Cannabinoid Agonists and Antagonists Modulate Lithium-induced Conditioned Gaping in Rats

Considerable evidence indicates that conditioned gaping in rats reflects nausea in this species that does not vomit. A series of experiments evaluated the potential of psychoactive cannabinoid agonists, delta-9-THC and HU-210, and non-psychoactive cannabinoids, Cannabidiol (CBD) and its dimethylheptyl homolog (CBD-dmh), to interfere with the establishment and the expression of conditioned gaping in rats. All agents attenuated both the establishment and the expression of conditioned gaping. Furthermore, the CB1 antagonist, SR-141716, reversed the suppressive effect of HU-210 on conditioned gaping. Finally, SR-141716 potentiated lithium-induced conditioned gaping, suggesting that the endogenous cannabinoid system plays a role in the control of nausea.     

Central cannabinoid receptors modulate acquisition of eyeblink conditioning

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning.     

The antiemetic drug ondansetron interferes with lithium-induced conditioned rejection reactions, but not lithium-induced taste avoidance in rats

Conditioned rejection reactions displayed in the taste reactivity test are exclusively produced by treatments that elicit nausea. The present experiments demonstrate that pretreatment with the antinausea agent ondansetron interferes with both the establishment and the expression of conditioned rejection reactions. Ondansetron did not interfere with lithium-induced taste avoidance in either a 1-bottle or a 2-bottle test. In fact, when rejection reactions were measured during a consumption test, ondansetron selectively attenuated rejection reactions, with only a slight modification of consumption. These results suggest that conditioned rejection reactions, but not conditioned taste avoidance, reflect nausea in rats that can be attenuated by ondansetron pretreatment.     

Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats

Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3 min received a footshock (1.5 mA, 1 s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25 mg/kg, AM404 10 mg/kg, SR141716 A 1 mg/kg) and were re-exposed to the conditioning chamber for 30 min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3 min to the conditioning chamber. A drug-free test of contextual memory (3 min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.     

Conditioned nausea in rats: Assessment by conditioned disgust reactions, rather than conditioned taste avoidance

The terms conditioned taste avoidance and conditioned taste aversion are often used interchangeably in the literature; however, considerable evidence indicates that they may represent different processes. Conditioned taste avoidance is measured by the amount that a rat drinks in a consumption test that includes both appetitive phases and consummatory phases of responding. However, conditioned taste aversion is more directly assessed using the taste reactivity (TR) test that includes only the consummatory phase of responding. Rats display a conditioned taste aversion as conditioned disgust reactions (gapes, chin rubs, and paw treads) during an intraoral infusion of a nausea-paired flavored solution. Only treatments that produce nausea produce conditioned disgust reactions, but even rewarding drugs produce conditioned taste avoidance. Furthermore, treatments that alleviate nausea prevent the establishment and the expression of conditioned disgust reactions, but they do not necessarily modify conditioned taste avoidance. Considerable evidence exists indicating that these two measures can be independent of one another. The potential of a compound to produce conditioned disgust reactions is a reflection of its nausea-inducing properties. Taste avoidance may be motivated by conditioned fear rather than conditioned nausea, but conditioned disgust is motivated by conditioned nausea. (PsycINFO Database Record (c) 2008 APA, all rights reserved).     

Retention and extinction of delay eyeblink conditioning are modulated by central cannabinoids

Rats administered the cannabinoid agonist WIN55,212-2 or the antagonist SR141716A exhibit marked deficits during acquisition of delay eyeblink conditioning, as noted by Steinmetz and Freeman in an earlier study. However, the effects of these drugs on retention and extinction of eyeblink conditioning have not been assessed. The present study examined the effects of WIN55,212-2 and SR141716A on retention and extinction of delay eyeblink conditioning in rats. Rats were given acquisition training for five daily sessions followed by one session of retention training with subcutaneous administration of 3 mg/kg of WIN55,212-2 or 5 mg/kg of SR141716A and an additional session with the vehicle. Two sessions of extinction training were then given with WIN55,212-2, SR141716A, or vehicle. Retention and extinction were impaired by WIN55,212-2, whereas SR141716A produced no deficits. The extinction deficit in rats given WIN55,212-2 was observed only during the first session, suggesting a specific impairment in short-term plasticity mechanisms. The current results and previous findings indicate that the cannabinoid system modulates cerebellar contributions to acquisition, retention, and extinction of eyeblink conditioning.     

