Attenuation of cyclophosphamide-induced taste aversions in mice by prochlorperazine, delta 9-tetrahydrocannabinol, nabilone and levonantradol

A series of experiments were performed with adult CD-1 male mice to evaluate the antiemetic effects of several compounds using the conditioned taste aversion procedure. The antiemetics were administered IP immediately prior to a 30-min conditioning trial in which a novel tasting solution (0.3% saccharin) was presented to the subjects. The emetics, apomorphine and the cancer chemotherapeutic drug cyclophosphamide, were given IP immediately after the conditioning trial at doses that induced taste aversions. Three days later the mice received a two bottle preference test (saccharin vs. water) and the percent saccharin consumed of the total fluid intake was calculated. Doses of the phenothiazine antiemetic prochlorperazine (1 and 3 mg/kg) attenuated the aversions produced by 0.3 and 1.0 mg/kg apomorphine. Doses of drugs currently approved or under clinical investigation as antiemetics in conjunction with cancer chemotherapy, i.e., prochlorperazine (1.0 mg/kg), delta 9-tetrahydrocannabinol (0.3 and 1.0 mg/kg) and nabilone (0.01 and 0.03 mg/kg), significantly attenuated the taste aversions induced by cyclophosphamide. Levonantradol at doses of 0.03 and 0.06 mg/kg, however, did not attenuate cyclophosphamide-induced taste aversions. Conditioned taste aversions produced by emetic drugs warrants investigation as a model for evaluating potential antiemetics.     

Ethanol preexposure attenuates the interaction of ethanol and cocaine in taste aversion learning

Although the potentiating effects of ethanol and cocaine have been well documented, little has been reported regarding the effects of ethanol or cocaine history on this interaction. In the present study, female Long-Evans rats received five exposures to ethanol (3.5 g/kg ip) or vehicle prior to taste aversion conditioning in which a novel saccharin solution was paired with either ethanol (0.56 g/kg ip), cocaine (25 mg/kg sc) or the combination (or the drugs' vehicle) for a total of five conditioning trials. Nonpreexposed subjects conditioned with the ethanol/cocaine combination displayed aversions, drinking levels significantly less than nonpreexposed subjects conditioned with either drug alone. Further, the aversions produced by the combination were greater than the sum of the aversions produced by ethanol and cocaine, alone. Ethanol-preexposed animals conditioned with the combination displayed an attenuated aversion, drinking significantly greater amounts of saccharin than nonpreexposed conditioned subjects and not differing from controls. Although the basis for the attenuation by ethanol of the aversions induced by the drug combination is not known, the present findings may have implications for the use and abuse of the combination in that alcohol history may reduce the subsequent toxicity of the combination that in turn may affect its acceptability.     

Strain differences in the acquisition of nicotine-induced conditioned taste aversion

Lewis (LEW) and Fischer (F344) rat strains differ on a variety of physiological and behavioral endpoints, including reactivity to drugs of abuse. Although they differ in drug reactivity, such assessments are generally limited to morphine and cocaine. To determine if these differences generalize to other drugs, the present study examined these strains for their reactivity to the affective properties of nicotine, specifically their sensitivity to nicotine in the conditioned taste aversion preparation. For four or five conditioning cycles given every other day, rats from both strains were allowed access to saccharin and injected with nicotine (0.1, 0.4, 0.8 mg/kg) or vehicle. On intervening days, all rats were given access to water and injected with vehicle. Under this one-bottle training and testing procedure, neither strain displayed aversions at the lowest dose of nicotine (0.1 mg/kg). Aversions were evident for both strains at 0.4 and 0.8 mg/kg, although the F344 rats acquired the aversions at 0.4 mg/kg faster and displayed a significantly greater aversion at 0.8 mg/kg than subjects from the LEW strain. For both strains, aversions were evident at all doses (and in a dose-dependent manner) when subjects were given access to saccharin and water in a two-bottle test. There were, however, no strain differences on this test. Differences between the two strains in their acquisition of nicotine-induced taste aversions were discussed in the context of aversion assessments with other compounds as well as in relation to differences in the self-administration of nicotine in the two strains.     

