The phenomenon of one-trial tolerance to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze test is abolished by previous administration of chlordiazepoxide or buspirone.

It has been repeatedly reported that the anxiolytic action of benzodiazepines in the elevated plus-maze test is abolished in rats that have received a single prior experience of the test apparatus (one-trial tolerance effect). To analyze whether the one-trial tolerance effect of chlordiazepoxide can be influenced by administration of chlordiazepoxide or buspirone on trial 1, male Wistar rats received an IP injection of vehicle, chlordiazepoxide (8 mg/kg) or buspirone (2.5 mg/kg) 30 min. before testing for 5 min. in the plus-maze (trial 1). Seventy-two hours later, the rats received vehicle or chlordiazepoxide 30 min. before the re-exposure to the plus-maze for 5 min. (trial 2). Groups injected with chlordiazepoxide or buspirone on trial 1 and with chlordiazepoxide on trial 2 showed an anxiolytic effect of chlordiazepoxide on trial 2, as opposed to rats injected with vehicle on trial 1 and with chlordiazepoxide on trial 2. As opposed to previous studies, the present results suggest that the influence of prior experience with the plus-maze on the anxiolytic action of chlordiazepoxide during re-exposure seems to depend critically on the drug state in which trial 1 is experienced. These results are discussed with respect to the hypothesis proposed to explain the phenomenon of one-trial tolerance.

Lesions of nucleus accumbens reduce instrumental but not consummatory negative contrast in rats.

In Experiment 1, rats provided with brief daily access to 4% sucrose which preceded brief access to 32% sucrose (4-32) suppressed licking the 4% solution relative to 4-4 controls. This anticipatory negative contrast (ANC) was diminished when the 32% solution was downshifted to 4%. Licking the second 4% solution in shifted rats (4-32-4) was lower than licking of the second 4% solution in 4-4 control rats - a successive negative contrast (SNC) effect. Neither SNC nor ANC or their recovery were influenced by electrolytic lesions of the nucleus accumbens (NAC). Latency to initiate licking followed a concentration function, with rats initiating licking faster for 32 than 4% sucrose, but was not affected by the lesion. In Experiment 2, rats showed clear SNC in consummatory behavior when shifted from 32 to 4% sucrose and also showed SNC in running speed when shifted from a 12- to 1-pellet reward in a straight runway. As in Experiment 1, consummatory SNC was not affected by the lesion. However, in the runway, lesioned animals showed contrast later (after more trials) than the sham-lesioned rats and did not show contrast in the goal section, when goal speed was averaged across the postshift period. Reward downshift also increased the animals' tendency to backtrack in the runway and backtracking was greater in the lesioned rats during both the preshift and postshift periods. These data suggest that the NAC is not a necessary structure for the generation of expectancies, the comparison of rewards or the modulation of ingestive behavior. However, the NAC may be involved in responding to unmet expectancies when the task involves approach or instrumental behavior.

Absolute and relative rewarding properties of fructose, glucose, and saccharin mixtures as reflected in anticipatory contrast.

Rats preferred 2% fructose (F) to 2% glucose (G) in daily 5-min two-bottle preference tests, but preferred 8% G to 8% F with the same testing procedure. In four subsequent experiments brief (3 min) once-per-day sequential presentations of two F or two G solutions showed the following results. Anticipatory negative contrast (suppressed intake of the initial solution) was greater with quantitative variations in fructose (2% F followed by either 8, 16, or 32% F) than was the case when the same concentrations of G were paired. No contrast occurred with qualitative pairings of the two sugars--instead G enhanced the intake of F whether it was presented before or after F. A solution of 0.15% saccharin produced more suppression (contrast) of 2% glucose than of 2% fructose. Also, mixtures of 0.15% saccharin with either sugar (2 or 8% F or G) enhanced absolute intake of the sugars but did not substantially increase their contrast-producing properties--suggesting a distinction between absolute and relative rewarding properties of sugar/saccharin mixtures. In summary, anticipatory negative contrast can be produced by either taste or postingestive factors but the relationship between two-bottle preference, absolute reward value (as reflected in consumption in noncontrast conditions), and relative reward value (measured by the capacity to produce contrast) is complex.