Taste Aversion Learning Based on Swimming and Lithium Chloride Injection in Rats: Implications From Cross-familiarization Tests and Stimulus Selectivity1

In rats, swimming causes avoidance of the taste solution consumed immediately before the swimming. Several lines of research have shown that this taste avoidance reflects Pavlovian conditioned aversion based on correlations between the taste and swimming-induced nausea. The present research compared swimming-based taste aversion learning (TAL) with conventional TAL based on nausea-inducing lithium chloride (LiCl). By exploiting cross-familiarization techniques, Experiments 1A and 1B suggested that different physiological states are induced by swimming and LiCl. This claim was supported by Experiment 2, which reports stimulus selectivity in saccharin and sucrose aversions based on swimming and LiCl.     

Effect of exposure to lithium-paired or amphetamine-paired saccharin solution on open arm avoidance in an elevated plus maze

Recent evidence suggests that drug-induced conditioned taste avoidance may be mediated by conditioned fear (e.g., Parker, 2003). The experiments reported here evaluated the effect of exposure to a drug-paired flavor on open arm exploration in an elevated plus maze (EPM), a measure of fear. When rats were tested on a familiar (trial 2) EPM, but not on a novel (trial 1) EPM, prior exposure to a lithium-paired saccharin solution enhanced open arm activity relative to saline-paired saccharin. On the other hand, when rats were exposed to lithium-paired saccharin during plus maze exposure, they displayed suppressed open arm activity relative to unpaired controls when tested in a familiar maze. The pattern of results was specific to the conditional affective properties of the taste, because exposure to unconditional sickness produced by administration of lithium, and unconditionally unpalatable quinine solution did not produce this pattern. These results were interpreted in terms of the opponent process model of motivation; that is, exposure to a lithium-paired flavor elicits conditioned fear which is immediately followed by conditioned relief when the exposure is terminated. On the other hand, exposure to an amphetamine-paired flavor either before or during EPM testing enhanced open arm exploration. Since the strength of taste avoidance did not differ among amphetamine and lithium conditioned rats, these results provide further evidence that the nature of a saccharin-lithium association differs from that of a saccharin-amphetamine association.     

乳头体对海马齿状回习得性长时程突触增强的影响

用高频电脉冲刺激大鼠乳头体（ＭＢ）,可一过性抑制由刺激穿通纤维（ＰＰ）诱发的海马齿状回（ＤＧ）群体锋电位（ＰＳ）。训练作业前先刺激ＭＢ,导致ＤＧ的习得性长时程突触增强（ＬＤＬＴＰ）的形成显著延缓,相应地延缓了条件性饮水反应的建立。电刺激ＭＢ对ＰＰ─ＤＧＰＳ的这种抑制作用在训练所产生的ＰＳ增大达最高水平时显著减弱,刺激ＭＢ对ＬＤＬＴＰ的保持及相应地对条件反应的巩固没有明显影响。结果表明ＭＢ对ＤＧＬＤＬＴＰ的形成有抑制性调制作用。     

Selective association learning in the rat: Generality of response system

Three experiments with rats examined the possibility that the cue-consequence specificity effect is not mediated by the conditioning of selective associations, but instead reflects the selective behavioral expression of taste-illness and exteroceptive-shock conditioning. Experiment 1 showed that the selective aversion performance could be obtained despite the use of locomotor withdrawal from the CS as the index of conditioning. Experiment 2 compared the response profiles of animals conditioned with footshock or illness to presentation of a saccharin or noise CS. During the test with the noise CS, lithium-conditioned subjects did not differ from control rats on any of several behavioral categories, but shock-conditioned rats showed high levels of freezing in response to the noise cue. During the saccharin test, lithium-treated rats engaged in behaviors such as chin wiping, head shaking, and gaping; these behaviors were rarely or never seen in shock-conditioned rats or controls, whose behavioral profiles during the saccharin test were almost identical. Experiment 3, using a blocking design, found that a noise-lithium pairing did not attenuate subsequent conditioning of a saline-lithium association, nor did a saccharin-shock pairing interfere with conditioning of a noise-shock association. These results confirm that the cue-consequence specificity effect is mediated by the selective associability of taste with illness and of exteroceptive cues with footshock.     

