Do taste factors contribute to the mediation of ethanol intake? Ethanol and saccharin-quinine intake in three rat strains

Several recent studies have suggested that ethanol-preferring rodents may also have an affinity for sweet solutions (saccharin, sucrose) and, conversely, that saccharin preference may predict ethanol preference. The purpose of the present investigation was to determine whether intake of ethanol and saccharin-quinine (SQ) solutions would be related in three nonselected strains of rats who differ in their ethanol preference: Lewis, Wistar Kyoto, and Wistar. In the first phase of the experiment, all animals were presented with an ascending series of ethanol solutions (2 to 10%) in free choice with water, followed by a 10-day maintenance period of 10% ethanol with water. In the second phase, the same animals were presented with an ascending series of SQ solutions (saccharin: 0.4%, quinine: 0.001 to 0.04%) in free choice with water, followed by a 10-day maintenance period of 0.4% saccharin with 0.04% quinine and water. The results revealed an absence of a direct relationship between ethanol and SQ consumption. The ethanol-nonpreferring Lewis rats showed a greater preference for the SQ solutions than Wistar Kyoto rats, whereas the ethanol-preferring Wistar Kyoto strain consistently consumed significantly less SQ. Wistar rats showed relatively stable consumption levels for both solutions that fell between those of the other two strains. These results suggested that the relationship between ethanol and SQ preference in rats was not a direct one and did not support the findings in the literature of a simple overall positive relationship between sweet and ethanol preference. These data do, however, provide further evidence for taste factors in the mediation of self-selection of ethanol in rats.     

Alcohol-induced conditioned taste aversions in chemically labyrinthectomized rats

Male rats were chemically labyrinthectomized (n = 22) by intratympanic injections of sodium arsanilate, and control rats (n = 15) received intratympanic injections of isotonic saline. All rats were tested for labyrinthine integrity and then adjusted to a 23 h.d-1 water deprivation schedule. Both labyrinthectomized and control rats were exposed to a conditioned taste aversion (CTA) procedure or a control procedure. The CTA technique involved pairing a novel saccharin taste with subsequent intraperitoneal injection of ethanol (1.5 g.kg-1; 15% solution). The control CTA procedure paired a novel saccharin taste with injections of isotonic saline. Following two conditioning trials and 3 d of water only, saccharin preference ratios were obtained in two-bottle choice tests (saccharin vs. water) over 4 consecutive days. Control rats conditioned with ethanol exhibited a strong CTA (p < 0.01) relative to control rats injected with saline. Labyrinthectomized rats drinking saccharin followed by ethanol injections showed a strong CTA (p < 0.01) if conditioning occurred 29-30 d post-labyrinthectomy. However, CTA's were not apparent in labyrinthectomized rats conditioned with ethanol 19 d post-labyrinthectomy. Thus, ethanol-induced CTA formation varied across the post-labyrinthectomy time period.     

Self-administration of ethanol and saccharin in newborn rats: Effects on suckling plasticity.

Responsiveness to a surrogate nipple providing water, saccharin, 5% ethanol, or 10% ethanol was tested in newborn rats naive to suckling (3–5 hr old) on Postnatal Day (P) 0 and in older neonates with regular suckling experience on P1 or P2. At all ages, pups demonstrated greater nipple attachment for saccharin or 5% ethanol than for water. Intake of saccharin and 5% ethanol was high in newborns, far exceeding that of water. At P1 and P2, pups exhibited a preference for saccharin, but not for 5% ethanol. Preexposure to a nipple providing ethanol or saccharin (but not a nipple alone or fluids alone) increased subsequent responsiveness toward an empty surrogate nipple (no fluid), both 1 hr and 24 hr after preexposure. Although, during preexposure, pups responded most positively to the nipple providing saccharin, the longest time spent on an empty nipple was observed in pups preexposed to 10% ethanol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Benzodiazepine receptor antagonists modulate the actions of ethanol in alcohol-preferring and -nonpreferring rats

