Acetaldehyde may mediate reinforcement and aversion produced by ethanol. An examination using a conditioned taste-aversion paradigm

Groups of water-deprived rats were exposed to acetaldehyde, ethanol or vehicle control. On the conditioning day, the animals were first presented with a solution of saccharin after which the animals that were exposed to acetaldehyde received ethanol and those exposed to ethanol received acetaldehyde. Saccharin was again presented on three more occasions (testing days) without injection of drug. Using the percentage change in saccharin consumed from the first presentation as a measure of aversion, it was found that exposure to acetaldehyde blocked the taste aversion conditioned by ethanol. Animals exposed to ethanol showed no aversion to the saccharin which was paired with a small dose of acetaldehyde, indicating a symmetrical relationship between ethanol and acetaldehyde at this dose. However, exposure with ethanol did not block the aversion produced by conditioning with larger doses of acetaldehyde. These results suggest that the mechanism underlying the smaller dose of the taste aversion conditioned with acetaldehyde may be central while the mechanism underlying the larger dose is probably peripheral.     

Nicotine-induced conditioned taste aversion in the rat: effects of ethanol

It has been shown that small doses of ethanol antagonise the discriminative stimulus properties of nicotine in the rat. The aim of the present study was to evaluate whether ethanol could antagonise the aversive stimulus effects of nicotine. Wistar rats were trained to associate nicotine injections with a novel tasting fluid (0.1% saccharin) in the conditioned taste aversion procedure. Nicotine (0.3 mg/kg, s.c.) was injected 5 min after the end of a 20-min exposure to the saccharin solution. Ethanol (0.25-0.5 g/kg, i.p.) was administered 5 or 50 min before nicotine. In general, ethanol did not inhibit nicotine-induced conditioned taste aversion. Contrary to the findings in drug discrimination studies, a slight but significant enhancement of nicotine-induced taste aversion conditioning was observed after ethanol pre-treatment. Blood ethanol levels were measured in a separate group of rats. Maximal blood ethanol levels after i.p. administration of 0.25 or 0.5 g/kg ethanol exceeded 20 and 80 mg%, respectively. Concluding, the present results may indicate that ethanol does not attenuate nicotine-induced conditioned taste aversion in the rat.     

The effects of Ro 15-4513 on ethanol-induced taste aversions

Ro 15-4513 is an imidazobenzodiazepine that has been reported to block a range of behavioral effects of ethanol. In the present experiments, the effects of Ro 15-4513 were assessed on the acquisition of an ethanol-induced conditioned taste aversion. Specifically, rats were given a novel saccharin solution to drink followed by an injection of one of a range of doses of Ro 15-4513 (0.5 and 1.0 mg/kg, Experiment 1A, and 2.0 and 3.0 mg/kg, Experiment 1B) and an injection of ethanol (1.75 g/kg). Ro 15-4513 failed to block the acquisition of the ethanol-induced taste aversion. Possible reasons for this failure were discussed.     

Differences in response to the aversive properties of ethanol in rats selectively bred for oral ethanol preference

A conditioned taste aversion (CTA) paradigm was used to determine whether aversion to the pharmacological effects of ethanol, apart from orosensory cues, can contribute to genetic differences in voluntary ethanol consumption. Four doses of ethanol, administered IP, were paired with the consumption of a 0.1% saccharin solution in rats from the alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Repeated pairing of saccharin and ethanol in a dose of 1.0 g/kg produced stronger and more prolonged aversion to saccharin in NP rats, compared with P rats, at comparable blood ethanol levels. A low dose of ethanol (0.25 g/kg) produced transient conditioned facilitation of saccharin consumption in P rats, but not in NP rats, at comparable blood ethanol levels. The results suggest that rats of the NP line find the postingestional effects of high-dose ethanol more aversive, and low-dose ethanol less reinforcing, than do rats of the P line. Genetic differences in voluntary ethanol consumption may be due, in part, to differences in aversion to the postingestional effects of ethanol.     