Studies on D1 and D2 dopamine receptor involvement in conditioned taste aversions

This series of studies investigated the ability of compounds selective for either the D1 or D2 dopamine receptor to induce a conditioned taste aversion (CTA) in thirsty rats. Neither the D1 antagonist SCH23390 (0.12-0.60 mg/kg) nor the D2 antagonist haloperidol (0.125-0.375 mg/kg) were able to induce CTAs to a saccharin solution. In contrast, the D1 agonist SKF38393 produced a dose-dependent taste aversion which was stereoselective to the (R-) enantiomer. The aversion to (R,S)-SKF38393 was not blocked by pretreatment with either SCH23390 or haloperidol, suggesting that the aversion is not mediated through stimulation of either dopamine receptor subtype. The D2 dopamine receptor agonist quinpirole was also found to produce a dose-dependent CTA. This aversion was blocked by injections of haloperidol and was attenuated following injections of domperidone, suggesting involvement of peripheral dopamine receptors in the aversion. Pretreatment with SCH23390 failed to affect the quinpirole-induced CTA, providing additional evidence that the D1 and D2 dopamine receptor subtypes can function independently of one another in the control of behavior. Finally, it does not appear that the area postrema is importantly involved in these taste aversions since lesions of this brain region did not affect the CTAs induced by either SKF38393 or quinpirole.     

Interaction of haloperidol and area postrema lesions in the disruption of amphetamine-induced conditioned taste aversion learning in rats

Two experiments were run to determine the mechanisms underlying the acquisition of an amphetamine-induced conditioned taste aversion. In the first experiment, it was shown that pretreatment with haloperidol (0.1-0.5 mg/kg, IP) attenuated. but did not prevent, taste aversion learning produced by amphetamine (3 mg/kg, IP). In the second experiment, combining area postrema lesions with haloperidol (0.5 mg/kg) pretreatment completely blocked the acquisition of an amphetamine-induced taste aversion. The results are interpreted as indicating that amphetamine-induced taste aversion learning has both a central component, which is mediated by dopaminergic receptors, and a nondopaminergic peripheral component, which is mediated by the area postrema.     

Learned taste aversion to saccharin produced by orally consumed d-amphetamine

Rats were presented with solutions containing both saccharin and d-amphetamine and the development of taste aversions to solutions of either or both of these substances was studied. In Experiment 1 it was found that taste aversions developed to solutions of saccharin (1 mg/ml) which contained amphetamine at concentrations of 0.01, 0.03 and 0.1 mg/ml. Experiment 2 showed that a taste aversion conditioned to a solution of saccharin (2 mg/ml) and amphetamine (0.2 mg/ml) generalised to solutions containing saccharin at concentrations between 0.625 and 20 mg/ml but not to a solution containing only amphetamine. In the third experiment it was found that the degree of generalisation of a taste aversion to lower saccharin concentrations depended upon the concentration used during conditioning trials. When the conditioning concentration was 0.625 mg/ml the aversion generalised to concentrations as low as 0.075 mg/ml but when a 10 mg/ml solution was used for conditioning the aversion did not generalise to concentrations below 2 mg/ml. The characteristics of taste aversions conditioned with orally consumed amphetamine are similar to those of conditioning involving injections of the drug.     

Pimozide attenuates conditioned taste preferences induced by self-stimulation in rats

Conditioned taste preferences (CTPs) were observed in rats who drank flavored water followed by a session of self-stimulation. Control groups that did not self-stimulate did not exhibit CTPs. Other taste/SS pairings conducted under the influence of the dopamine receptor antagonist pimozide (0.1 or 0.3 mg/kg, IP) resulted in dose-dependent reductions in the size of the CTPs. No evidence of any aversive effects (conditioned tast aversions) of the pimozide treatment were observed in the no-stimulation control groups. These data suggest that, in addition to its effects on responding, low doses of pimozide reduce the rewarding properties of self-stimulation.     

