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Does recovery from reward devaluation or partial reinforcement (PR) involve the counterconditioning of frustration? Transfer among tasks involving reward loss was used to uncover frustration counterconditioning. In Experiment 1, Phase 1 training in consummatory successive negative contrast (cSNC; 32-to-4% sucrose devaluation) eliminated Phase 2 iSNC in one-way avoidance (40-to-3 s safety-time reduction), but the opposite sequence generated no detectable transfer. In Experiment 2, transfer from Phase 1 cSNC to Phase 2 autoshaping extinction after continuous reinforcement increased lever pressing in previously downshifted animals relative to unshifted controls. However, Phase 1 training in autoshaping under partial reinforcement (PR) had no effect on Phase 2 cSNC. Transfer from PR to cSNC also failed when sucrose pellets were used in autoshaping (Experiment 3), when autoshaping acquisition was extended from 100 to 300 trials (Experiment 4), and when preshift training in cSNC was extended from 10 to 20 sessions (Experiment 5). In Experiment 6, Phase 1 training in PR for licking enhanced Phased 2 cSNC, also involving licking, and in Experiment 7 Phase 1 PR training in autoshaping enhanced Phase 2 cSNC after a 22-to-4% sucrose downshift. Whereas prior exposure to cSNC (consummatory task) increased resistance to extinction in autoshaped lever pressing, prior training in one-way avoidance, PR in autoshaping, or PR in taste conditioning (all anticipatory tasks) either had no effect or they enhanced the cSNC effect. Frustration counterconditioning developed during these tasks, but the type of transfer effect depends on task sequence.

Temporal specificity of latent inhibition of conditioned taste aversion (CTA) has been demonstrated after prolonged habituation to temporal contexts in the stages preceding conditioning, and it has been eliminated by restricting consumption during conditioning. However, it is not known if latent inhibition of CTA is still dependent on the temporal context when fluid consumption is limited in the stages prior to conditioning. We tested temporal specificity of latent inhibition in rats with (different time of day for the conditioning stage) and without (same time of day for pre-exposure and conditioning stages) temporal changes on the conditioning day. All animals had limited access to water in the morning sessions of the stages prior to the conditioning day and 15 min of free access to fluid in the evening sessions of these stages. Compared to animals without temporal changes between stages, animals with a different temporal context during conditioning did not show evidence of latent inhibition. Unlike the effects observed after taste stimulus restrictions during conditioning, these results suggest that the temporal specificity of latent inhibition of CTA is not abolished when access to water is limited in the stages preceding conditioning.

SummaryTaste memories allow animals to modulate feeding behavior in accordance with past experience and avoid the consumption of potentially harmful food [1]. We have developed a single-fly taste memory assay to functionally interrogate the neural circuitry encoding taste memories [2]. Here, we screen a collection of Split-GAL4 lines that label small populations of neurons associated with the fly memory center—the mushroom bodies (MBs) [3]. Genetic silencing of PPL1 dopamine neurons disrupts conditioned, but not naive, feeding behavior, suggesting these neurons are selectively involved in the conditioned taste response. We identify two PPL1 subpopulations that innervate the MB α lobe and are essential for aversive taste memory. Thermogenetic activation of these dopamine neurons during training induces memory, indicating these neurons are sufficient for the reinforcing properties of bitter tastant to the MBs. Silencing of either the intrinsic MB neurons or the output neurons from the α lobe disrupts taste conditioning. Thermogenetic manipulation of these output neurons alters naive feeding response, suggesting that dopamine neurons modulate the threshold of response to appetitive tastants. Taken together, these findings detail a neural mechanism underlying the formation of taste memory and provide a functional model for dopamine-dependent plasticity in Drosophila.