The pyrazoloquinoline CGS 8216 (2-phenylpyrazolo-[4,3-c]-quinolin-3 (5H)-one, 0.05-2 mg/kg) and the beta-carboline ZK 93426 (ethyl-5-isopropyl-4-methyl-beta-carboline-3-carboxylate, 1-10 mg/kg) benzodiazepine receptor antagonists were evaluated for their capacity to modulate the behavioral actions of ethanol in alcohol preferring and -nonpreferring rats. When alcohol-preferring rats were presented with a two-bottle choice test between ethanol (10% v/v) and a saccharin (0.0125% g/v) solution, both antagonists dose-dependently reduced intake of ethanol by 35-92% of control levels on day 1 at the initial 15 min interval of the 4 h limited access. Saccharin drinking was suppressed only with the highest doses. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) unmasked the anxiolytic effects of a hypnotic ethanol dose (1.5 g/kg ethanol) on the plus maze test in alcohol-preferring rats, but potentiated the ethanol-induced suppression in alcohol-nonpreferring rats. CGS 8216 (0.25 mg/kg) and ZK 93426 (4 mg/kg) attenuated the ethanol (0.5 and 1.5 g/kg)-induced suppression in the open field in alcohol-nonpreferring rats; however, CGS 8216 potentiated the depressant effects of the lower ethanol dose (0.5 g/kg) in alcohol-preferring rats. These findings provide evidence that benzodiazepine receptor antagonists may differentially modulate the behavioral actions of ethanol in alcohol-preferring and-nonpreferring rats. It is possible that the qualitative pharmacodynamic differences seen in the present study may be related to selective breeding for alcohol preference. The findings indicate the potential for development of receptor specific ligands devoid of toxic effects which may be useful in the treatment of alcohol abuse and alcoholism.     

Genetic Correlational Analyses of Ethanol Reward and Aversion Phenotypes in Short-Term Selected Mouse Lines Bred for Ethanol Drinking or Ethanol-Induced Conditioned Taste Aversion.

Short-term selective breeding created mouse lines divergent for ethanol drinking (high drinking short-term selected line [STDRHI], low drinking [STDRLO]) or ethanol-induced conditioned taste aversion (CTA; high [HTA], low [LTA]). Compared with STDRLO, STDRHI mice consumed more saccharin and less quinine, exhibited greater ethanol-induced conditioned place preference (CPP), and showed reduced ethanol stimulation and sensitization under some conditions; a line difference in ethanol-induced CTA was not consistently found. Compared with LTA, HTA mice consumed less ethanol but were similar in saccharin consumption, sensitivity to ethanol-induced CPP, and ethanol-induced locomotor stimulation and sensitization. These data suggest that ethanol drinking is genetically associated with several reward-and aversion-related traits. The interpretation of ethanol-induced CTA as more genetically distinct must be tempered by the inability to test the CTA lines beyond Selection Generation 2. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol-induced conditioned aversion: Genotypic specificity in mice (Mus musculus).

Previous studies show that acetaldehyde poisoning from ethanol ingestion may lead to aversion to ethanol among DBA mice but not among C57 mice, since the former are relatively deficient in aldehyde dehydrogenase activity. The present study paired ingestion of saccharin with a single intraperitoneal injection of 1 of 4 concentrations of ethanol for 60 DBA/2J and 60 C57BL/6J mice. Ss were then given a 2-bottle saccharin vs water preference test for 10 days. Substitution of saccharin for the taste of ethanol resulted in avoidance of saccharin with all concentrations of ethanol by DBAs but not by C57s, consistent with the conditioned taste aversion paradigm as a model for genetically mediated ethanol avoidance. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of palatability and feeding conditions on digestive functions in rats