Selective and nonselective serotonin antagonists block the aversive stimulus properties of MK212 and m-chlorophenylpiperazine (mCPP) in mice

Serotonin_2C (5-HT_2C) receptors have been implicated to treat mood disorders such as depression and anxiety. In the present study, the capacities of two 5-HT_2C agonists, MK212 and mCPP, to produce conditioned taste aversions in mice were evaluated. On two training days, Swiss-Webster male mice (19–34 g) were trained to associate the flavor of a novel solution with the injection of various doses of MK212 or mCPP. On two alternate training days, mice were trained to associate a different flavored solution with an injection of saline. For testing, both flavored solutions were presented simultaneously and an avoidance of the MK212 or mCPP-paired solution indicated conditioned taste aversion. Robust conditioned taste aversions were observed to solutions paired with 1.0 or 10 mg/kg MK212 or mCPP. Acquisition of conditioned taste aversions was blocked by nonselective serotonin antagonists cyproheptadine, bromo-LSD, metergoline, methysergide and mianserin. Selective 5-HT_2B/2C antagonist SB206,553 blocked both MK212- and mCPP-induced conditioned taste aversion although selective 5-HT_2B/2C antagonist SB200,646 only blocked mCPP-induced conditioned taste aversion. In a single-bottle procedure, MK212, bromo-LSD, and mianserin failed to alter acquisition rate of a LiCl-induced conditioned taste aversion. Taken together, these data indicate that the serotonin agonists MK212 and mCPP produce conditioned taste aversion and that these effects are mediated predominantly through 5-HT_2C receptors.     

Attenuation and cross-attenuation in taste aversion learning in the rat: studies with ionizing radiation, lithium chloride and ethanol

The preexposure paradigm was utilized to evaluate the similarity of ionizing radiation, lithium chloride and ethanol as unconditioned stimuli for the acquisition of a conditioned taste aversion. Three unpaired preexposures to lithium chloride (3.0 mEq/kg, IP) blocked the acquisition of a taste aversion when a novel sucrose solution was paired with either the injection of the same dose of lithium chloride or exposure to ionizing radiation (100 rad). Similar pretreatment with radiation blocked the acquisition of a radiation-induced aversion, but had no effect on taste aversions produced by lithium chloride (3.0 or 1.5 mEq/kg). Preexposure to ethanol (4 g/kg, PO) disrupted the acquisition of an ethanol-induced taste aversion, but not radiation- or lithium chloride-induced aversions. In contrast, preexposure to either radiation or lithium chloride attenuated an ethanol-induced taste aversion in intact rats, but not in rats with lesions of the area postrema. The results are discussed in terms of relationships between these three unconditioned stimuli and in terms of implications of these results for understanding the nature of the proximal unconditioned stimulus in taste aversion learning.     

Peripheral receptors mediate the aversive conditioning effects of morphine in the rat

Previous evidence has shown that morphine produces positive reinforcing effects (as measured in the place conditioning paradigm) through an action in the central nervous system (CNS). The aversive conditioning effects of morphine (as measured in the place and taste conditioning paradigms) were produced when drug action was restricted to peripheral sites, particularly in the gut region. We now demonstrate that most of the aversive conditioning effects of morphine (using place and taste conditioning paradigms) are receptor mediated effects exerted through an action on peripheral opiate receptors. The conditioned taste aversions induced by intraperitoneal (IP) morphine (15 mg/kg) but not amphetamine (1 mg/kg) were attenuated by low IP doses of opiate antagonists (0.1 mg/kg of naltrexone or 1 mg/kg of the peripherally acting antagonist methynaltrexone (MN]. Morphine-, but not amphetamine-induced conditioned taste aversions were also attenuated in animals whose small sensory neurons, bearing the majority of primary afferent opiate receptors, were destroyed by neonatal treatments with capsaicin. In the place conditioning paradigm, the aversive conditioning effects produced by low IP administrations of morphine were blocked by opiate antagonists. Intraperitoneal pretreatments with 1 mg/kg of the quaternary opiate antagonist MN (which does not cross the blood-brain barrier effectively) were shown to block the conditioned place aversions produced by low IP doses of morphine (0.05 mg/kg), but not the place aversions produced by lithium chloride (75 mg/kg IP), or by high doses of naloxone (10 mg/kg SC). These results demonstrate that the aversive conditioning effects of morphine are primarily mediated through an action on peripheral opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Conditioned taste aversions induced by phencyclidine and other antagonists of N-methyl-D-aspartate