Motivational properties of ethanol in mice selectively bred for ethanol-induced locomotor differences

Ethanol-induced locomotor stimulation has been proposed to be positively correlated with the rewarding effects of ethanol (Wise and Bozarth 1987). The present experiments provided a test of this hypothesis using a genetic model. Three behavioral indices of the motivational effects of ethanol (drinking, taste conditioning, place conditioning) were examined in mice from two independent FAST lines, selectively bred for sensitivity to ethanol-induced locomotor stimulation, and mice from two independent SLOW lines, selectively bred for insensitivity to ethanol-induced locomotor stimulation. In a single-bottle procedure, mice were allowed access to drinking tubes containing ethanol in a concentration (1–12% v/v) that increased over 24 consecutive days. FAST mice consumed greater amounts of ethanol solution. In a two-bottle procedure, mice were allowed access to tubes containing water or various concentrations of ethanol (2–8% v/v) over 6 days. FAST mice generally showed greater preference for ethanol solutions than SLOW mice. In a conditioned taste aversion procedure, mice received access to saccharin solution followed by injection of 2.5 g/kg ethanol (IP). SLOW mice developed aversion to the saccharin flavor more readily than FAST mice. In a series of place conditioning experiments, tactile stimuli were paired with various doses of ethanol (0.8–2.0 g/kg). During conditioning, FAST mice showed locomotor stimulation after 1.0, 1.2 and 2.0 g/kg ethanol while SLOW mice did not. During testing, mice conditioned with 1.2 g/kg and 2.0 g/kg ethanol showed conditioned place preference, but there were no line differences in magnitude of preference. These results indicate that genetic selection for sensitivity to ethanol-stimulated activity has resulted in genetic differences in ethanol drinking and ethanol-induced conditioned taste aversion but not ethanol-induced conditioned place preference. Overall, these data provide mixed support for the psychomotor stimulant theory of addiction.     

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.     

Role of acetaldehyde in ethanol-induced conditioned taste aversion in rats

Rationale. In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives. The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. Methods. A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. Results. Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. Conclusions. The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA. Electronic Publication     

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.     

Effects of plant ingestion in rats determined by the conditioned taste aversion procedure

The conditioned taste aversion procedure was used to compare the aversive effects produced by 40 plants (mostly common household varieties) to those of amphetamine, lithium chloride and ethyl alcohol. Test substances (plant homogenates or drug solutions) were given to rats by force-feeding 5 min after the subjects' first exposure to 0·1% saccharin solution, which was available for 15 min from a water bottle. The comparison of the consumption of saccharin solution, two days after test substance administration, to the initial saccharin consumption was taken as a measure of the aversive effects produced by the test substance, e.g. greater suppression of saccharin intake indicating greater aversive properties. Dose dependent suppression of saccharin intake was obtained with most of the substances tested at more than one concentration. Administration of Pokeberry seeds, Japanese Yew, Norfolk Island Pine and Oleander leaves suppressed saccharin intake more than ethyl alcohol. The rest of the plants tested produced less conditioned aversion than ethyl alcohol. Some plants which are frequently called poisonous (Poinsettia, Philodendron and Dieffenbachia) were not particuarly effective in producing conditioned taste aversion. Good correlation existed between suppression of saccharin intake produced by the three drugs tested and their approximate acute lethal doses in rats and humans, suggesting that the conditioned taste aversion procedure may indicate the approximate acute lethality of these substances. Good correlation was also found between the dry weight of the plants and the suppression of saccharin intake.     

