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Tegmental pedunculopontine lesions in rats decrease saccharin's rewarding effects but not its memory-improving effect.

The tegmental pedunculopontine nucleus (TPP) of the brainstem has been identified as a critical substrate for both opiate and food reward in nondeprived rats. In this study of rats, TPP lesions blocked saccharin-conditioned place preferences, in both the presence and the absence of water deprivation. TPP lesions also attenuated the unconditioned intake of saccharin and water over several hours after recovery from food and water deprivation. TPP lesions did not block saccharin preferences over water in short-duration tests. The researchers propose that the absence of a lesion effect may reflect previously conditioned discriminations. TPP lesions had no effect on the ability of posttrial presentations of a 3.2% saccharin solution to improve lithium-chloride-conditioned taste aversions. TPP lesions dissociate 2 behavioral processes elicited by saccharin: One mediates unconditioned-reward-conditioned-reinforcing effects, and another mediates the memory-improving effect.

Animals↗

Stress and consumption: inescapable shock, neophobia, and quinine finickiness in rats.

Exposure to inescapable shock has been shown to result in reduced consumption of quinine in water (the finickiness effect) in rats. In the present experiment, (a) a clear difference in finickiness occurred between male adult rats exposed to inescapable shock and those exposed to escapable shock (the first such demonstration), (b) finickiness was reinstated 20 days later, and (c) finickiness was eliminated by quinine exposure prior to treatment. The first 2 results support the role of uncontrollability and/or unpredictability in finickiness and extend its potential impact to long-term consequences. This allows greater potential for the modeling of long-term effects, such as eating disorders and depression in humans. The finding that preexposure to quinine eliminated finickiness is contrary to current accounts of the effect. Accounts of finickiness are proposed in terms of classically conditioned aversions, bitterness, and neuropeptide control of ingestion.

Animals↗

Gustatory parabrachial lesions disrupt taste-guided quinine responsiveness in rats.

This study examined the effects of electrophysiologically placed electrolytic lesions in the gustatory zone of the parabrachial nuclei (PBN) on the rat's taste-guided unconditioned licking of quinine hydrochloride during repeated 10-s trials. Concentration-response functions measured in water-deprived rats before and after surgery significantly shifted to the right as a result of the bilaterally placed lesions. These same rats were tested on their ability to acquire a lithium chloride (LiCl)-based conditioned taste aversion (CTA) to 0.1 M sucrose. Although the largest lesions severely affected performance in both tasks, there was only a modest correlation (r = -.447) between the extent of the lesion-induced shift in the quinine concentration-response curves and the degree of sucrose intake suppression after the first CTA conditioning trial. Thus, PBN lesions can disrupt performance on both tasks, but it appears that the neural processes governing unconditioned responsiveness to quinine may be to some extent dissociable from those subserving acquisition of a sucrose LiCl-based CTA.

Animals↗

Neurobiology of withdrawal motivation: evidence for two separate aversive effects produced in morphine-naive versus morphine-dependent rats by both naloxone and spontaneous withdrawal.

In drug-naive rats, the rewarding effects of morphine are blocked by lesions of the tegmental pedunculopontine nucleus (TPP), but not by neuroleptics. In dependent rats (chronically treated with morphine), morphine reward is blocked by neuroleptics, but not by TPP lesions. Just as this activation of opiate receptors in naive versus dependent rats produces different mechanisms of reward, this study concludes that reduced opioid activity on these opiate receptors produces different mechanisms of aversion. Neuroleptics blocked the conditioned place aversions produced by naloxone and spontaneous withdrawal in morphine dependent, but not naive, rats, without attenuating the somatic withdrawal syndrome induced by naloxone in dependent rats. The researchers suggest that the aversive effects of endogenous opioid withdrawal in naive rats are mediated by different neural substrates than the aversive effects of exogenous opioid withdrawal in dependent rats.

Animals↗

Fos expression in the spinal cord is suppressed in rats displaying conditioned hypoalgesia.