Taste aversions can be conditioned in rats by a variety of psychoactive drugs, including those with reinforcing properties. Previous research, however, has not established clearly whether phencyclidine and related drugs are active in such procedures. The present study was carried out to investigate whether phencyclidine would induce a conditioned taste aversion and whether several other compounds (MK-801, the stereoisomers of NANM and ifenprodil) which, like phencyclidine, are known to antagonise the actions of N-methyl-D-aspartate (NMDA), would produce similar effects. When rats received injections of these compounds, after consuming a novel solution of saccharin, their subsequent consumption of the same solution decreased. The smallest doses of the different drugs which induced clear taste aversions were: phencyclidine 3 mg/kg, MK-801 0.3 mg/kg, (+)-NANM 10 mg/kg, (-)-NANM 3 mg/kg and ifenprodil 10 mg/kg. Thus, all the drugs were active. However, as neither the potencies nor the efficacies of the different compounds in inducing taste aversions correlated with their other behavioural effects or with their relative potencies in antagonising the effects of NMDA or in displacing phencyclidine from its binding sites, the mechanisms involved are unclear.     

The effects of cocaine, alcohol and cocaine/alcohol combinations in conditioned taste aversion learning

We have recently reported that alcohol attenuates cocaine place preferences. Although the basis for this effect is unknown, alcohol may attenuate cocaine reward by potentiating its aversive effects. To examine this possibility, these experiments assessed the effects of alcohol on cocaine-induced taste aversions under conditions similar to those that resulted in attenuated place preferences. Specifically, Experiments 1 and 2 assessed the effects of alcohol (0.5 g/kg) on taste aversions induced by 20, 30 and 40 mg/kg cocaine. Experiment 3 examined the role of intertrial interval in the effects of alcohol (0.5 g/kg) on cocaine (30 mg/kg) taste aversions. In Experiments 1 and 2, cocaine was effective at conditioning aversions. Alcohol produced no measurable effect. Combining cocaine and alcohol produced no greater aversion than cocaine alone (and, in fact, weakened aversions at the lowest dose of cocaine). In Experiment 3, varying the intertrial interval from 3 days (as in the case of Experiments 1 and 2) to 1 day (a procedure identical to that in which alcohol attenuated cocaine place preferences) resulted in significant alcohol- and cocaine-induced taste aversions. Nonetheless, alcohol remained ineffective in potentiating cocaine aversions. Thus, under these conditions alcohol does not potentiate cocaine's aversiveness. These results were discussed in terms of their implication for the effects of alcohol on cocaine-induced place preferences. Further, the effects of alcohol on place preferences conditioned by cocaine were discussed in relation to other assessments of the effects of alcohol on the affective properties of cocaine and the implications of these interactions for alcohol and cocaine co-use.     

The effects of pimozide on the establishment of conditioned reinforcement as a function of the amount of conditioning

In an attempt to understand some inconsistent findings, the present experiment investigated the effects of pimozide, a dopamine (DA) receptor blocker, on the establishment of conditioned reinforcement as a function of the amount of conditioning. In Experiment 1, rats received three phases of training in a two-lever box. The pre-exposure phase measured the operant rates of pressing the levers; one produced a 3-s tone and the other turned the lights off for 3 s. In the conditioning phase, with the levers absent, the light-off stimulus was paired with food for two or four sessions. The test phase again measured the rate of pressing the levers. Conditioned reinforcement was shown by a relative increase in responding on the light lever during the test. Of the groups receiving four conditioning sessions, pimozide (0.5, 1.0, 2.0 and 4.0 mg/kg) produced a dose-dependent attenuation of conditioned reinforcement, those rats treated with 4.0 mg/kg failing to demonstrate a significant effect. When 2 conditioning days were employed, pimozide treatment also produced a dose-dependent attenuation; however, in these less conditioned animals 2.0 mg/kg blocked the effect. The possibility that pimozide produced a conditioned taste aversion to the food was ruled out in Experiment 2. These data suggest that DA transmission may be necessary for the establishment of conditioned reinforcement and that the effects of receptor blockade may be related to the amount of conditioning.     

