Interstimulus interval determines whether ethanol produces conditioned place preference or aversion in mice

DBA/2J mice were exposed to a distinctive floor stimulus (CS+) and ethanol (2 g/kg) in a place conditioning paradigm. A different floor stimulus (CS?) was presented with saline. Mice injected just before or 30 min before CS exposure (Groups 0, ?30) showed conditioned place preference, whereas mice injected right after exposure to the CS (Group 5) displayed place aversion (Experiment 1). None of the other groups (?120, ?60, 15, 60) showed place conditioning. Handling and saline injection given just before or after CS exposure were unable to produce place conditioning (Experiment 2). However, there was a positive relationship between ethanol concentration (10% vs. 20%) and test performance, suggesting that peritoneal irritation influences place conditioning (Experiment 3). Overall, these findings support the suggestion that intraperitoneal injection of ethanol produces an initial short-duration aversive effect that is followed by a longer lasting positive motivational effect.     

Competition between ethanol-induced reward and aversion in place conditioning

Previous place conditioning studies in mice have shown that injection of ethanol immediately before a conditioned stimulus (CS+) produces conditioned preference, whereas injection of ethanol immediately after CS+ produces conditioned aversion. In the present experiments, we examined the learning that occurs when ethanol is injected in “ambiguous“ procedures that provide the opportunity for both types of conditioning. When ethanol was given midway through the CS (Experiments 1 and 2) or both before and after the CS (Experiment 3), the direction of place conditioning was the same as when mice were exposed only to whichever contingency occurred first (a primacy effect). That is, injection of ethanol in the middle of the CS conditioned aversion, whereas injection both before and after the CS conditioned preference. Because these results support the idea that ethanol elicits both aversive and rewarding effects, they are most consistent with conditioning theories that conceptualize unconditioned stimuli (USs) as events that can activate multiple representational components.     

Pentobarbital-induced place aversion learning

Pentobarbital is self-administered by rats but has also been reported to produce a conditioned place aversion. Since the self-administration and place preference paradigms both are considered to assess drug reward, we further examined the hedonic properties of pentobarbital, using place conditioning. In Experiment 1, a dose of 15 mg/kg (intraperitoneal) of pentobarbital produced a conditioned place aversion after 4 conditioning trials of various durations (5, 15, 30, or 60 min). Since rats are typically drug experienced in the self-administration paradigm, in Experiments 2 and 3, we examined the effect of drug history on pentobarbital-induced place conditioning. Although preexposure to pentobarbital attenuated the place aversion, it never resulted in a place preference. As has been reported with alcohol, pentobarbital is hedonically aversive in rats, when novel.     

Independent effects of stimulus and cycle duration in conditioning: The role of timing processes

Rats received delay conditioning procedures with a white-noise conditioned stimulus (CS), a food unconditioned stimulus (US), and head entries into the food cup as the conditioned response. The stimulus duration (S) and the interval between food deliveries (C) were varied between groups:S=15, 30, 60, and 120 sec;C=90, 180, and 360 sec. The stimulus/cycle duration ratio was negatively related to the asymptotic level of conditioning but had no effect on the rate of acquisition. Conditioning and timing of responses emerged together in training. Timing occurred during the CS-US interval (ISI) and the US-US interval (ITI), as evidenced by increasing response rate gradients that were steeper for shorter intervals. The effects of the stimulus/cycle ratio on conditioning were attributed to independent timing of theS andC durations. Serial-, parallel-, and single-process accounts of conditioning and timing are compared.     