Excitotoxic lesions of the hippocampus disrupt runway but not consummatory contrast.

Rats shifted from a 12-pellet to a 1-pellet reward for running in a straight runway showed a decrease in start, run, and goal speed to levels below rats that received only the 1-pellet reward throughout training (a negative contrast effect). Contrast was greatest in the goal region of the runway. Rats with damage to the hippocampus produced by the excitotoxin ibotenic acid failed to show a negative contrast effect under these conditions. The same lesioned rats tested in a consummatory, contrast procedure following a shift from 32% to 4% sucrose showed a negative contrast effect equivalent to sham-lesioned rats. These data suggest that the hippocampus is necessary for behavioral outcomes based on encoding or comparison that affect approach behavior, but not for such outcomes that affect consummatory behavior.

Effect of chlordiazepoxide on the response to repeated reductions in sucrose concentration in free-fed rats.

Free-fed rats were shifted from brief access to 32% sucrose (5 min per day for 3 days) to 4% sucrose (5 min per day for 2 days) 8 separate times. During preshift, rats given access to 32% sucrose licked less than rats given access to 4% sucrose (the opposite of what is typically obtained with deprived rats). The shift from 32% sucrose to 4% sucrose resulted in a further decline in lick frequency, suggesting a successive negative contrast effect. Degree of negative contrast diminished with repeated downshifts. Administration of chlordiazepoxide (CDP), 8 mg/kg, on either the first or second postshift day completely offset the effect of reward reduction. The diminution of contrast and the pattern of effectiveness of CDP differed from results obtained with food-deprived rats. The reduction of contrast by CDP was interpreted as being separate from an appetite-stimulation effect of the drug. Finally, all groups showed tolerance to the sedative effects of CDP in an open-field test, a result consistent with that obtained with deprived rats.

Lack of tolerance to contrast-reducing actions of chlordiazepoxide with repeated reward reductions.

In each of eight cycles of repeated reward reduction, the performance of rats given brief access to 32% sucrose for 3 days, and then 4% sucrose for 2 days, was compared to rats that received 4% on all 5 days. Shifted rats consumed less than unshifted rats following each shift, with little evidence of diminution of negative contrast across the eight shifts. Acute administration of chlordiazepoxide (CDP, 8 mg/kg) on the second postshift day reduced contrast on each shift with no evidence of tolerance development to these anticontrast actions (Experiment 1a). Acute administration of CDP on the first postshift day had no effect on contrast through the first four shifts, but reliably reduced contrast on the following four shifts (Experiment 2a). There was tolerance to the sedative effects of CDP, as measured in an open field (Experiments 1b and 2b). The data thus show: a) that contrast is not lost with repeated shifts; b) no tolerance develops to the anticontrast actions of CDP and, instead, CDP gains anticontrast actions, in regard to initial contrast occurrence; c) but, concurrently, tolerance does develop to the sedative effects of CDP in an open field.

Investigation of the devaluation interpretation of anticipatory negative contrast.

Rats suppress intake of an acceptable substance (e.g., 0.15% saccharin) when it is followed by a preferred substance (e.g., 32% sucrose) in once per day pairings. The role of a learned devaluation of the initial solution in suppressed intake (anticipatory negative contrast) was investigated. The findings included the following: (a) Flavors or odors as within-subject cues precluded the occurrence of anticipatory contrast, conditioning flavor and odor preferences instead, which appeared to antagonize suppressed intake. (b) Anticipatory contrast was obtained when within-subject context cues, temporal alternation cues, or drinking-spout cues were used. (c) Preference tests conducted with the spout cues showed that devaluation of the initial substance was not necessary for the occurrence of negative anticipatory contrast.

Relative hedonic value modulates anticipatory contrast.