The attenuation of a specific cue-to-consequence association by antiemetic agents

Previous research has shown that rats develop a conditioned taste aversion after a single pairing of a distinct taste and subsequent toxicosis. The experiments reported here test the hypothesis that the expression of a taste aversion may reflect classically conditioned nausea mediated by activation of brainstem emetic centers by taste stimuli. Rats were allowed to drink a saccharin solution (1 g/l) and 10 min later were intubated with LiCl (180 mg/kg) to produce nausea. When control rats were posttested for saccharin preference they consumed less than 50% of their pretest intake. Experimental rats were injected with one of four pharmacologically distinct antiemetic drugs 30 min prior to their posttest with saccharin. Each drug significantly attenuated the aversion to saccharin at one dose level. The antiemetic drugs we used were scopolamine HBr, cyclizine, prochlorperazine dimaleate, and trimethobenzamide. These drugs had no effect on the conditioned fear of a noise that signaled foot shock or on a natural aversion to a bitter fluid (quinine monohydrochloride, 100 mg/l). Our data suggest that pharmacological suppression of the neural mechanisms of emesis selectively disrupts conditioned taste aversions, and that moderate dose levels are critical for obtaining this effect.     

Differential aversive stimulus properties of β-phenylethylamine and of d-amphetamine

In a conditioned taste-aversion experiment with male Wistar rats (two-bottle test, single pairing), the effects of -phenylethylamine (PEA 12.5, 25.0, 50.0, 100.0 mg/kg IP) and of d-amphetamine (2.5 mg/kg IP) were compared with the effect of the saline vehicle. The amphetamine-treated group exhibited a marked aversion to saccharin on each of four retention trials. A decrease in saccharin intake after PEA was limited to the highest dose group (100 mg/kg) and the first retention trial for that group. Doses of up to 50 mg/kg of PEA were also ineffective with a single-bottle conditioned taste-aversion procedure involving multiple conditioning trials, although doses of 25 and 50 mg/kg of PEA induced marked changes in spontaneous motor activity. These data demonstrate that behaviourally active doses of PEA are ineffective in inducing a conditioned taste aversion to saccharin. This result extends previous reports that structurally similar compounds may have different potencies in this paradigm. It is proposed that further studies of structureactivity relationships may help to reveal the features of drug action that are necessary for the induction of a conditioned taste aversion.     

Conditioned taste aversion induced by inhalation exposure to methyl bromide in rats

The toxic effect of methyl bromide vapor was assessed by a conditioned taste aversion regime. Rats kept under a water deprivation schedule for 7 days, were permitted access to 0.3% (w/v) sodium saccharin, and were exposed to methyl bromide at 0, 25, 50, and 100 ppm for 4 h. 3 days after the exposure, saccharin preference tests were carried out, revealing dose-dependent saccharin aversion in the exposure group. This result suggests that the conditioned taste aversion method is effective for assessing the toxicity of gaseous substances such as methyl bromide.     

Effects of prenatal ethanol exposure and postnatal handling on conditioned taste aversion

Studies have shown that animals prenatally exposed to ethanol (E) exhibit deficits in conditioned taste aversion as well as displaying hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness during exposure to stressors. In contrast, postnatal handling has been shown to attenuate both emotional and HPA reactivity under certain conditions. The present study tested the hypothesis that handling could attenuate adverse effects of prenatal ethanol exposure on consummatory behavior and HPA activity in a conditioned taste aversion task. We found that both prenatal ethanol exposure and handling independently increased saccharin consumption over 5 days of pretoxicosis exposure, suggesting that neophobia decreased at a faster rate in these animals. When conditioned aversion was assessed in handled animals under nondeprived conditions, E animals showed increased consumption compared to controls. Furthermore, across prenatal groups, lower corticosterone (CORT) levels were found in handled compared to nonhandled animals during reexposure under food-deprived conditions, emphasizing the importance of assessing both behavior and HPA function when examining an animal's response to a task and indicating that handling may not be effective at attenuating some deficits in E animals.     