Two experiments used c-fos expression as a marker of spinal nociceptive processing to study the neural correlates of hypoalgesic responses to conditioned stimuli (CSs) paired with an aversive event. Immunoreactive (ir) neuronal labeling of Fos, the nuclear protein encoded by the c-fos gene, was examined in the spinal cords of rats killed 2 hr after injection of dilute formalin into a hind paw. Compared with control rats either not conditioned or conditioned in one environment but tested elsewhere, there were significantly fewer Fos-ir neurons in the spinal cords of rats displaying hypoalgesic responses when tested in the presence of aversive CSs. Naloxone abolished hypoalgesic responses and reinstated spinal Fos expression, indicating that aversive CSs activated opioid-based antinociceptive mechanisms. The results confirm that aversive CSs produce hypoalgesia by inhibiting the transmission of ascending nociceptive information.

Animals↗

Dorsal hippocampal lesions impair blocking but not latent inhibition of taste aversion learning in rats.

The aim of the present experiments was to study the effect of nonselective electrolytic lesions of the rat dorsal hippocampus on 2 learning phenomena: the L.J. Kamin (1969) blocking effect and latent inhibition of taste aversion learning. Bilateral dorsal hippocampal lesions selectively impaired blocking induced by 1 saccharin-lithium chloride pairing previous to 1 serial compound (saccharin-cider vinegar)-lithium pairing, but lesions had no effect on latent inhibition of a saline aversion, induced by 6 saline preexposures, in the same group of animals. Moreover, dorsal hippocampal lesions did not affect latent inhibition of saccharin-conditioned aversion induced by 1 or 6 preexposures. It is argued that blocking and latent inhibition of taste aversion learning do not share a common neural mechanism.

Animals↗

Taste-potentiated odor conditioning: impairment produced by infusion of an N-methyl-D-aspartate antagonist into basolateral amygdala.

Two experiments examined the effects of infusing an N-methyl-D-aspartate (NMDA) receptor antagonist, d-2-amino-5-phosphonovalerate(d-APV), on taste-potentiated odor conditioning: a form of learning that is dependent on information processing in 2 sensory modalities. In Experiment 1, rats infused with d-APV were impaired in their acquisition of the potentiated learning to an odor cue. Expression of this learning and acquisition of a simple taste aversion remained intact following drug treatment. In Experiment 2, dose dependence and stereoselectivity were demonstrated for the antagonist compound. These results are consistent with previous studies demonstrating that either basolateral amygdala lesions, or treatment with NMDA antagonists, by other routes (systemic or intraventricular) produce selective deficits in taste-potentiated odor conditioning.

2-Amino-5-phosphonovalerate↗

Clonidine antagonizes the aversive effects of opiate withdrawal and the rewarding effects of morphine only in opiate withdrawn rats.

The researchers asked whether clonidine, an alpha 2-noradrenergic agonist, would block selectively the motivational effects of opiate withdrawal and whether clonidine's effects would respect the boundary between nondeprived and deprived motivational states. In a place conditioning paradigm, clonidine (0.05 mg/kg ip) blocked the rewarding effects of morphine in opiate-withdrawn rats (as well as the aversive properties of withdrawal itself), but did not affect morphine place preferences (2 and 20 mg/kg) in drug-naive rats. Furthermore, clonidine blocked the acquisition of morphine (15 mg/kg), but not LiCl (15 mg/kg), conditioned taste aversions in water-deprived rats. The results suggest that the motivational system activated in deprived animals includes dopaminergic and noradrenergic components that are in series with each other.

Adrenergic alpha-Agonists↗

Lack of a temporal gradient of retrograde amnesia following NMDA-induced lesions of the basolateral amygdala assessed with the fear-potentiated startle paradigm.

M. Kim and M. Davis (1993b) previously reported that electrolytic lesions of the central nucleus of the amygdala, made 6 or 30 days after training, completely blocked the expression of fear-potentiated startle in rats. The present study shows that excitotoxic lesions of the basolateral amygdala also block fear-potentiated startle and do so whether the lesions are made soon (i.e., 6 days) or long (i.e., 30 days) after training. The relevance of these findings to various theories of amygdala function is discussed.

Amygdala↗

Mutations that prevent associative learning in C. elegans.