以兔抗鼠淋巴细胞血清为非条件刺激的条件性免疫抑制

采用一种生物类免疫抑制剂-兔抗鼠淋巴血清（rabbit anti-rat lymphocyte serum,ALS）为非条件刺激（UCS）,糖精水为条件刺激（CS）,以双瓶给水法置于鼠笼前端饮用偏好侧。在一次性CS-UCS结合训练后,单独再次给予CS,使卵清蛋白（OVA）免疫过的大鼠表现出脾淋巴细胞对有丝分裂原PWM的增殖反应降低,血抗OVA抗体的总量及脾内抗OVA抗体生成细胞的减少,但动物未表现出条件性味觉厌恶的行为反应。这些结果表明条件性免疫抑制与味觉厌恶行为条件反射没有必然联系,并非是厌恶行为反应或情绪应激的伴随产物。UCS也并非必需具有感觉的毒副作用,条件性免疫抑制是脑高级神经活动调节免疫功能的结果。     

Burying by rats in response to aversive and nonaversive stimuli

Previous investigations have shown that rats bury a variety of conditioned and unconditioned aversive stimuli. Such burying has been considered as a species-typical defensive reaction. In the present studies, rats buried spouts filled with Tabasco sauce, or condensed milk to which a taste aversion was conditioned, but did not bury water-filled spouts or spouts filled with a palatable novel food (apple juice) to which a taste aversion was not conditioned. However, in other experiments rats consistently and repeatedly buried Purina Rat Chow, Purina Rat Chow coated with quinine, and glass marbles. This indicates that a variety of stimuli, not all aversive or novel, evoke burying by rats. Whereas the behavior may reasonably be considered as a species-typical defensive behavior in some situations, the wide range of conditions that occasion burying suggests that the behavior has no single biological function.     

Conditioned nausea after cancer chemotherapy and autonomic nervous system conditionability

There are marked individual differences in conditioned nausea after cancer chemotherapy. To examine if part of this variation is associated with individual differences in autonomic nervous system conditionability, the present study addressed whether patients with conditioned nausea acquired conditioned heart rate and electrodermal responses at a different rate than patients without conditioned nausea. Of 28 relapse-free patients who had completed cisplatinum treatment for testicular cancer between 1981 and 1986, 10 reported persistent conditioned nausea, 8 extinguished conditioned nausea and 10 no conditioned nausea. These three groups were subjected to a differential conditioning paradigm with 8 sec pictorial stimuli (circles and triangles) serving as conditioned stimuli for an unconditioned electric shock while heart rate and electrodermal activity was monitored. There were 4 habituation, 8 acquisition and 8 extinction trials with each of the two cues. Analyses of variance using nausea status as the independent variable and physiological responses as the dependent lended some support to the notion that conditioned heart rate deceleration developed in response to the reinforced compared to the nonreinforced cue during acquisition in the two groups with persistent or extinguished conditioned nausea but not in the group with no conditioned nausea. In addition, patients that displayed good, as compared to poor heart rate conditionability during acquisition, were more likely to have persistent conditioned nausea, whereas those who showed poor heart rate conditioning mostly were those without conditioned nausea. Electrodermal variables revealed no systematic differences between groups. This tentatively supports that individual differences in parasympathetic but not sympathetic nervous system conditionability may be associated with individual differences in conditioned nausea resulting from cancer chemotherapy.     

Conditioned taste aversion is enhanced when the unconditioned stimulus is presented in a different context

Using a conditioned taste aversion procedure with rats as the subjects, two experiments examined the effect of presenting a conditioned stimulus (CS saccharin solution) in one context followed by an unconditioned stimulus (US LiCl) in a different context. Experiment 1 showed that animals which received the above-mentioned procedure (Group D) showed a more marked conditioned aversion to the CS than animals which were given both the CS and the US in the same context (Group S). Experiment 2 found that in both Group D and Group S, aversion to the CS increased when the subjects were exposed to the conditioned context after the conditioning. These findings supported the argument that the strength of the CS-US association acquired during conditioning is compared with that of the context-US to determine the magnitude of aversion revealed to the CS.     