OBJECTIVE: Information concerning various post prandial gastrointestinal functions modulated by taste stimulation is rather limited. Thus, effects of different types of palatability and feeding condition on digestive functions were studied. METHODS: Male Sprague-Dawley rats were divided into two different feeding groups, meal feeding and ad libitum. In meal feeding, the daily feeding period was shortened gradually and was restricted eventually only 3 hours. In ad libitum feeding, food was freely available for 24 hours until experiment. After each rat in both feeding groups was fed 8.29 mM saccharin or 1.28 mM quinine flavored diet as a taste stimulant for 15 minutes, changes of gastric and intestinal nitrogen and pH and pancreatic amylase activities were compared with meal feeding vs ad libitum feeding. RESULTS: In meal feeding, no difference was observed between before and after taste stimulation or between saccharin and quinine flavored diets on gastric and intestinal nitrogen contents, pH in the stomach and in the small intestine, and amylase activity. On the other hand, in ad libitum feeding, intestinal nitrogen contents tended to stagnate until 60 minutes after tasting quinine, although there was little difference between saccharin and quinine diets on gastric nitrogen contents. Gastric juice was hardly secreted before tasting (pH 6.2) and then pH in the stomach changed to become more acid following taste stimulation. Although amylase secreted in small intestine was hardly secreted before tasting, activities after tasting saccharin were increased immediately and lasted until 120 minutes. Amylase activity in rats fed the quinine diet, however, showed slower increase and faster recovery than that in rats fed the saccharin diet. CONCLUSIONS: The results confirmed that various postingestive functions after taste stimulation depend on feeding conditions and it suggests that the ad libitum feeding condition is more appropriate than meal feeding on the experiment related to gustatory response.     

Effects of gamma-aminobutyric acid agonists and N-methyl-D-aspartate antagonists on a multiple schedule of ethanol and saccharin self-administration in rats

Recently, it has been shown at both the cellular and behavioral levels that ethanol has effects on the N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)a receptor systems, leading to the possibility that the reinforcing effects of ethanol may be, at least partially, mediated via these receptor ionophores. In this study, a multiple schedule of ethanol and saccharin self-administration was used to study that possibility. Adult male Long-Evans rats were trained during 1-hr sessions to press on two different levers for 10% (w/v) ethanol and 0.1% (w/v) saccharin solutions, under an alternating 5-min, fixed-ratio-4 schedule of liquid availability. After training, tests were conducted with ethanol, NMDA antagonists and GABA agonists given before six consecutive sessions. Pretreatment with ethanol selectively decreased ethanol self-administration without altering saccharin self-administration. The competitive NMDA antagonist CPPene (D-3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid [SDZ EAA 494]) and the noncompetitive NMDA antagonist phencyclidine decreased both ethanol and saccharin self-administration. The GABA agonists pentobarbital and diazepam also failed to reduce ethanol self-administration, relative to saccharin. Although these results do not support the hypothesis that antagonism of the NMDA receptor system or activation of the GABA receptor system can selectively modify ethanol-reinforced responding, they identify important issues for designing the best strategies to be used to assess selective drug effects on ethanol self-administration.     

Comparison of the stimulus properties of ethanol and the Ca2+ channel antagonist nimodipine in rats