Effect of glycine site/NMDA receptor antagonist MRZ2/576 on the conditioned place preference and locomotor activity induced by morphine in mice

Objective： To study the effect of glycine site/NMDA （N-methyl-D-aspartate） receptor antagonist MRZ2/576 on the conditioned place preference （CPP） and locomotor activity induced by morphine in mice. Methods： Different doses （1.25, 2.5 and 5 mg/kg, i.p.） of MRZ2/576 were used to evaluate the effect of MRZ2/576 on the acquisition and expression of CPP induced by morphine （5 mg/kg） in mice. In addition, we examined the locomotor activity of mice in conditioning and testing phase of CPP paradigm. Results： MRZ2/576 alone could not establish place preference, but a 5 mg/kg dose of MRZ2/576 could block both acquisition and expression of morphine-induced CPP. In testing phase of CPP, there was no statistical difference for locomotor activity between the groups; injection of MRZ2/576 showed a dose-dependent decrease of locomotor activity on both control and morphine-treated mice, especially 5 mg/kg of MRZ2/576 significantly suppressed the locomotor activity of mice. Conclusion： Based on the present results, we assume that MRZ2/576 can antagonize the rewarding effect of morphine, suggesting that this glycine site/NMDA receptor antagonist could be used to treat addictions due to its light side effect profile.     

Acquisition and retention of conditioned aversions to context and taste in laboratory mice

We compared the rate of acquisition and strength of retention of conditioned context aversion (CCA) with conditioned taste aversion (CTA) using pigmented, genetically heterogeneous mice (derived from Large and Small strains). Extending previous findings, in Experiment 1, mice accustomed to drinking from large glass bottles in the colony room learned to avoid graduated tubes after a single conditioning trial when drinking from these novel tubes was paired with injections of LiCl. The results also showed that CCA could be developed even when there was a 30-minute delay between conditioned stimulus and unconditioned stimulus. Retention of the aversion lasted for 4 weeks in both Immediate and Delay groups. Studies of conditioned saccharin aversion were conducted in Experiment 2. CTA acquisition was very similar to that observed in CCA and duration of aversion retention was similar in the CCA and CTA Delay groups, although at least 2 weeks longer in the Immediate group. Thus, CCA acquisition and retention characteristics are closer to those seen for CTA than has previously been reported. In Experiment 3, we examined whether albino mice (which are known to have weaker visual abilities compared to pigmented mice) would develop CCA comparable to those of pigmented mice. The development of conditioned aversion and its duration of retention was similar in albinos and pigmented mice. Nonspecific aversion emerged as an important contributor to strength of aversion during retention trials in both CCA and CTA paradigms with pigmented (but not albino) mice and deserves additional scrutiny in this field of inquiry.     

Effects of proximal unconditioned stimulus preexposure on ingestional aversions learned as a result of taste presentation following drug treatment

Taste aversions were conditioned by exposing subjects to a 1.0% saccharin solution 30 min after an injection of lithium chloride. The aversion learning was disrupted if subjects had also received an additional lithium injection some time earlier (Experiments 1–3). This interference effect of US preexposure was a decreasing function of the preexposure interval, beyond the optimal interval (105 min) for observing the phenomenon (Experiment 1), and was directly related to the dose of the preexposure injection (Experiment 2). No interference with conditioning occurred at short (e.g., 30-min) preexposure intervals (Experiment 1), probably because under these circumstances the preexposure injection itself conditioned a strong aversion (Experiment 4). At moderate (105-min) but not at short (30-min) preexposure intervals, the interference with aversions learned as a result of taste exposure following drug injection was comparable to the interference with learning in a more conventional forward conditioning procedure (Experiments 3 and 4). These findings are similar to previously documented effects of proximal CS- and US-preexposure and are consistent with recent stimulus rehearsal and opponent-process theories.     

Pavlovian conditioning to contexts that precede the place where shock occurs as measured by freezing and activity suppression in mice