Preclinical animal research has contributed greatly to our understanding of numerous human disease states and will continue to provide a method for investigating the various biochemical events, physiological processes, and behavioral implications of various diseases. For substance use disorder, this research has enabled scientists to gain a greater understanding of the neurochemical events involved in the brain’s response to drugs, both licit and illicit, and to provide a means by which to design and test novel pharmacotherapeutic interventions. To enable these discoveries, scientists have developed numerous animal models that attempt to replicate human drug addiction. The current review explores two popular Pavlovian conditioning procedures, conditioned place preference and conditioned taste aversion, used to investigate the rewarding and aversive effects (respectively) of drugs of abuse. For each procedure, a brief history of the field is followed by the advantages of the procedures and a step-by-step explanation of each procedure’s conditioning protocol.

Reduced sensitivity to aversive effects of methamphetamine (MA) may increase risk for MA abuse. Studies in two replicate sets of mouse lines that were selectively bred for high and low levels of MA intake support this view. Current studies examined the extent of insensitivity to aversive MA effects of mice bred for high levels of MA drinking. Conditioning procedures in which drugs are delivered shortly after cue exposure have been used to detect aversive drug effects and, in some cases, are more sensitive to such effects. Aversive effects induced by MA injected immediately after exposure to cues from two different sensory modalities were examined. In addition, effects of higher MA doses than those used previously were examined. MA-associated place conditioning utilized tactile cues, whereas MA-induced taste conditioning utilized a novel tastant. Second replicate, MA high drinking (MAHDR-2) and low drinking (MALDR-2) mice were treated with doses of MA up to 4 mg/kg. MAHDR-2 mice were insensitive to aversive effects of MA, except after place conditioning with the 4 mg/kg dose; MALDR-2 mice exhibited sensitivity to aversive effects of MA at doses as low as 1 mg/kg. These studies show that the expression of aversion is dependent upon procedure and MA dose, and that MAHDR-2 mice have markedly reduced sensitivity to the aversive effects of MA. The current and previous results support a strong genetic relationship between level of MA intake and level of sensitivity to aversive effects of MA, a factor that could impact risk for MA use in humans. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Five experiments explored facilitated taste-aversion conditioning (odor-mediated taste augmentation), using rats that experienced odor (A) and taste (X) in an A+/AX+ design. Augmentation occurred when the stimuli were presented simultaneously during AX+ conditioning, and significantly weaker conditioning occurred after a sequential presentation (Experiment 1). Experiments 2 and 3 demonstrated that augmented conditioning decreased if the odor aversion was reduced through preexposure or extinction following A+ conditioning. A second-order conditioning explanation was not supported by the results of Experiment 4. Experiment 5 showed that extinction of the odor aversion after AX+ conditioning did not alter the strength of the augmented taste aversion. Odor-mediated taste augmentation is similar to potentiation, in which odor and taste cues operate in a synergistic, not competitive, manner.

The hedonic properties of chlordiazepoxide (CDP) were examined using the place conditioning and the taste conditioning paradigms. Following four conditioning trials, CDP (5–20 mg/kg) produced a conditioned place aversion in an “unbiased” paradigm in which the chamber paired with CDP was counterbalanced among two equally preferred chambers. In a “biased” place-conditioning paradigm, CDP (5 and 20 mg/kg) prevented the dissipation of the natural aversion to the nonpreferred chamber. Finally, although CDP unconditionally potentiated sucrose consumption, it produced a sucrose aversion in the taste reactivity test and sucrose avoidance in the taste avoidance test when the taste conditionally preceded injections of CDP. The pattern of findings suggest that, when novel to rats, CDP is hedonically aversive.

The learning capacities of rats with electrolytic lesions of the gustatory thalamus (GT) were investigated in 3 experiments. In Experiment 1, the presence of a taste cue failed to overshadow odor aversion learning in the lesioned rats, yet these same animals acquired normal taste and odor aversions. Thalamic lesions had no discernible effect on the acquisition of a conditioned flavor preference in Experiment 2. Finally, GT lesions completely reversed the anticipatory contrast effect shown by control subjects in Experiment 3. These results suggest that damage to the GT spares taste detection and recognition and simple associative learning but interferes with learning that involves more complex gustatory information processing.