Non-specific enhancement of ethanol-induced taste aversion by naloxone

The conditioned taste aversion paradigm (CTA) was used to examine the effects of naloxone on ethanol-induced aversion towards a saccharine solution (3 conditioning and 11 extinction trials). Six groups of rats received conditioning trials consisting of two IP injections after saccharine presentation of different combinations of either ethanol (E: 1.75 g/kg), LiCl (L: 12 mEq/kg, 0.1 M), naloxone (N: 10 mg/kg) or saline (S); S-S, S-N, E-S, E-N, L-S and L-N. Naloxone by itself produced no aversion to the saccharin flavor. Based on the onset and extinction of aversion, naloxone significantly enhanced ethanol but also LiCl-induced CTA. The comparative data argues in favor of different mechanisms of action (1) between the aversive central effects of ethanol and morphine and (2) between ethanol's acute behavioral effects and negatively reinforcing properties. Enhancement of ethanol and LiCl-induced CTA by naloxone is compatible with hypernociceptive action of the opiate-antagonist and with the pain-modulating role of opiates in the CNS.     

Does hypothermia play a relevant role in the glycemic alterations induced by ethanol?

The potential role of ethanol-induced hypothermia on the glycemic alterations induced by this drug were evaluated. In Experiment 1 ambient temperature was manipulated. After 4.0 g/kg of ethanol blood glucose levels and body temperatue were assessed in fed or 48 hr starved rats at either 21°C or 28°C room temperature. Hyper or hypoglycemia was observed depending on both the feeding condition and the environmental temperature. In Experiment 2, this hypothesis was tested by determining if rats tolerant to the thermic effects of ethanol would show a decreased glycemic response. The results support this assumption.     

Ethanol-induced hypothermia and biogenic amine metabolites

Ethanol is known to cause hypothermia. The rectal temperature of rats receiving ethanol, 4 g/kg i.p., at an ambient temperature of 23 degrees C decreased by 2 degrees C. This body temperature decrease could be prevented by keeping the animals at an ambient temperature of 34 degrees C. Irrespective of the body temperature it was found that the concentration of the major metabolites of dopamine and serotonin in brain tissue was significantly increased. Thus, the change in brain monoamine metabolite levels in rats after administration of ethanol are not due to ethanol-induced hypothermia.     

Effects of concentration of ethanol injected intraperitoneally on taste aversion,body temperature,and activity

Levels of ethanol-induced conditioned taste aversion and hypothermia were found to be directly related to the concentration of fixed amounts of ethanol injected i.p. in a range of doses (1.0–1.8 g/kg) and concentrations (8–32% v/v) commonly used in behavioral studies. No effect of ethanol concentration on locomotor activity was obtained. The results of blood-ethanol determinations indicate that a given dose of ethanol is absorbed more rapidly, and thus reaches greater peak levels, when injected in a higher concentration. Thus ethanol dosage might be better manipulated by varying the volume of a single concentration rather than by altering concentration. In this way, dose-response data will not be obscured by concentration-induced differences in absorption.     

Amphetamine-induced taste aversion: a comparison of d- versus l-amphetamine

A comparison of the effects in rats of four dose levels of d- and 1-amphetamine (0.5, 1.0, 2.0 and 4.0 mg/kg) on development of a taste aversion to a 0.1% saccharin solution showed that d-amphetamine was approximately 4 times as potent as 1-amphetamine in inducing a taste aversion to saccharin. The aversion was obtained in both forced- and free-choice tests. A 2–4 fold differential in efficacy was found when the same dose levels of both amphetamine isomers were tested for their effects in reducing water intake. The approximately 4-fold greater effectiveness of the d-isomer suggested that the taste aversion may be mediated by a dopaminergic system. In addition, it was suggested that the taste aversion behavior represented a conditioned anorexic effect rather than being indicative of a noxious or aversive consequence of the amphetamine.     

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.     

Morphine conditioned taste aversion revered by periaqueductal gray lesions

The role of the periaqueductal gray (PAG) in morphine conditioned taste aversion (CTA) was studied using male Wistar rats as subjects. Following the presentattion of a novel saccharin solution, animals with or without a lesion of the PAG were intraperitoneally injected with either morphine, lithium, ethanol or fenfluramine. As evident by the amount of saccharin of saccharin solution consumed on a subsequent presentation, a PAG lesion reversed a morphine CTA but not CTAs produced by the other drugs used. The results suggest that the PAG may in part mediate morphine CTA.