Chronic alcohol consumption in alcohol-preferring P rats attenuates subsequent conditioned taste aversion produced by ethanol injections

Rats of the P line were tested for the development of tolerance to the aversive effects of ethanol during 33 days of continuous availability of food, water and a 10% (v/v) ethanol solution. Beginning on the day following the removal of ethanol, five daily conditioned taste aversion (CTA) trials were administered to the ethanol-drinking P rats and an ethanol-naive control group. The CTA trials consisted of a 20-min access to a Polycose solution, followed by IP injection of saline, 0.5, 1.0, or 1.5 g ethanol/kg. The ethanol-drinking rats developed a preference for the Polycose solution when it was paired with 0.5 g ethanol injections, but the control rats did not. Both control and ethanol groups had similar CTAs at the 1.5 g dose. However, at the 1.0 g dose, the ethanol group had an attenuated CTA compared with the water control group. The results suggest that P rats develop tolerance to aversive effects of ethanol during chronic drinking. This tolerance could contribute to the high ethanol intake in these selectively-bred rats.     

Metrazol produces conditioned taste aversion in rats

Employing a two bottle drinking procedure where an animal's preference is measured between plain water and a novel fluid, it was found that the convulsant drug Metrazol produced a conditioned taste aversion to saccharin. This finding is contrary to that of previous reports and highlights the sensitivity of the two bottle method in detecting a taste aversion.     

D-Cycloserine enhances conditioned taste aversion learning in rats

Conditioned taste aversion (CTA) is a form of associative learning in which the pairing of a taste with a toxin causes an animal to avoid the taste. NMDA receptor mediated neurotransmission has been implicated in CTA, but the role of the NMDA receptor glycine-binding site has not been examined. To examine the effects on CTA of the glycinergic NMDA receptor agonist D-cycloserine, rats received D-cycloserine (15 mg/kg, i.p.) or vehicle 15 min before 10-min access to 0.125% saccharin, followed by a low dose of LiCl (19 mg/kg, i.p.). CTA was measured with 24-h, 2-bottle preference tests between water and saccharin. Vehicle-treated rats formed a mild CTA that rapidly extinguished, while d-cycloserine-treated rats formed a stronger CTA that extinguished slowly. The effect of d-cycloserine was specific to the NMDA receptor glycine-binding site, because pretreatment with HA-966 (6 mg/kg), a partial glycinergic agonist, blocked enhancement by D-cycloserine. Three follow-up experiments suggest that the enhancement of CTA was not due to an aversive effect of D-cycloserine. First, saccharin paired with D-cycloserine (15 mg/kg) alone did not induce a CTA, although a higher dose (30 mg/kg) did significantly lower saccharin preference. Second, pretreatment with D-cycloserine did not increase the duration of "lying-on-belly" behavior induced by LiCl. Third, pretreatment with D-cycloserine did not increase c-Fos induction by either LiCl or vehicle injection in central visceral relays (the nucleus of the solitary tract, the parabrachial nucleus, the central nucleus of the amygdala, the supraoptic nucleus, and the paraventricular nucleus). These results confirm the participation of NMDA receptor, and specifically the glycine-binding site of NMDA receptor, in CTA learning.     

5-Hydroxytryptophan-induced conditioned taste aversion to ethanol in the rat

This experiment was conducted to determine the efficacy of 5-HTP in producing conditioned taste aversions (CTAs) to ethanol in rats restricted to a one-hour daily access to fluid. Administration of 100 mg/kg of DL-5-HTP immediately following novel exposure to ethanol resulted in an aversion of such magnitude that some rats refused to consume the ethanol solution. Since ethanol was the only fluid available to these rats, they eventually died, presumably of dehydration. By comparison, LiCl administration also produced a CTA to ethanol, but no such persistent rejection was observed. Both 5-HTP and LiCl also produced CTAs when saccharin and tartaric acid solutions were used as novel fluids, but these aversions were short-lived and all rats resumed drinking. The causative factor(s) in the persistent ethanol rejection until death observed in rats treated with 5-HTP remain undetermined but the results have indicated that simple CS-UCS associative learning mechanisms are probably not a primary causative factor.     

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.     

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.     

Effect of taste aversion learning on ethanol self-administration

Ethanol (EtOH) oral self-administration studies using rats have had inconsistent outcomes: studies in which rats are fluid deprived report decreasing EtOH intake over trials, whereas studies not employing fluid deprivation report increasing intake over trials. The present study supports the hypothesis that differential taste aversion learning may account for some of this discrepancy. This study indicates that taste aversion learning is maximized under fluid deprivation conditions and that "latent inhibition," i.e., exposure to non-intoxicating amounts of the EtOH solution prior to conditioning, reduces taste aversion learning. It is suggested that the effect of fluid deprivation on taste aversion resulting from EtOH self-administration may be at least in part due to the development of latent inhibition in non-deprived animals during initial exposure to the EtOH solution.     