A variety of L-type Ca2+ channel antagonists, including the dihydropyridine derivative nimodipine, have been shown to be effective in reducing ethanol intake and preference in animal models of alcoholism. The behavioral mechanism involved in the anti-alcohol effects of nimodipine are, however, not clear yet. The aim of the present study was to investigate the possibility that the effects of nimodipine on ethanol intake are based on stimulus substitution. Therefore, rats were trained to discriminate ethanol (12.5% w/v, 1000 mg/kg i.p.) from saline in a two-lever food-reinforced drug discrimination procedure (dose range of ethanol tested: 125-1000 mg/kg i.p., ED50 value: 488 mg/kg). In cross-generalization tests with nimodipine (0.15-15 mg/kg i.p.), stimulus substitution was not noted. In addition, a cross-familiarization conditioned taste aversion paradigm was utilized. In rats, 1000 mg/kg i.p. ethanol was used as the reference drug producing a conditioned taste aversion. Effects of preexposure to ethanol (500-1500 mg/kg i.p.) and nimodipine (7.5-30 mg/kg i.p.) on the magnitude of the ethanol-induced conditioned taste aversion were investigated as an index for stimulus similarity between preexposure and reference drug. Preexposure to both ethanol and nimodipine prevented the development of a conditioned taste aversion. Contrary to the drug discrimination results, these latter findings suggest that there may be similarities between the stimulus properties of nimodipine and ethanol. Moreover, the apparent discrepancy between the results obtained in drug discrimination and cross-familiarization conditioned taste aversion suggests that different stimulus properties of ethanol control behavior in both procedures. The finding that, under particular conditions, ethanol and nimodipine appear to share common stimulus properties needs to be further evaluated, as this may be related to the reported anti-alcohol effects of nimodipine and other Ca2+ channel antagonists.     

Behavioral discrimination between quinine and KCl is dependent on input from the seventh cranial nerve: implications for the functional roles of the gustatory nerves in rats

The rat glossopharyngeal nerve (GL), which innervates posterior tongue taste buds, contains several physiologically defined taste fiber types; at least one type is primarily responsive to certain alkaloids (such as quinine), and another is primarily responsive to acids and salts. In contrast, the chorda tympani (CT), which innervates anterior tongue taste buds, does not appear to contain fibers that differentially respond to quinine relative to salts and acids. It was therefore predicted that GL transection should disrupt behavioral discriminations between quinine and either acids or salts. Water-restricted rats were trained to press one of two levers if a sampled taste stimulus was quinine (0.1-1.0 mM) and the second lever if the sampled stimulus was KCl (0.1-1.0 M). Sham surgery, GL transection, and sublingual and submaxillary salivary gland extirpation were found to have no effect relative to presurgical performance. Both CT transection and combined GL and CT transection caused a substantial and approximately equal decrement in discrimination performance. Removal of the gustatory branches of the seventh cranial nerve [CT and greater superficial petrosal (GSP)] nearly eliminated the discrimination of the taste stimuli, and combined transection of the CT, GL, and GSP unequivocally reduced performance to chance levels. Although these findings were not presaged by the known electrophysiology, they nonetheless compare favorably with other studies reporting little effect of GL transection on behavioral responses to quinine. These results, in the context of other discrimination studies reported in the literature, suggest that, in rats, the neural coding of taste quality depends primarily on the input of the facial nerve.     

Influences of hypothyroidism on the taste detection performance of rats: A signal detection analysis.

Determined the influences of hypothyroidism on behavioral measures of the taste function in male and female Long-Evans rats. Experimental rats' preferences for and ability to detect NaCl, HCl, sucrose, and quinine sulfate were examined before, during, and after 9 wks of maintenance on 0.1% propylthiouracil (PTU), an agent that produces marked hypothyroidism, with similar determinations made for control animals. Despite significant decreases in PTU-treated rats' serum triiodothyronine (T?) and thyroxin (T?), there were no changes in sensitivity or responsitivity to the target tastants. However, altered preferences for NaCl, HCl, and quinine sulfate were observed for PTU-treated rats; elevated consumption of HCl and quinine sulfate was present at the end of the study when serum T? and T? had returned to near-baseline levels. The data confirm observations that PTU-induced hypothyroidism alters rats' taste preference behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Negative anticipatory contrast and preference conditioning: Flavor cues support preference conditioning, and environmental cues support contrast.