Intake of an initial substance (e.g., 0.15% saccharin) is suppressed when the presentation of this substance precedes the availability of a preferred solution (e.g., 32% sucrose) in brief daily pairings. The present experiments show that degree of this anticipatory contrast effect is related to the relative hedonic value of the substances paired each day. When the initial substance has low hedonic value relative to the second substance (e.g., water or empty tube paired with 32% sucrose), then a facilitation effect rather than contrast occurs. As the hedonic value of the initial substance increases (0.0015% saccharin, 0.5% sucrose, 0.015% saccharin, 1% sucrose, 2% sucrose, 0.15% saccharin), facilitation is replaced by contrast, which develops sooner and becomes larger the greater the hedonic value of the initial substance. The serotonin antagonist cyproheptadine increased absolute lick frequencies, but did not alter contrast. The serotonin1A agonist buspirone tended to decrease absolute lick frequencies, but did not alter contrast. The occurrence of contrast is discussed in terms of response competition, inhibition, and devaluation of the initial substance.

Selective breeding for negative contrast in consummatory behavior.

Rats showing either large or small reductions in licking following a shift from 32% to 4% sucrose were selectively bred for 7 generations. Rats from the 2 resulting lines reliably differed in successive negative contrast and in activity (radial-arm maze and open field). Differences in activity and contrast were not correlated. Heritability (h2) of the reaction to sucrose shift was reliable in the last 6 filial generations and equaled 0.64 in the F7 generation. The 2 lines did not differ (a) in response to the absolute rewarding value of sucrose or cocaine; (b) in open-field defecations or thigmotaxis; (c) in anticipatory contrast; or (d) in responsivity to midazolam. Responsivity to reward reduction may involve a relatively delimited psychological process that is amenable to selection.

Effect of chlorpromazine and haloperidol on negative contrast.

Rats shifted from 32 to 4% sucrose consume substantially less of the 4% solution than animals that have not had prior experience with the 32% sucrose. This negative contrast effect was not substantially influenced by chlorpromazine (1, 3, and 5 mg/kg) or haloperidol (0.1, 0.5, and 1.0 mg/kg). Haloperidol decreased overall lick frequency, but this decrease occurred proportionately in shifted and unshifted rats, leaving contrast intact. The benzodiazepine flurazepam (5, 10, and 20 mg/kg), included as a positive control, reduced contrast at the two highest doses. The results suggest that neuroleptics do not disrupt consummatory contrast and that dopaminergic antagonists may not influence reward relativity.

Cyproheptadine prevents the initial occurrence of successive negative contrast.

Rats shifted from 32% to 4% sucrose make fewer licks for 4% sucrose than rats having only experienced the lower reward. In Experiment 1, the occurrence of this contrast effect was prevented by the administration of the nonspecific serotonin antagonist cyproheptadine (3.0 or 6.0 mg/kg). These results of Experiments 2 and 3 demonstrated that the contrast-reducing action of cyproheptadine was not mediated by the antiserotonergic properties of the drug since systemic administration of the serotonin synthesis inhibitor, PCPA (150 or 300 mg/kg), failed to influence either the occurrence of contrast or the attenuation of contrast by cyproheptadine. The results of Experiment 4 indicated that the contrast-reducing action of cyproheptadine was not mediated by the antihistaminergic properties of the drug since the antihistamine, pyrilamine (6 or 12 mg/kg), also failed to prevent the occurrence of contrast. Finally, the contrast-reducing action of cyproheptadine was not due to rate-dependent and/or appetite stimulating effects since cyproheptadine did not serve to increase lick frequency in rate-dependent controls.

Behavior of Maudsley reactive and nonreactive rats (Rattus norvegicus) in three consummatory contrast paradigms.

Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats (Rattus norvegicus) were tested in successive, simultaneous, and anticipatory contrast procedures. The MR/Har rats showed smaller successive negative contrast effects than the MNRA/Har rats when shifted from 32% to 4% sucrose, and the degree of contrast was smaller in animals of both strains than that typically obtained with unselected Sprague-Dawley derived rats. Chlordiazepoxide (4 and 8 mg/kg), which typically reduces contrast, did not influence degree of contrast in rats of either strain. Animals of both strains showed positive and negative contrast in the simultaneous contrast procedure, but degree of contrast in both cases was smaller in rats of the MR/Har strain. Animals of both strains also showed anticipatory contrast when a 0.15% saccharin solution preceded 32% sucrose in once-per-day pairings. In terms of latency to initiate licking, the MNRA/Har rats showed a contrast effect, but the MR/Har rats showed a "reinforcement" effect--shorter latency when saccharin preceded sucrose than when saccharin preceded saccharin. Open-field tests showed typical strain differences: The MNRA/Har rats ambulated more, reared more, defecated less, and showed less thigmotaxis than the MR/Har rats.