Effect of body weight on ethanol-induced taste aversion learning

Saccharin aversions were conditioned using ethanol (EtOH) in rats of different body weights. There was a nonuniform relation between EtOH dose (g/kg) and strength of conditioned taste aversion. Heavier rats learned stronger aversions at the same dose, and a weak dose (i.e., 1.0 g/kg) was effective only in heavier rats. It is suggested that rats be equated on body weight in studies of EtOH-induced taste aversion learning and in studies of EtOH preference.     

Behavioral assessment of the toxicity of aspartame

Six experiments with rats assessed the toxicity of aspartame with behavioral measures. The first three experiments used a conditioned taste aversion procedure since taste aversions are typically observed after a taste is followed by a toxin. Thirty min after thirsty rats drank a sweet solution they were intraperitoneally injected (Experiment 1) or intragastrically intubated (Experiment 2) with saline or 176, 352, or 704 mg/kg of aspartame. Relative to rats given saline, rats injected with 704 and 352 mg/kg aspartame showed strong and mild aversions, respectively. Rats injected with 176 mg/kg of aspartame or intubated with any dose of aspartame did not show taste aversions. In Experiment 3, rats voluntarily consumed an aspartame solution sweetened with saccharin for 7 hr each day. Consumption of the taste paired with aspartame was not reduced. When 352 mg/kg aspartame was injected (Experiment 4), but not when intubated (Experiment 5), 5 min prior to access to a running wheel, running was reduced. Wheel running was not affected by the voluntary consumption of aspartame (Experiment 6). The route of administration effect (intraperitoneal vs. intragastric) on behavior corresponded with the amino acid levels in blood plasma (Experiment 7). Aspartate, phenylalanine, tyrosine and glutamate levels increased more after the injection, than the intubation, of aspartame (176 mg/kg). Overall, the results suggest that aspartame may have adverse effects when intraperitoneally injected but not when the route of administration is oral.     

Aversive conditioning properties of caffeine in rats

Four experiments tested the conditioning effects of caffeine. Flavor and place cues were paired with IP caffeine injections and followed by tests for cue preference. In Experiment 1A, saccharin was paired with 1.25, 5 or 20 mg/kg of caffeine. In Experiment 1B, caffeine was delivered 30 min before, 5 min before, or 30 min after saccharin. Dose- and time-dependent conditioned taste aversions were produced. In Experiment 2, a place and taste cue were paired simultaneously with 5 or 20 mg/kg of caffeine. Conditioned place and taste aversions developed at 20, but not at 5 mg/kg. In Experiment 3, a place cue alone was paired with 0, 5, or 20 mg/kg of caffeine; dose-dependent conditioned place aversions developed. In Experiment 4, place and taste cues were paired with control treatments: pH-buffered caffeine, purine or vehicle. Caffeine produced taste aversions whereas the purine and vehicle did not. These aversive conditioning effects of caffeine across a variety of situations, doses and temporal arrangements stand in contrast to results obtained with other psychoactive drugs, such as amphetamine and alcohol.     

Amphetamine-induced hypodipsia and its implications for conditioned taste aversion in rats

According to the conditioned anorexia hypothesis, conditioned taste aversions occur when flavour stimuli are classically conditioned to the anorexigenic or hypodipsic effects of drugs. The effects on water intake of a range of doses of amphetamine and of several related compounds have therefore been examined in an attempt to correlate their known potentices in tate aversion experiments with their hypodipsic potencies (+)-Amphetamine was more potent than (-)-amphetamine in suppressing water intake but under similar experimental conditions, the isomers were equipotent in the conditioning of taste aversions. Methamphetamine and p-chloromethamphetamine were equipotent in suppressing water intake, but the latter was a more potent agent for conditioning taste aversions. Furthermore, fenfluramine produced taste aversions at doses well below those which suppressed water intake. It was concluded that the ability of the drugs to induce taste aversion was not related to their unconditioned, hypodipsic effects. However, it was confirmed that when drugs with different durations of action are compared for anorexic or hypodipsic potency, the outcome can be greatly influenced by the time over which measurements are made.     