In 2 experiments, access to a .15% saccharin solution was followed on alternating days by access to a 32% sucrose solution and the same saccharin solution. In Exp 1, rats increased both intake of and preference for a flavored saccharin solution that predicted sucrose, but neither effect was found using a predictive odor cue alone. Exp 2 replicated the predictive flavor results but showed suppression of saccharin intake when environmental cues predicted sucrose. When both flavor and environment predicted sucrose, saccharin intake did not change, but preference for the predictive flavor increased. Discriminative taste cues appear to facilitate the development of preference conditioning, but environmental cues favor negative anticipatory contrast effects. Also, preference conditioning and contrast may develop concurrently and compete for expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sucrose, ethanol, and sucrose/ethanol reinforced responding under variable-interval schedules of reinforcement

Adding sweeteners to ethanol solutions is a common method of inducing rats to consume ethanol. However, it has usually been assumed that it is the sweet taste and/or the calories contained in the sweet solution that controls consumption. The present experiment examined the role of ethanol in controlling responding reinforced by ethanol or an ethanol/sucrose mixture compared with sucrose solutions of various concentrations. After initiation to self-administer 10% (v/v) ethanol using the sucrose-substitution method, rats were trained to respond under a concurrent VI 5" VI 5" schedule. During one condition, responding on one lever was reinforced by the presentation of 10% ethanol, and responding on a second lever was reinforced by water or one of the following sucrose solutions: 1% (w/v), 1.5%, 2%, 2.5%, 3%, and 5%. During a subsequent condition, responding reinforced by a 10% ethanol/2% sucrose mixture was compared under the concurrent schedule with responding reinforced by water, 2%, 2.5%, 3%, 5%, or 10% sucrose (w/v). The results indicated that the ethanol or ethanol/sucrose mixture maintained more responding than did sucrose solutions that were sweeter. Data support the conclusion that, after initiation, the taste and/or pharmacological effects of ethanol had become an important component of the reinforcing stimulus independent of the sweetener.     

Multielemental stimulus control: Effects of saccharin concentration on a discriminated morphine-saccharin taste aversion.

The effects of saccharin concentration on the stimulus control by a compound stimulus consisting of morphine, saccharin (0.01, 0.03, or 0.10%, wt/vol), and a ball bearing drinking nozzle in a discriminated taste aversion (DTA) procedure were examined in rats (Rattus norvegicus). In paired rats injections of lithium followed presentation of this compound stimulus, whereas in unpaired rats saline injections followed this stimulus. DTA acquisition was more rapid at higher saccharin concentrations. In testing with each individual stimulus element, stimulus control was clearly exerted by all 3 stimulus elements. When another stimulus element was presented jointly with saccharin, behavioral control was similar to that of saccharin alone. Behavioral control by saccharin increased with saccharin concentration. However, behavioral control by the 2 other stimulus elements was relatively unaffected when the saliency of the saccharin element was increased. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Making time count: Functional evidence for temporal coding of taste sensation.

Although the temporal characteristics of neural responses have been proposed as a mechanism for sensory neural coding, there has been little evidence thus far that this type of information is actually used by the nervous system. Here the authors show that patterned electrical pulses trains that mimic the response to the taste of quinine can produce a bitterlike sensation when delivered to the nucleus tractus solitarius of behaving rats. Following conditioned aversion training using either "quinine simulation" patterns of electrical stimulation or natural quinine (0.1 mM) as a conditioned stimulus, rats specifically generalized the aversion to 2 bitter tastants: quinine and urea. Randomization of the quinine simulation patterns resulted in generalization patterns that resembled those to a perithreshold concentration (0.01 mM) of quinine. These data provide strong evidence that the temporal pattern of brainstem activity may convey information about taste quality and underscore the functional significance of temporal coding. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine release during ethanol drinking in AA rats

The dopamine overflow in the nucleus accumbens of rats from the high alcohol drinking AA line was measured by microdialysis before, during, and after one-half hour sessions of cued drinking of ethanol flavored with saccharin and peppermint or, as a control, saccharin-peppermint drinking. The animals had had extensive previous experience with ethanol drinking. Self-administration of the ethanol solution did not raise the dopamine level substantially: there was a small (17%) but significant increase only during the first 10 min after the onset of drinking. Giving the rats a cue for ethanol, which was part of their daily routine drinking regime, did not raise the dopamine level before ethanol was presented to the rats (i.e., during "anticipation"). The results are consistent with our previous studies showing a lack of a large ethanol-induced dopamine response in rats with previous experience of drinking ethanol and with the idea that although dopamine may play some role in alcohol drinking, it is not the central substrate producing the reinforcement from ethanol in AA rats.     

