 to 35. The saline injection procedure used for some groups in phase 2 was continued throughout phase 3. On days 26, 29, 32, and 35, a 0.75% saccharin solution was substituted for tap water during the 1300-hr drinking session. All groups, with the exception of the saline Control group, were injected with Pent after saccharin removal. So, after saccharin removal the animals which were normally injected with saline after water removal were injected with Pent and the animals

EXAMINATION

OF AVFAIL

195

which were not injected normally after water removal were also injected with Pent. The saline control animals were injected with saline after saccharin removal. Results and Discussion

A 7 x 4 (Groups x Days) ANOVA of the saccharin suppression ratios, which are presented in Fig. 3, revealed a Groups effect [F(6, 112) = 16.681, a Days effect [F(3, 336) = 46.701, and a Groups x Days interaction F(18, 336) = 8.521. A Newman-Keuls test on the means of the simple main effects revealed that a partial Avfail effect was obtained. The groups did not differ reliably on the first trial, and the LiCl-*Pent/Sal and the LiCl-tPent groups had lower saccharin suppression ratios than the other groups on trials 2, 3, and 4. All other groups had lower saccharin suppression ratios than the saline Control group. The partial Avfail effect can be attributed to the unchanged dosage of LiCl. It was not increased to compensate for the increased weight of the experimental animals. Revusky, Taukulis, Parker, and Coombes (1979) reported that the magnitude of Avfail is reduced when a lower dosage of LiCl is used. The Pent*LiCYSal group and the Pent+LiCl group never differed reliably from each other. So, 136 exposures to handling cues did not reduce the magnitude of Avfail. The ineffectiveness of exposures to handling cues indicates that Cunningham and Linakis’s (1980) explanation of Avfail is incorrect. They suggested that animals associated handling cues with the drug-induced state during Phase 1 of the experiments of Revusky , Taukulis, Parker, & Coombes (1979). Cunningham and Linakis believed that such an association would block the formation of a Flavor-Pent association. The absence of any measurable effect indicates that Avfail is not dependent on an association between handling cues and the drug state. It is not clear why Cunningham and Linakis obtained an effect of handling cues in their situation, but regardless of its cause, it does not seem to have the theoretical importance they imputed to it. Exposure to Pent during Phase 2 did not extinguish the postulated association between Pent and LiCl. The Pent+LiCl/Pent group never differed from the other Pent+LiCl groups with the exception of trial 4, where it had a higher saccharin suppression ratio than the Pent+LiCl group. Comparison of the LiCl-*Pent/Pent group with the Pent+LiCl groups provides further evidence that exposure to Pent during phase 2 did not extinguish the postulated Pent*LiCl association. The LiCl+Pent/ Pent group had reliably lower saccharin suppression ratios than the Pent+LiCl/Pent group on trials 2, 3, and 4 and never differed reliably from the other Pent-+LiCl groups. The multiple exposures to handling cues by the LiCl-+Pent/Pent and the Pent+LiCl/Yent groups makes it

196

GERARD M. MARTIN

CONTROL Pent-LiCI/Li Cl - Pent/ Pent-LiCI/Saline LiCI-Pent/ Pent Pent -LiCI/ Pent LiCl -Pent/Saline

01

I

2

3

4

TRIALS FIG. 3. Mean saccharin suppression ratios for groups that were injected with Pent or physiological saline (Control) after saccharin removal.

unlikely that a learned association between handling cues and the Pent was blocking the association between the Flavor and the Pent during Phase 3. A more likely explanation is that the four additional exposures to Pent produced physiological tolerance to the Pent state. Hence, habituation to the Pent occurred in the LiCl+Pent/Pent group and the effect of Pent+LiCl pairings summated with Pent habituation in the Pent+LiCl/Pent group. Revusky, Taukulis, Parker, and Coombes (1979) made a similar observation when they compared animals which had received different numbers of Pent+LiCl or LiCl-+Pent pairings. They found that in addition to the loss of Pent’s aversiveness owing to the Pent+LiCI pairings, there was a loss of the Pent’s aversiveness as a function of the number of Pent exposures. GENERAL DISCUSSION The previous experiments show that Avfail is not disrupted by; (1) the presence of a flavor during the Pent+LiCl pairings, (2) interposing handling cues or injections of Pent between the Pent+LiCl trials and the Flavor+Pent trials, or (3) the presentation of two different aversive flavors during the Flavor-Pent trials. These findings are consistent with