Effect of serotonergic drugs on negative contrast in consummatory behavior.

The effect of acute and chronic administration of the 5-HT1A agonist buspirone on successive negative contrast was investigated in Experiments 1-6. Contrast in consummatory behavior was induced by shifting rats from a 32% to a 4% sucrose solution. Experiments 1-5 showed that buspirone (0.125, 0.25, 0.5, 1.0, 2.0, 15.0 mg/kg) was ineffective in alleviating contrast or in facilitating recovery from contrast. The 15 mg/kg dose substantially decreased consummatory responding. Experiment 6 showed that the chronic (24 days) administration of buspirone (0.5, 2.0 mg/kg) also did not alleviate contrast. The chronic, but not the acute administration of the 2.0 mg/kg dose decreased consummatory behavior. In Experiment 7 the 5-HT1A agonist gepirone (2.5, 5.0 and 10.0 mg/kg) was also found to be ineffective in reducing contrast but, at the higher doses, decreased overall sucrose intake. Experiments 8 and 9 found that the 5-HT2 antagonists ketanserin (2.0 and 8.0 mg/kg) and ritanserin (0.63 and 2.5 mg/kg) also did not alleviate contrast. Midazolam (1.0 mg/kg), included as a positive control, eliminated contrast. These data suggest that serotonergic mechanisms are not involved in negative contrast.

Chlordiazepoxide and the moderation of the initial response to reward reduction.

The effectiveness of chlordiazepoxide (CDP) in reducing negative contrast on the first day after a shift from 32% to 4% sucrose was investigated in four experiments using rats. Previous studies indicated that CDP was effective on the second, but not on the first postshift day. In Experiments 1 and 1a, neither initial experience (3 or 10 days) with the eventual postshift 4% solution (i.e. 4%, then 32%, then 4%), nor initial experience with alternating 4% and 32% sucrose, led to a reliable contrast-reducing effect of CDP on the first shift day. Evidence from Experiments 2 and 3 suggested that a range of doses of CDP (3, 5, 10, and 15 mg/kg) did not have reliable effects on the first postshift day, although the two lower doses did reduce contrast on the second postshift day (the higher doses were not administered on Day 2). The evidence suggests that the relative ineffectiveness of CDP in moderating the initial response to reward reduction is not related to a problem of recognizing the difference between the postshift solution and the memory of the preshift solution. Alternative interpretations in which CDP's lack of effect on the initial occurrence of contrast is related to an initial stage of unconditioned frustration and/or exploratory behaviour are considered.

Effect of anxiolytics and antidepressants on extinction and negative contrast.

Anxiolytics, particularly the benzodiazepines and barbiturates tend to retard, but not prevent, extinction, promote recovery from negative contrast, and elevate S- responding in discrimination training. Anxiolytics, administered during acquisition, tend to eliminate the partial reinforcement extinction effect, but this result is substantially influenced by parametric considerations. Behaviors that are energized in extinction may have a different pharmacological profile than behaviors that decline. Conclusions regarding the effects of antidepressants must be more tentative but, in general, acutely administered antidepressants are relatively ineffective in all of these paradigms. However, antidepressants may enhance the efficiency of responding on DRL schedules whereas anxiolytics tend to disrupt such behavior.

The effect of dexamethasone-21-acetate on meal size, meal frequency and macronutrient self-selection in rats.

In Experiment 1, the measurement of 24-hour food intake in two rats showed that treatment with dexamethasone-21-acetate (DEX) (0.5 mg/kg IP) produced a decrease in body weight which was at least partially due to a decrease in food intake (both meal frequency and meal size). In Experiment 2, the daily intake of three macronutrient sources was measured. These data showed that treatment with DEX (0.5 and 1.0 mg/kg IP) led to an acute increase in protein intake, a sustained decrease in fat intake and no change in carbohydrate consumption. We suggest that this change in macronutrient selection may be an adaptive response which serves to ameliorate some of the effects of DEX treatment.