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     

Buspirone antagonizes the expression of conditioned taste aversion in rats

When the parameters of taste aversion conditioning and testing have been appropriately adjusted, benzodiazepines and barbiturates will markedly antagonize the expression of moderate taste aversions in rats. We call this the taste aversion conflict model of anxiety. In the present study, we investigate whether buspirone HCl (buspirone; p.o. and i.p.) is active in the taste aversion conflict model and whether buspirone will also increase unsuppressed saccharin (SACC) intake. We also investigated the effects of imipramine, desipramine, phenelzine sulfate, chlorpromazine, scopolamine and d-amphetamine sulfate in the taste aversion conflict model. To assess the possible effects of buspirone on the GABA-benzodiazepine supramolecular receptor complex, we compared buspirone with certain benzodiazepines, meprobamate and sodium phenobarbital on the antagonism of pentylenetetrazol-induced lethality in mice. Unlike benzodiazepines, meprobamate and phenobarbital, buspirone did not antagonize pentylenetetrazol-induced lethality. However, like those other anxiolytics, buspirone markedly antagonized the expression of conditioned taste aversion. All nonanxiolytic drugs tested had either no effect or very slight effects on the expression of conditioned taste aversion. These results suggest that the taste aversion conflict model is sensitive to novel anxiolytics and that it is selective for drugs clinically effective in the treatment of generalized anxiety disorders in man.     

Effect of ethanol on brain neuropeptides in adolescent and adult rats

OBJECTIVE: Alcohol misuse early in life is associated with an increased risk of alcoholism. It is possible that this increased risk in adolescent drinkers is in part related to the susceptibility of the adolescent brain to ethanol. This study assessed the effects of ethanol exposure on several neuropeptides to begin to elucidate potential substrates that could mediate the differential effects of ethanol on adolescent and adult rats. METHOD: Male Sprague Dawley rats were exposed to ethanol vapor or air during adolescence (30 days old, n = 9, controls = 8) or adulthood (80-90 days old, n = 9, controls = 8) for 10 days. Blood alcohol concentrations averaging 250 mg/dl were maintained during this period. After 7 weeks of cessation from ethanol vapor, brain tissue was collected from the frontal cortex, caudate, hippocampus, amygdala and hypothalamus to assess the immunoreactivity levels of neuropeptide Y (NPY-LI), corticotropin-releasing hormone, substance P (SP-LI) and neurokinins (NK-LI). RESULTS: Ethanol exposure decreased overall hippocampal NPY-LI and increased SP-LI and NK-LI in the caudate, but these effects were more prominent in adult rats. Rats in the adult treatment groups (both ethanol exposed and controls) also had significantly lower levels of frontal cortical NK-LI, frontal cortical SP-LI and hypothalamic SP-LI relative to rats in the adolescent treatment groups. CONCLUSIONS: These data indicate that brief exposure to alcohol has long-term effects on levels of NPY-LI, SP-LI and NK-LI. As these effects were primarily the result of changes in rats exposed to ethanol during adulthood, however, they are unlikely to contribute to the increased susceptibility of adolescents to the effects of chronic ethanol exposure.     

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.     

Effects of atropine on conditioned taste aversion

Atropine sulfate, which has a deleterious effect on various learning tasks, was found to have a similar effect on the acquisition of conditioned taste aversion. Thus, intraperitoneal injection of atropine sulfate shortly before tasting was found to interfere with conditioning of the aversion, but injection of atropine after tasting did not. The interference effect was also obtained with intraventricular administration of atropine sulfate, but not with intraperitoneal injection of the peripherally-acting atropine methylnitrate. These results show that central rather than peripheral mechanisms are involved in this effect, and suggest that conditioned taste aversion, like other kinds of learning, involves cholinergic mediation.     

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.     

Attenuation by alpha-methyltyrosine of amphetamine induced conditioned taste aversion in rats

Pretreatment with alpha-methyl-p-tyrosine (AMPT) was found to block a conditioned taste aversion (C.T.A.) induced by injection of d-amphetamine sulphate (2.0 mg/kg per kg, i.p.) immediately after first access to 0.1% sodium saccharin. This finding implicates catecholaminergic systems in the induction of C.T.As by amphetamine, and suggests that the aversive properties of the drug are mediated by neurochemical systems which are similar to, or the same as, those which mediate the stimulant, anorectic and rewarding effects of the drug. The results refute a recent suggestion that the use of AMPT in the study of neurochemical mechanisms involved in drug induced taste aversions is precluded by the ability of AMPT itself to induce a C.T.A.; and illustrate an important distinction between pretreatment and post-treatment in taste aversion studies. The results provide further support for recent suggestions that the study of drug induced C.T.As may be of significance for an understanding of drug abuse.     