EXAMINATION

OF AVFAIL

197

Lett’s (1981) suggestion that Pent*LiCl pairings produce conditioning of an antisickness response. The data also highlight some features of the association which is being formed between the Pent and the LiCl during the Pent+LiCl pairings. The antisickness response which is elicited by the Pent after several Pent+LiCl pairings is similar to the compensatory response which develops with repeated presentations of a UCS (Solomon & Corbit, 1974). Repeated presentations of a UCS cause the development of a compensatory response which is opposite to the primary effect of the UCS. Repeated Pent+LiCl pairings result in Pent eliciting a compensatory, antisickness, response which eliminates the normally aversive properties of Pent. The antisickness response, unlike the compensatory response described by Solomon and Corbit, does not seem to dissipate with disuse. Twenty-nine days intervened between Pent*LiCl trials and Flavor-Pent trials in Experiment 2 without a measurable reduction in the postulated antisickness response. The antisickness response, unlike the compensatory response described by Solomon and Corbit, seems to be the result of Pavlovian conditioning, since only the Pent+LiCl group displays Avfail. Groups that have had equal handling and drug experience without the proper pairings do not show Avfail. The associative nature of the antisickness response indicates that it is similar to the conditioned compensatory response which is believed to attenuate the effects of morphine (Siegel, 1977). External cues, such as handling cues, injection cues, and the room in which the experimental manipulations are carried out elicit the compensatory response, which attenuates the effect of the morphine. The antisickness response, in contrast, seems to be elicited by the Pentinduced state since multiple exposures to handling cues do not extinguish the postulated antisickness response. Demonstration of Avfail in the Pent+LiCl groups after exposure to Pent in Experiments 2 and 3 may not be inconsistent with an associative interpretation of Avfail. Repeated exposures to Pent in the absence of LiCl may produce some extinction of the antisickness response. The amount of extinction, however, may be limited to a level which prevents Pent from producing a flavor aversion. Reduction below this level may not be possible when Pent is repeatedly presented, if the antisickness response prevents disruption of the animal’s homeostatic balance, as measured by a flavor aversion. The antisickness response, albeit a weaker one, could be elicited by the onset of the Pent-induced state, with the result that Pent would not produce a flavor aversion. Hence, the apparent absence of extinction of the compensatory response could be attributed to an insensitive test. The finding that an association between vinegar and LiCl is formed at the same time that the Pent+LiCl association is formed is surprising.

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GERARD M. MARTIN

On the basis of the Pavlovian principle of overshadowing, one might expect the powerful association between a flavor and LiCl to influence the development of any association between Pent and LiCl. The absence of any apparent interaction indicates that the two associations are being formed in parallel. The flavor is being associated with the primary response to the LiCl, while the Pent-induced state is being associated with the antisickness response elicited by the LiCl. Cunningham and Linakis’s (1980) findings are consistent with this suggestion. Injections of ethanol paired with injections of LiCl produced an aversion to the flavor of alcohol and eliminated the ability of ethanol state to produce aversions to other flavors. Hence, the flavor of alcohol was associated with the primary response to LiCl, while the alcohol state was being associated with the antisickness response elicited by the LiCl. It is also possible that handling cues were also associated with the antisickness response in their study, since repeated exposures to these attenuated the Avfail effect. Demonstration of Avfail with a flavor that had been paired with LiCl in Experiment 3 is consistent with the notion that Avfail represents a reduction in the aversiveness of the Pent state owing to the antisickness response. Following vinegar consumption with an injection of Pent, after Pent+LiCl pairings, is comparable to following vinegar consumption with an injection of saline. The result, in both cases, is extinction of the vinegar aversion. This analysis indicates the need to examine other changes which occur in the animals’ treatment of the flavor which precedes the Pent. REFERENCES Cappell, H. D., & LeBlanc, A. E. Gustatory avoidance conditioning by drugs of abuse. Relationships to general issues in research on drug dependence. In N. W. Milgram, L. Krames, & T. M. Alloway (Eds.), Food aversion learning. New York: Plenum, 1976. Cunningham, C. L., & Linakis, J. G. Paradoxical aversive conditioning with ethanol. Pharmacology, Biochemistry and Behavior, 1980, 12, 337-341. Deneau, G., Yanagita, T., & Seevers, M. H. Self-administration of psychoactive substances by the monkey. A measure of psychological dependence. Psychopharmacologia, 1969, 16, 30-48. Lett, B. T. Drug-drug associations: Evidence for the conditioning of a compensatory resporue. Paper presented at the meeting of the Eastern Psychological Association, New York, 1981. Pavlov, I. P. Conditioned reIfexes (Translated by G. V. Anrep). New York: Dover, 1927. Revusky, S. The role of interference in association over a delay. In W. K. Honig & P. H. R. James (Eds.), Animal memory. New York: Academic Press, 1971. Revusky, S., Taukulis, H. K., & Coombes, S. Dependence of avfail effect on the sequence of training operations. Behavioral and Neural Biology, 1980, 29, 430-455. Revusky, S., Taukulis, H. K., Parker, L. A., & Coombes, S. Chemical aversion therapy: Rat data suggest it may be countertherapeutic to pair an addictive drug state with sickness. Behavior Research and Therapy, 1979, 17, 177-188. (a)

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