This experiment tested the proposal that events taking place before a rat has access to a taste can proactively interfere with acquisition of an aversion to the taste when this has been followed by lithium chloride injection. Rats were initially given context discrimination whereby placement in one distinctive context (target) was followed by lithium injection, while placement in a second context (safe) was followed by saline injection. In the subsequent 1-trial taste conditioning session, rats were first placed in either their target context (Blocking group), their safe context (Control-Safe group) or a neutral context (Control-Neutral group), then given access to sucrose and 30 min later were injected with lithium. Subsequent tests of sucrose intakes revealed a blocking effect. These results indicate that proactive interference with taste aversion learning by a context can occur that is unlikely to be based on generalization decrement.

Although caffeine may be the most widely used behaviorally active drug, few studies have examined its rewarding properties. In the present study, the designs of place-conditioning and taste-conditioning paradigms were combined in a single experiment to provide two independent measures of drug reward. During 3 preconditioning sessions, undrugged rats received access to 2 distinctive chambers connected by a small tunnel. During the 8-session conditioning phase, groups were given home cage access to either a sweet or salty solution, administered caffeine (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg IP; 30.0 mg/kg SC), and confined to one of the chambers. On alternate sessions, rats were given home cage access to the remaining solution, injected with the vehicle, and confined to the opposite chamber. On test sessions 1 and 2, undrugged animals were given home cage access to one of the flavored solutions and water, and then allowed access to both conditioning chambers. On test session 3, rats were given access to both flavored solutions, injected with the drug used during conditioning, and again allowed access to both chambers. Caffeine (3.0 mg/kg) produced a significant place preference. The highest dose (30.0 mg/kg IP and SC) produced significant place and taste aversions. A control group given (+)-amphetamine illustrated a significant place preference and taste aversion as expected. Thus caffeine appeared to produce a dose-dependent biphasic effect; a lower dose was rewarding, whereas higher doses produced aversions to environmental stimuli associated with the drug.

Researchers have long sought an animal model for human alcohol consumption. This article describes an economic-based approach to a model of alcohol preference in rats. The procedures are based on an analogy between clinical accounts of human drinking and the economic analysis of consumption. Both clinical and economic investigators typically define consumption patterns in terms of the influence of negative consequences. For example, the clinical account emphasizes the persistence of heavy drinking despite mounting alcohol-related aversive consequences, and in economic analyses, the term “inelastic demand” is used to refer to the persistence of consumption despite large increases in prices. In the experimental procedure described here, rats worked for alcohol and food. Presses on one lever earned a drink of 10 percent alcohol plus saccharin, and presses on a second lever earned isocaloric drinks of a starch solution. After behavior stabilized, the response requirements (which are analogous to prices) for one or both drinks were increased. The rats maintained baseline alcohol consumption levels despite large increases in the “price” of alcohol. In contrast, the same price increases markedly reduced starch intake. That is, food consumption was sensitive to price hikes, but alcohol consumption was not. The results demonstrate that a common economic framework can be used to describe human and animal behavior and, hence, the possibility of an animal model of human alcohol consumption. The article also points out that economic concepts provide a framework for understanding a wide range of human drinking patterns, including controlled social drinking and excessive alcoholic drinking.

Male Sprague-Dawley rats were injected daily with saline (morphine-naive rats) or 20 mg kg-1 morphine (morphine-experienced rats), starting 15 days before the experiment. Subsequent taste conditioning indicated that 0.1 mg kg-1 buprenorphine significantly decreased 0.025% saccharin consumption in morphine-naive, but not in morphine-experienced rats. A 10 mg kg-1 dose of morphine gave similar results, while d-amphetamine (0.75 mg kg-1) was consistently aversive. It was concluded that morphine experience selectively blocks the aversive effects of buprenorphine in rats; thus it possibly increases the potential for buprenorphine abuse.