Effects of intrahippocampal administration of colchicine on incentive contrast and on radial maze performance.

The behavior of rats given intradentate injections of the neurotoxin colchicine was examined in three experimental settings. In Experiment 1, colchicine-treated, artificial cerebrospinal fluid (CSF)-treated, and untreated animals did not differ in the intake of 32% and 4% sucrose solutions, nor did they differ in degree of successive negative contrast when the 32% solution was changed to 4% sucrose. In Experiment 2, the colchicine-treated and CSF-treated animals did not differ in degree of suppression in the intake of a 0.15% saccharin solution when it preceded 32% sucrose in once-daily pairings (anticipatory contrast), nor did they differ in reversal performance when saccharin-sucrose and saccharin-saccharin pairings were reversed. In Experiment 3, the colchicine-treated animals were substantially impaired in radial-arm maze performance compared with CSF-treated controls. These results suggest that a completely functioning hippocampus is not necessary for the memory of reward quality, the comparison of rewards, the suppression of behavior when reward is decreased, the formation of associations between two levels of reward, and the reversal of this association, as long as these processes are reflected in consummatory behavior. The data are interpreted in terms of differences between instrumental behavior and sensory memory and/or consummatory behavior--an interpretation that is not incompatible with a deficiency in working memory in the animals with lesions.

Rats (Rattus norvegicus) selectively bred to differ in avoidance behavior also differ in response to novelty stress, in glycemic conditioning, and in reward contrast.

The behavior of the Syracuse high avoidance (SHA) and Syracuse low avoidance (SLA) rats, selectively bred by Brush (F. R. Brush, J. C. Froehlich, & P. Sakellaris, 1979, Behavior Genetics, 9, 309-316) to differ in avoidance behavior, was examined in several different tasks. The SLA rats showed a greater elevation in plasma glucose when exposed to a novel environment; after 7 days of exposure to this environment there was evidence of habituation in the SHA rats but not in the SLA rats; the SHA rats showed a hyperglycemic conditioned response in a glycemic conditioning procedure, the SLA rats showed no evidence of conditioning but had higher overall levels of plasma glucose; both strains showed reliable successive negative contrast effects in consummatory behavior when shifted from 32 to 4% sucrose, but the contrast was larger in the SLA rats; the administration of chlordiazepoxide eliminated negative contrast in the SLA rats but had no effect on contrast in the SHA rats; and the SLA rats were reliably heavier than the SHA rats. The behavioral differences were considered in the context of differences in emotional reactivity between the two strains.

Effect of clonidine on sucrose intake and water intake varies as a function of dose, deprivation state, and duration of exposure.

Lick frequency was monitored in five-minute intervals over a one-hour period in rats given access to 8% sucrose (Experiment 1) or water (Experiment 2). Prior to the session, the rats were administered either isotonic saline or clonidine (6.24, 12.5, or 25 micrograms/kg). In deprived rats (82%) clonidine led to a dose-related increase in consummatory behavior. Water intake in deprived rats was depressed by clonidine. In rats maintained on a free-feeding schedule, the higher clonidine doses led to a decrement in sucrose intake over the first 15 minutes of access; whereas the 6.25 micrograms/kg dose stimulated consummatory behavior, but only during the first five minutes of access. There were no reliable effects of clonidine on sucrose intake late in the access period for the free-feeding rats. Water intake in free-feeding rats tended to be enhanced by the low dose of clonidine, particularly late in the access period. In general, deprivation enhanced sucrose intake and depressed water intake and clonidine exaggerated both of these trends.

Negative contrast in the consumption of sucrose and quinine adulterated sucrose solutions.

Rats shifted from a 40% sucrose solution to a quinine-adulterated (30 mg/100 ml) 40% sucrose solution showed a reduction in consumption to a level considerably below that of animals exposed to only the quinine-adulterated solution. The animals tended to recover from this negative contrast effect over a 5-day postshift period and, in general, the degree of contrast was about equivalent to that of animals shifted from a 32% to a 4% sucrose solution. There were no sex differences in the rats shifted from 32% to 4% sucrose, but female rats shifted to the quinine-adulterated sucrose showed larger contrast effects than male rats exposed to the same shift.