Three experiments were conducted to demonstrate that the place where an organism has been, before the organism is moved to a place with aversive consequences, can also become aversive through classical conditioning. In Experiment 1, two groups of 8 mice were exposed to three different contexts in succession, with a single shock occurring in the third context. The distal context was a putative 3-min conditioned stimulus (CS) for freezing; the second context was a delay manipulation; and the unconditioned stimulus (US) occurred in the proximal context. The group delayed for 15 sec showed significantly more freezing to the distal CS context than did the group delayed for 3 h. In a second experiment, conditioning to the distal context was demonstrated with a discrimination procedure for 8 more mice by using two different distal contexts as CS+ and CS? for the proximal context with shock. On CS+ days, 3 min of exposure to the distal context was followed within 5 sec by placement in the proximal box where shock occurred, whereas on CS? days, exposure to a second distal context was followed immediately by return to the home cage. Very strong differences in freezing between the CS+ and CS? distal contexts were found in all 8 mice after 14 days of conditioning. In a third experiment, the discriminative procedure was repeated for 9 more mice, with two changes. More objective stabilometertype activity measures were substituted for observed freezing, and, in addition to the CS+ and CS? distal context trials, each mouse was also exposed to a third discriminative distal context, which was followed by 15 min in a delay chamber followed by shock in the proximal context. This discrimination procedure with the activity suppression measure again resulted in significant differences between the contexts. The CS+ context and the context followed by a 15-min delay did not differ, but both of them differed from the CS? context.     

Effects of US parameters on classical conditioning of cat hindlimb flexion

Unconditioned stimulus (US) intensity and duration were manipulated to determine their effects on cat hindlimb flexion conditioning. Seven consecutive days of acquisition training of a hindlimb flexor response to a tone conditioned stimulus (CS) were followed by 2 days of extinction. Eight animals in each of 12 groups received a 1-, 2-, 3-, or 4-mA, 60-Hz shock delivered to the right hindleg for 25, 50, or 100 msec as the US. Analysis of conditioned-response (CR) frequency indicated that conditioned responding was a positive function of both the intensity and duration of shock, although these variables did not interact with one another. CR latency and amplitude were decreased and increased, respectively, by increases in US intensity. The pattern of results reported here may support a contiguity notion of conditioning, and are discussed in the context of other conditioning preparations.     

Conditioning of tentacle lowering in the snail (Helix aspersa): Acquisition, latent inhibition, overshadowing, second-order conditioning, and sensory preconditioning

In a series of related experiments, we studied associative phenomena in snails (Helix aspersa), using the conditioning procedure of tentacle lowering. Experiments 1A and 1B demonstrated a basic conditioning effect in which the pairing of an odor (apple) as the conditioned stimulus (CS) with the opportunity to feed on carrot as the unconditioned stimulus (US) made snails exhibit increased levels of tentacle lowering in the presence of the CS. Experiments 2 and 3 showed that the magnitude of the conditioning was reduced when snails were exposed to the CS prior to the conditioning trial (a latent inhibition effect). Experiment 4 examined the effects produced by pairing a compound CS (apple—pear) with food presentations and demonstrated the existence of an overshadowing effect between the two odors. Experiment 5 revealed that pairing one CS with another previously conditioned stimulus increased tentacle lowering to the new CS (a second-order conditioning effect). Finally, Experiment 6 showed that pairing two odors prior to conditioning of one of them promoted an increase in tentacle lowering in response to the other (a sensory preconditioning effect). The results are discussed in terms of an associative analysis of conditioning and its implications for the study of cognition in invertebrates.     

Contextual associations in trace conditioning

Rats were given tone-footshock pairings with a 0-, 10-, or 30-sec trace interval between tone offset and shock onset. Half the rats within each trace interval were tested for their conditioned fear of the tone through a lick suppression procedure; the remaining rats were evaluated for their fear of the background or contextual cues through their avoidance of the compartment in which conditioning had occurred. Less conditioning was observed to the tone with increasing trace intervals. However, conditioned fear of the context increased with increases in the trace duration. The ability of the more predictive stimulus, the tone, to overshadow the contextual cues was determined by the tone’s temporal contiguity with the footshock. The need to incorporate temporal parameters within current theories of conditioning is discussed.     