Modulation of fear and anxiety by the endogenous cannabinoid system

The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.     

Food choice in rats (Rattus norvegicus): the effect of exposure to a poisoned conspecific

Three experiments were conducted to examine the effects of exposure to a poisoned conspecific on subsequent food aversion in rats. In Experiment 1A, rats that had been aversively conditioned to a cocoa-flavored food were exposed to a poisoned conspecific that had eaten the same food. On the subsequent choice test, the animals increased their aversion to that food. These results were reconfirmed in Experiment 1B, in which a cinnamon-flavored food was used as the stimulus. In Experiment 2, subjects were first exposed to a poisoned conspecific and then conditioned to the food which the conspecific had eaten. On the test, they showed no sign of increased aversion to that food.     

The role of pre-exposure to novel food tastes in activity-based conditioned taste avoidance

Rats were given differential exposure to three distinct and novel foods. One of these foods was exposed for 7 days; another for 2 days, and the last was not exposed. Next, half of the rats received six daily sessions in which a compound of the three flavors was followed by opportunities to run in wheels. The other rats received the food compound but without wheel running. On the next day, all rats were given a choice among the three food flavors presented concurrently in separate dishes. When the compound food had been followed by wheel running, rats ate little of the food given no pre-exposure, more of the food given 2 days of pre-exposure, and considerably more of the food given 7 days of pre-exposure. In comparison, rats who did not receive an opportunity to run ate equal and moderate amounts of the three foods. The results suggest that pre-exposure to a food’s taste produces latent inhibition that interferes with conditioned taste avoidance produced by pairing a taste (CS) with wheel running (US).     

The effects of preexposure-test and conditioning-test intervals on the magnitude of latent inhibition

Using the conditioned taste aversion paradigm, two experiments were conducted to examine the effects of the interval between preexposure and test and that between conditioning and test on the magnitude of latent inhibition. Experiment 1 revealed that the degree of latent inhibition was attenuated when rats were given a 21‐day interval between preexposure and test. It was also found that this attenuation was more marked in subjects which were given conditioning immediately after preexposure than those which were conditioned shortly before the test. Retention interval between preexposure and test was reduced to 12 days in Experiment 2, and exactly the same pattern of results as those found in Experiment 1 was obtained. These findings suggest that the memory of conditioning as well as that of preexposure decreases its retrievability after a long retention interval, although the former is more retainable than the latter.     

Second-order conditioning during a compound extinction treatment

Two conditioned taste aversion experiments with rats were conducted to establish if a target taste that had received a prior pairing with illness could be subject to second-order conditioning during extinction treatment in compound with a flavor that also received prior conditioning. In these experiments, the occurrence of second-order conditioning was indicated by protection from extinction of the aversion elicited by the target taste. This possibility, although intuitive, deserves attention because current associative models [e.g., Rescorla, R. A., & Wagner, A. R. (1972). A theory of Pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. In A. H. Black & W. F. Prokasy (Eds.), Classical conditioning II: Current research and theory (pp. 64-99). New York: Appleton-Century-Crofts.] predict exactly the opposite outcome, namely, that compound extinction of two CSs should result in enhanced extinction.     

Modulation of Taste Aversions by a Pentobarbital Drug State: An Assessment of Its Transfer Properties

In a drug-discrimination procedure using conditioned taste aversions, a pentobarbital injection signaled a taste–toxin pairing while the vehicle injection signaled the same taste in the absence of the toxin. In transfer tests, drug states transferred control over consumption to other targets. If the training target was a fluid (saccharin), then transfer occurred to other fluids (both novel and familiar) but not to solid food. If the training target was food, then some transfer occurred to novel targets (both fluids and solid food) but not to familiar targets. Control rats revealed that the differential consumption seen during acquisition and during transfer tests was not due to the summation of two simple associations (i.e., drug–toxin and flavor–toxin) but rather reflected conditional control over consumption by the drug state.