Characteristics of conditioned taste aversion produced by nicotine in rats.

1 Nicotine produced conditioned taste aversions in rats which were directly related to the dose of nicotine and to the number of conditioning trials. 2 The tobacco alkaloid (-)-nicotine was four to five times as potent as its stereoisomer, (+)-nicotine. 3 Mecamylamine but not hexamethonium blocked the development of taste aversions produced by nicotine. 4 Mecamylamine did not block the development of taste aversions produced by apomorphine. 5 Prolonged treatment with mecamylamine prior to conditioning did not produce supersensitivity to nicotine.     

Genetic differences in naloxone enhancement of ethanol-induced conditioned taste aversion

The influence of the opioid system on acquisition of an ethanol-induced conditioned taste aversion was examined in alcohol-preferring and avoiding inbred strains of mice (C57BL/6J and DBA/2J). Fluid-deprived mice from each strain received either ethanol alone, naloxone alone, or both ethanol and naloxone immediately after access to a novel tasting fluid. Naloxone alone (1 or 3 mg/kg) did not induce a conditioned taste aversion in either strain of mice. Administration of ethanol (1.5 g/kg) to DBA/2J mice produced a moderate taste aversion that was not affected by co-administration of naloxone. Although ethanol administered alone (3 g/kg) did not cause a taste aversion in C57BL/6J mice, the combination of ethanol and the higher dose of naloxone produced a significant taste aversion that increased across trials. A second experiment addressed the possibility that naloxone failed to enhance the ethanol-induced condition taste aversion in DBA/2J mice due to a floor effect on consumption. A lower ethanol dose (1 g/kg) was given alone or in combination with naloxone (1 or 3 mg/kg). Again, ethanol produced a moderate conditioned taste aversion that was not potentiated by naloxone. Subsequent conditioning with a high ethanol dose produced further suppression of intake, confirming that naloxone's failure to enhance aversion on earlier trials was not due to a floor effect. These data demonstrate a strain specific interaction between the aversive effect of ethanol and naloxone. More specifically, the results indicate that blockade of opioid receptors enhances the aversive effect of ethanol in C57BL/6J but not DBA/2J mice, suggesting that genetically determined differences in the endogenous opioid system of alcohol-preferring mice may mitigate ethanol's aversive effect.     

Asymmetric serial interactions between ethanol and cocaine in taste aversion learning

Although the interaction between ethanol and cocaine is well documented, it has generally been limited to situations in which the two drugs are given concurrently. Little exists on the interaction between ethanol and cocaine when one drug is given prior to the other. In Experiment 1, female Long-Evans rats were given five exposures to ethanol (2 g/kg ip) or vehicle prior to taste aversion conditioning with cocaine (32 mg/kg sc) for a total of five conditioning trials. In Experiment 2, rats were given five exposures to cocaine (32 mg/kg sc) or vehicle prior to taste aversion conditioning with ethanol (2 g/kg ip) for a total of five conditioning trials. Ethanol-preexposed, cocaine-conditioned animals (Experiment 1) displayed attenuated aversions to the cocaine-associated solution, drinking significantly greater amounts of saccharin than vehicle-preexposed, conditioned subjects. Conversely, cocaine-preexposed, ethanol-conditioned animals (Experiment 2) displayed robust aversions to the ethanol-associated solution, drinking levels comparable to those consumed by vehicle-preexposed, conditioned subjects and drinking significantly less than controls. Although the basis for these asymmetric effects is not known, they may have implications for abuse vulnerability in that drug history may impact subsequent drug toxicity that, in turn, may alter drug acceptability.