Male Sprague Dawley rats were injected daily with saline (morphine naive rats) or 20 mg/kg morphine (morphine experienced rats), starting at least 12 days before training. Subsequent place and taste conditioning indicated that 2.5 mg/kg morphine caused a significant increase in the amount of time spent on the least preferred side by morphine experienced but not by morphine naive rats; furthermore, saccharin consumption was markedly decreased and slightly increased by 10-20 mg/kg morphine in naive and experienced rats, respectively. It was concluded that morphine experience enhances the reinforcing efficacy of morphine and broadens the conditions under which the drug is reinforcing; thus it possibly increases morphine abuse potential.

This paper summarizes a decade of human evaluative flavor-taste conditioning research. After a neutral fruit-flavor A (CS+) has been presented repeatedly in compound with bad-tasting Tween20 (US), participants typically develop a dislike for flavor A relative to a flavor B (CS-) that has been presented equally often in plain water. Likewise, differential pairings of neutral flavors with liked sugar (US) have been found to result in an enhanced liking for the CS+ flavor. Whereas the flavor-sugar effect is rather fragile, the flavor-Tween effect is very robust, allowing for substantial parametric variation in acquisition and lest conditions. Evaluative flavor-taste learning does not require contingency awareness, is resistant to extinction, is not affected by CS-US contingency manipulations, and is not sensitive to modulation, suggesting that it is an instance of merely referential learning. Finally, the finding that evaluative flavor-taste learning is not sensitive to post-conditioning US inflation indicates that only the affective characteristics of the US are encoded, not its sensory-descriptive properties.

Three experiments were conducted to compare the effectiveness of intraperitoneally (IP) administered or subcutaneously (SC) administered cocaine to produce place and/or taste conditioning after four conditioning trials. In each experiment, IP (5–20 mg/kg) cocaine produced a place preference, but SC (0.5–20 mg/kg) cocaine at concentrations that prevented necrosis, did not produce a place preference. The failure of SC cocaine to produce a place preference was not a function of conditioning trial duration. On the other hand, SC cocaine (20 mg/kg) produced conditioned taste avoidance, but IP cocaine (20 mg/kg) did not produce conditioned taste avoidance. The results suggest that IP cocaine, but not SC cocaine, is rewarding.

Preconditioning exposure to a lithium chloride unconditioned stimulus (US) interferes with the subsequent conditioning of a taste aversion. Multiple US preexposures produce a long-lasting or durable interference with aversion learning, whereas a single US exposure produces a transient interference effect. The present experiments demonstrate that the durable US preexposure effect is substantially reduced if the method of drug treatment (infusion versus injection of the drug into the peritoneal cavity) or the spatial cues present during drug treatment (home cage versus a distinctive environment) are changed between the preexposure and taste conditioning phases of the experiment. In contrast, these manipulations do not attenuate the proximal/transient US preexposure effect. These findings indicate that different mechanisms are responsible for the two US preexposure effects. The results are consistent with previous suggestions that the durable effects of lithium preexposure are due to associative interference produced by the exteroceptive stimuli that accompany drug administrations and indicate that the proximal/transient US preexposure effect is mediated by nonassociative mechanisms.

Five experiments were done on the effects of low frequency whole body vibration on rats. In Experiment I, it was found that vibration mediated escape learning throughout a 50-day period. Predictable vibration (Experiment II) and incremental training (Experiment III) were observed to produce less escape responding than random unpredictable vibration. In Experiments IV and V, taste conditioning was studied using vibration as an US. It was concluded that vibration is an aversive stimulus like shock which mediates escape conditioning but not taste conditioning.

The effects of subcutaneous adrenaline administration on preference for ethanol (2.5% solution) have been investigated, using a two-bottle choice situation. Administration of the amine (50 μg/kg) immediately after the conditioning session significantly attenuated ethanol preference. Adrenaline treatment (10, 50 or 100 μg/kg) prior to the first retention test induced a significant reduction in ethanol preference. When the amine was injected prior to conditioning only the dose of 100 μg/kg reduced later ethanol preference. Our results indicate that systemically administered adrenaline impairs the acquisition of preference to a weak ethanol solution. It is suggested that this effect of the amine may be linked to interference with consolidation of memory and retrieval processes.