Specificity of cue to consequence in aversion learning in the rat: Control for US-induced differential orientations

In four experiments, each using a single conditioning trial, rats avoided a light more than a saccharin solution after these stimuli had been paired with footshock, whereas saccharin was avoided more than the light after these stimuli had been paired with lithium injection. The use of a single conditioning trial precludes possible US-induced differential orientations from influencing which stimuli will be associated on the conditioning trial. This cue-consequence specificity effect was obtained even when subjects conditioned with lithium received a non-contingent footshock prior to the test session, and when subjects conditioned with footshock received a noncontingent lithium injection before testing (Experiments 2–4). Weak aversions to the light in rats given a light-lithium pairing and noncontingent footshock and to the saccharin in subjects that received a saccharin-footshock pairing and noncontingent lithium administration were obtained in Experiment 2. However, these weak aversions were not obtained when subjects were given three nonreinforced exposures to the test chamber before the test session (Experiments 3 and 4). These results indicate that US-induced differential orientations do not mediate the cue-consequence effect in aversion learning.     

Pavlovian conditioning with ingested saline solution as the US

Experience with 2% saline as the sole available fluid for drinking produced a decrement in preference for .9% saline in a two-bottle test with water as the alternative. This outcome was interpreted as a consequence of Pavlovian conditioning, with the taste of salt acting as the conditioned stimulus and postingestive consequences of saline ingestion acting as the unconditioned stimulus. An overshadowing group experienced salt mixed with vanilla as its sole fluid during the conditioning phase. This group showed an attenuated saline aversion relative to a group that drank 2% saline solution during the conditioning phase. In addition, a vanilla aversion developed in the former group. In the second experiment, conditioning of the aversion to the taste of vanilla mixed with 2% saline was attenuated by preexposing the vanilla. The results support a Pavlovian analysis of the modification of salt preference through experience with the postingestive consequences of saline ingestion.     

小鼠条件性电击社交恐惧行为模型的建立与评价

目的：建立稳定而特异性强的小鼠社交恐惧行为模型。方法：采用针对社交接触行为给予条件性足底电击（O．7mA,1S,1～5次）的方式建立小鼠社交恐惧模型。分别于电击后d2和d15检测小鼠的社交探究行为,以探究时间百分比（investigationtime％,1T％）为社交恐惧行为评价指标。分别采用小鼠高架十宁迷宫实验、明暗穿箱实验和强迫性游泳实验评价小鼠的广泛性焦虑行为和抑郁样行为。结果：在条件性电击后d2和d15的社交探究实验中,与非丰十交刺激（non．socialstimulus,NSS）组比较,条件性社交刺激（conditionedsocialstimulus,CSS）组小鼠IT％均显著减少。在小鼠高架十字迷宫实验、明暗穿箱实验和强迫性游泳实验上,CSS组与NSS组各行为指标差异均无显著意义。结论：采用条件性足底电击方式可成功建立小鼠社交恐惧行为模型,模型症状可持续至少2周,且不伴随广泛性焦虑行为或抑郁样行为,具有良好的稳定性和特异性。     

Higher order conditioning of a taste aversion

Two groups of rats each received 5 drops of NaCl solution from a dropper placed directly inside the mouth. The experimental group was then injected with lithium chloride to establish a conditioned taste aversion. The control group was injected 24 h later. After a recovery day the above procedures were repeated. On the next day both groups received 5 drops of a saccharin solution followed immediately by 5 drops of the NaCl solution. Subsequent preference tests established that the experimental group had learned an aversion to the saccharin solution as a result of its pairing with the NaCl solution which had previously been associated with poisoning. These results demonstrate that higher order conditioning of a taste aversion can be established using tastes as both the first-order stimulus and the second-order stimulus.     

Trial and intertrial durations in appetitive conditioning in rats

The effects of trial (T) and intertrial (I) durations were examined in two Pavlovian conditioning experiments with rats, in which a noise conditioned stimulus (CS) was paired with food delivery. In Experiment 1,T was either 10 or 20 sec, andI ranged from 15 to 960 sec, in separate groups of rats. The acquisition rate and final level of conditioned responding showed ratio invariance: They were better predicted by theI/T ratio than byI orT alone. In Experiment 2, theI/T ratio was 6.0 in all the groups, andT was 20, 40, 80, or 160 sec. Ratio invariance was not observed: Despite the commonI/T ratio, the rate of acquisition, final level of conditioned responding, and the ability of the CS to block conditioning of another stimulus differed among the groups. At the same time, the temporal distribution of conditioned responding withinT was similar in all the groups throughout conditioning and extinction and showed superpositioning when normalized acrossT. Many but not all aspects of the data were consistent with scalar timing theory.     