The nematode Caenorhabditis elegans offers a promising system for the reductionist study of learning and memory. In this article, classical conditioning in C. elegans is demonstrated with a variety of associative learning assays. These assays allowed for the isolation and behavioral characterization of 2 mutant C. elegans lines impaired in associative learning. Both lines show no short-term or long-term associative conditioning; however, they appear relatively normal in tests of nonassociative learning and sensorimotor function. In combination with the well-described genetics and neuroanatomy of C. elegans, the isolation of mutants selectively, yet completely, blocked in associative learning provides the basis for an effective characterization of the cellular and molecular aspects of associative learning.

Animals↗

Cooling the area postrema induces conditioned taste aversions in male rats and blocks acquisition of LiCl-induced aversions.

The experiments presented in this article were designed to examine whether area postrema (AP) lesions attenuate LiCl-induced conditioned taste aversions (CTAs) by disruption of information about the illness-producing properties of LiCl or by a lesion-induced malaise. Reversible lesioning of the AP caused by cooling induced a CTA in male rats. The cooling-induced CTA could be blocked if males were exposed to cooling for several days before acquisition day. Acquisition of a LiCl-induced CTA was blocked in males if they were exposed to cooling before acquisition day and during LiCl administration on acquisition day was attenuated but not blocked in males if they were exposed to cooling only before acquisition day, and was unchanged in males if they were exposed to cooling only during LiCl administration. Taken together these results indicate that the AP is important for acquisition of LiCl-induced CTAs but that inactivation of this area is so aversive it will induce CTAs that can obscure the attenuation of LiCl-induced aversions.

Animals↗

Encoding and selective activation of "metabolic memories" in the rat.

Experiment 1 used Pavlovian conditioning procedures to show that rats formed distinct memorial representations of 2 (peanut oil and sucrose pellets) unconditioned stimuli (USs) that could be activated by 2 different conditioned stimuli (CSs). After training in Experiment 2, rats injected with the lipid antimetabolite Na-2-mercaptoacetate (MA) responded more to the CS for oil than to the CS for sucrose. This pattern was not shown by rats that received isotonic saline or systemic 2-deoxy-d-glucose (a glucose antimetabolite). By contrast, intracerebroventricular infusion of the glucose antimetabolite 5-thioglucose selectively promoted responding to the CS for sucrose (Experiment 4). Thus, lipoprivic and glucoprivic treatments selectively promoted the activation of the memories of fat and carbohydrate USs, respectively. In Experiment 3, the capacity of MA to augment responding to a CS for oil was abolished for rats that received subdiaphragmatic vagal deafferentation. This indicates that the capacity of lipoprivic signals to selectively activate the representations of fat USs may depend on vagal afferent fibers.

Animals↗

Startle potentiation: shock sensitization, aversive learning, and affective picture modulation.

This study investigated the size of, and relationship between, different modulatory effects of aversive stimulation on the acoustic startle reflex. This reflex is potentiated by shock exposure and associative shock conditioning (in animals and human volunteers) and unpleasant pictures (in human volunteers). In this study, dramatic sensitization of the probe-startle response was observed after shock exposure but not after a control task. Magnitude of sensitization was significantly larger than associative shock conditioning and picture modulation effects (also significant). Sensitization and conditioning scores showed modest, significant correlations with one another but not with picture modulation scores, consistent with animal data showing that partially overlapping brain mechanisms (i.e., amygdaloid-reticular projections) mediate these effects. The present results also indicate that sensitization of startle in human volunteers is a relatively more robust defensive response to aversive stimulation.

Acoustic Stimulation↗

Effects of US devaluation on win-stay and win-shift radial maze performance in rats.

Previous studies have shown double dissociations between win-stay and win-shift radial maze learning in terms of their underlying neural substrates. To examine the content of the associations formed in the two tasks, the authors devalued the food unconditioned stimulus (US) by taste aversion to differentiate stimulus-stimulus(CS-US) and stimulus-response (CS-CR) learning. US devaluation was performed in rats that were over- or undertrained on the win-stay task. Devaluation substantially reduced food consumption on the maze but failed to disrupt choice accuracy, regardless of the amount of training. Devaluation did not affect latency in overtrained rats but did increase latency in undertrained rats. In the win-shift task, devaluation caused rats to reject the reinforcer, yet they continued to accurately win-shift, but with significantly longer latencies (Experiment 3). The results suggest that an S-R association may mediate performance after extended win-stay training. In contrast, a US representation appears to be recalled during early win-stay and win-shift performance.