Pre-exposure to morphine and the attenuation of conditioned taste aversion in rats

Three experiments were done using male Wistar rats to determine whether the mechanisms underlying the attenuation of a conditioned taste aversion to morphine by pre-exposure to the drug were similar to those involved in the development of tolerance to the analgesic response to morphine. This was tested by determining whether the effect of pre-exposure on conditioned taste aversion was situation-specific. In Experiment 1 it was found that having different environments for the pre-exposure injections and for the conditioning injections of morphine had no effect on the attenuation of the taste aversion. This finding was replicated in Experiment 2 in which it was also found that the attenuation of the analgesic effect, tested for in the same animals, was specific to the environment in which repeated injections were given. It was concluded that the attenuation of conditioned taste aversion involved processes different from those responsible for the attenuation of the analgesic effect morphine. Experiment 3 showed that pairing the pre-exposure injections of morphine with one distinctive taste stimulus prevented the attenuation of the conditioned taste aversion to a second taste stimulus. These results suggest that different associative processes are responsible for the two types of attenuation.     

HPLC-purified human satietin does not produce conditioned taste aversion in rats

Human satietin is thought to be an endogenous glycoprotein that can suppress food intake and body weight. However, it was also found to be aversive when rats infused intracerebroventricularly (ICV) with human satietin were subjected to a two-bottle taste aversion test. More recently, the human satietin previously thought homogenous was separated by HPLC into two Peaks, denoted as A and B. In the present study, male Sprague-Dawley rats were fitted with chronic third ventricle cannulas and presented with fluid for 1 h/day, while food was given ad lib. After training, the rats were ICV infused with either artificial cerebrospinal fluid, Peak A or Peak B of human satietin. Peak B significantly reduced short-term and 24-h food intake, whereas their fluid intake was nonsignificantly attenuated. Peak A had no affect on either food or fluid intake on the day it was administered. When the rats were given the two-bottle taste aversion test neither compound was found to be aversive. These data suggest that Peak B may contain satietin(s) which could be a candidate for an endogenous satiety agent.     

Effects of ephedrine enantiomers on conditioned taste aversion and kaolin intake in rats.

The ephedrine (EPH) enantiomers, (-)-EPH and (+)-EPH, have different biological activity in the rat, with the (-)-EPH enantiomer exerting a greater impact on suppression of feeding, induction of locomotion, and activation of brown adipose tissue thermogenesis. Recent studies document that (-)-EPH treatment produces an alteration of extracellular dopamine in the brain, an effect that is consistent with the locomotor-stimulating and reinforcing effects of this drug. Whether the EPH enantiomers exert aversive actions in the rat is unknown. Experiment 1 examined the impact of systemically administered (+)-EPH (0, 5, 10, or 20 mg/kg) or (-)-EPH (0, 5, 10, or 20 mg/kg) on conditioned taste aversion (CTA) in adult male rats relative to the effect of 32 mg/kg lithium chloride (LiCl). No dose of either enantiomer produced CTA, whereas strong CTA was evident for LiCl. In Experiment 2, consumption of kaolin (a nonnutritive clay) over a 24-h period was used to assess drug toxicity. Rats treated with either 0, 5, 10, 20, or 40 mg/kg (+)-EPH or 0, 5, 10, 20, or 40 mg/kg (-)-EPH did not exhibit alteration of kaolin intake. In contrast, systematic increases in kaolin intake were observed in rats after systemic administration of LiCl (0, 16, 32, 64, and 96 mg/kg). These findings suggest that the enantiomers of EPH do not exert aversive effects at behaviorally relevant doses.     

Alcohol-induced conditioned taste aversion in rats. Effect of concentration and prior exposure to alcohol.

The effects of prior opportunities to drink alcohol solutions on the subsequent production of conditioned taste aversion by the oral ingestion of alcohol were evaluated. The consumption of 5 and 7% alcohol solutions produced conditioned aversion; the consumption of 3% alcohol solution did not result in aversion. Prior exposure to alcohol did not alter the extent of the aversion.     

Central mediation of the conditioned taste aversion induced in rats by harmaline

The assumption that drugs used as unconditioned stimuli in conditioned taste aversion (CTA) studies act centrally was tested by comparing the effects of systemic and intracerebral injections of harmaline hydrochloride (H) in 340 rats. Intraperitoneal injection of 5–20 mg/kg but not of 2.5 mg/kg H administered 5 min after 15-min saccharin (0.1%) drinking decreased saccharin-water preference in a two-choice retention test, performed 48 h later, from 55% to 20%. Since CTA was not diminished when H (10 mg/kg) was injected into rats anesthetised immediately after saccharin drinking by pentobarbital (40 mg/kg), H (1.7–50 g) was administered intracerebrally to anesthetised rats fixed in the stereotaxic apparatus. Injection of 3–6 g H into the inferior olive elicited CTA comparable to that of systemic injection of 10 mg/kg H. Injections of 6 and 50 g H into cerebellum and bulbar reticular formation elicited weaker CTA while neocortical, hypothalamic and mesencephalic applications were ineffective. CTA could also be elicited when 50 g but not 6 g H was injected into the inferior olive 1 or 2 h after saccharin drinking. This delay-dependent effect and failure of non-contingent H administration to change saccharin preference indicates that the H-induced CTA is not contaminated by a non-specific increase in neophobia. It is concluded that H probably elicits CTA by activation of caudal bulbar structures, including the nucleus of the solitary tract, area postrema and lateral reticular formation.