Latent habituation of the orienting response in the preweanling rat

The effect of inhibiting the orienting response on information processing was examined in four experiments. A nonsignal auditory stimulus was presented four times to preweanhng rats either 30 sec or 15 min after they had been placed in an unfamiliar environment (Experiments 1A and 2), shocked (Experiment 1B)5 or experienced a shift in environmental context (Experiment 1C). Both an autonomic (heart rate) and a behavioral componentx of the orienting response to the novel stimulus were recorded. In the 15-min condition, the auditory stimulus elicited a consistent orienting response on the first trial that habituated rapidly with successive trials. In contrast, the auditory stimulus did not elicit a detectable orienting response in the 30-sec condition on any of the four trials. However, when the auditory stimulus was re-presented after a brief retention interval, a comparable level of habituation was seen in both groups. These results demonstrate that animals in the 30-sec condition detected, attended to, and encoded the auditory stimulus even though they did not orient, either autonomically or behaviorally, to that stimulus when it was first presented. This process of response-independent habituation is best described as latent habituation. Like latent learning, latent habituation took place in the absence of any observable change in behavior. The implications of this effect for current theories of habituation and of the orienting response are discussed.     

One-trial simultaneous and backward fear conditioning as reflected in conditioned suppression of licking in rats

In three experiments, groups of albino rats received one strictly simultaneous pairing of a 4-sec auditory conditioned stimulus (CS) and a 4-sec 1-mA shock unconditioned stimulus (US). Other groups received a backward pairing, in which the US began before the CS, or a forward pairing, in which the CS began before the US. Control groups received only the US or received both the CS and the US but widely separated in time. Later, the CS was presented while the rats licked a drinking tube for water, and CS-elicited suppression of licking was taken as an index of the Pavlovian conditioned response (CR). It was found that groups receiving a single forward or a single simultaneous pairing suppressed more than groups that had received a backward pairing; and the backward groups, in turn, suppressed more than the control groups. It appears, then, that excitatory fear conditioning, as reflected in conditioned suppression of licking in rats, can be produced in a single trial by both backward and simultaneous conditioning procedures.     

Context excitation and modulation of conditioned sexual behavior

Three experiments were conducted to investigate direct and modulatory influences of context in the conditioned sexual behavior of male Japanese quail. A preference test procedure was used to assess the acquisition of contextual excitation. In Experiment 1, following direct context-unconditioned stimulus (US) pairings, male quail shifted their contextual preference from an initially preferred context to one in which they received copulatory opportunity with a female quail (US). Unpaired control group subjects did not demonstrate this shift in preference. This place preference procedure was used in Experiments 2 and 3 to assess contextual excitation when context was trained in the presence of a discrete conditioned stimulus (CS). Experiment 2 provided evidence that context can modulate responding to a discrete CS. In Experiment 3, we varied the spatial contiguity between the context and the US. Some subjects received the US directly in the training context, whereas other subjects received the US in an alternate context. Contextual excitation was evident only in subjects that received the former. Thus, there is a dissociation between the modulatory and excitatory properties of context in sexual conditioning that may depend on the context-US spatial contiguity.     

Stimulus duration and conditioned reinforcing value measured by a learning-tests procedure

The relationship between the duration of stimuli and their conditioned reinforcing effect was investigated using a learning-tests procedure. In Experiment 1, stimuli were the same duration on training (stimulus → reward) and test (choice response → stimulus). Ten- and 30-sec stimuli provided effective differential conditioned reinforcement but 3-sec stimuli did not. In Experiment 2, different pigeons had each combination of the 3- and 30-sec stimuli on training and test trials. Evidence of conditioned reinforcement was obtained only for the birds with 30-sec stimuli on both training and test. The results were interpreted as indicating that stimuli become effective conditioned reinforcers on test trials only when their duration exceeds the duration of differential short-term memory cues resulting from a difference in the events that precede them on training and test trials.