Animals↗

The suppressive effects of sucrose and cocaine, but not lithium chloride, are greater in Lewis than in Fischer rats: evidence for the reward comparison hypothesis.

Rats suppress intake of a saccharin conditioned stimulus (CS) when it is paired with an aversive unconditioned stimulus (US), an appetitive US, or a drug of abuse such as morphine or cocaine. It is unclear, however, whether the reduction in intake induced by these drugs is mediated by their aversive or their rewarding properties. The present set of experiments addressed this question by comparing the suppressive effects of a known aversive US (LiCl), a known reinforcing US (sucrose), and a drug of abuse (cocaine) in two strains of rats (i.e., Lewis and Fischer 344 rats) that differ in their preference for rewarding stimuli. The results show that, although both strains readily acquired a LiCl-induced conditioned taste aversion (CTA), the suppressive effects of sucrose and cocaine were robust in the drug-preferring Lewis rats and absent in the Fischer rats. These data argue against a CTA account and in favor of the reward comparison hypothesis.

Animals↗

Reinforcer devaluation abolishes conditioned cue preference: evidence for stimulus-stimulus associations.

In the conditioned cue preference (CCP) task, the subject is presented with a cue paired with food reward, resulting in a preference for the paired cue when allowed to choose later. To clarify the learning involved, the authors devalued the reinforcer after training by inducing a taste aversion to the food. In five 30-min sessions, rats were confined in 1 arm of a radial arm maze and presented with food. These reinforced sessions alternated with 5 unreinforced sessions in a nonadjacent arm. Devaluation was then accomplished in 1 group by inducing taste aversion; controls received either saline or unpaired lithium chloride treatment. When tested later, both the saline group and the unpaired group preferred the previously reinforced arm, but the devalued group showed aversion to it. Thus, CCP is mediated by the stimulus-reinforcer association; when the reinforcer is devalued, the preference is also abolished.

Animals↗

Interaction between drug discriminative stimuli and exteroceptive, sensory signals.

Interactions between drug discriminative stimuli (based on 5.6 mg/kg and 10 mg/kg pentobarbital) and exteroceptive stimuli (visual and auditory) were studied in a T-maze. In three groups, visual stimuli (light vs. dark) were differentially paired with drug stimuli; the fourth group discriminated combinations of tonal frequencies (1 kHz or 10 kHz) and the presence or absence of pentobarbital. (10 mg/kg). In general, visual stimuli controlled choice behavior (left or right turn) to a greater extent than did the drug training stimuli, whereas the auditory stimuli exerted no apparent control over the pentobarbital stimulus in Group 4. Tests with doses higher than the training doses indicated augmented stimulus control by the drug dimension in two groups (Group 1, 10 mg/kg pentobarbital vs. saline; Group 2, 5.6 mg/kg vs. 10 mg/kg pentobarbital) but not in the third group (5.6 mg/kg pentobarbital vs. saline) in the "conflict" situation, that is, the exteroceptive conditions signaled one response whereas the drug stimulus signaled the opposite response. Discrimination training with only one of the stimulus dimensions resulted in stimulus control in the following order: 10 mg/kg vs. saline greater than 5.6 mg/kg vs. saline greater than 1 kHz vs. 10 kHz, results indicating that the auditory stimuli were of marginal significance. In conclusion, drugs can complete with exteroceptive, visual stimuli for associative strength.

Animals↗

The US-preexposure effect in lithium-induced flavor-aversion conditioning is a consequence of blocking by injection cues.

In 2 experiments, rats received flavor-aversion conditioning in which the unconditioned stimulus (US) was an orally consumed solution of lithium chloride (LiCl). The resulting aversion was not attenuated by giving preexposure to injections of LiCl, although such preexposure did attenuate aversions established using injected LiCl as the US (Experiment 1). This outcome suggests that blocking by injection-related cues is responsible for the US-preexposure effect observed in this situation. Experiment 2 confirmed this interpretation by showing that presenting such cues (by giving an injection of saline) at the time that the LiCl was drunk resulted in an attenuation of conditioning in animals preexposed to injections of LiCl. The US-preexposure effect obtained in these experiments can be explained solely in terms of blocking by injection cues, although other mechanisms may contribute to the effect seen in other flavor-aversion paradigms.

Administration, Oral↗