Comparison of innate EEG parameters in rat lines selected for ethanol preference

Through bidirectional selective breeding, lines of rats that differ greatly in their voluntary alcohol drinking behavior have been developed--namely, the alcohol-preferring (P) and high-alcohol-drinking (HAD) lines and the alcohol-nonpreferring (NP) and low-alcohol-drinking (LAD) lines. The present experiments were designed to determine if an association exists between ethanol preference and features of the electroencephalogram (EEG) during various sleep-wake behaviors. Of the EEG parameters measured, only theta activity in the hippocampus revealed differences in the lines. However, these differences were not generally associated with ethanol preference. The peak frequency and distribution mean of hippocampal theta activity during REM sleep were significantly higher in NP rats than in P, HAD, and LAD rats. In addition, theta frequency during alert immobility tended to be higher in NP rats than in P, HAD, and LAD rats. A qualitative comparison of these data with published data from unselected rats further suggested that the NP rats are uniquely different with respect to theta frequency.     

Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion

Metabotropic glutamate receptors (mGluRs) consist of eight different subtypes and exert their effects on second messengers and ion channels via G-proteins. The function of individual mGluR subtypes in the CNS, however, largely remains to be clarified. We examined the fear response of freezing after electric shock in wild-type and mGluR7(-/-) knockout littermates. Wild-type mice displayed freezing immediately after and 1 d after footshock. In comparison, mGluR7(-/-) knockout mice showed significantly reduced levels in both immediate postshock and delayed freezing responses. However, the knockout mice exhibited no abnormalities in pain sensitivity and locomotor activity. To further examine amygdala-dependent behavior, we performed conditioned taste aversion (CTA) experiments. In wild-type mice, the administration of saccharin followed by intraperitoneal injection of the malaise-inducing agent LiCl resulted in an association between saccharin and LiCl. This association caused strong CTA toward saccharin. In contrast, mGluR7(-/-) knockout mice failed to associate between the taste and the negative reinforcer in CTA experiments. Again, the knockout mice showed no abnormalities in taste preference and in the sensitivity to LiCl toxicity. These results indicate that mGluR7 deficiency causes an impairment of two distinct amygdala-dependent behavioral paradigms. Immunohistochemical and immunoelectron-microscopic analyses showed that mGluR7 is highly expressed in amygdala and preferentially localized at the presynaptic axon terminals of glutamatergic neurons. Together, these findings strongly suggest that mGluR7 is involved in neural processes subserving amygdala-dependent averse responses.     

Vestibular lesions selectively abolish body rotation-induced, but not lithium-induced, conditioned taste aversions (oral rejection responses) in rats.

Pairing a novel taste with provocative vestibular stimulation results in conditioned taste aversions in both rats and humans. Vestibular system involvement in gustatory conditioning was examined in sham-lesioned or labyrinthectomized rats. Three conditioning trials consisted of 30 min access to a saccharin (0.1%) solution followed by 30 min of rotation (70 rpm) or sham rotation. In a taste reactivity test with saccharin, rotated sham-lesioned rats, but not labyrinthectomized rats, exhibited increased oral rejection reactions compared with control rats. When conditioned with lithium chloride, both labyrinthectomized and sham-lesioned rats displayed robust conditioned rejection reactions. The finding that normal vestibular function is necessary in obtaining rotation-induced conditioned taste aversions supports the face and construct validity of a rat model of motion sickness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behaviorally functional opioid systems in infant rats: I. Evidence for olfactory and gustatory classical conditioning.

Conducted 2 series of experiments to characterize the behavioral function of opioid systems in neonatal rats. In the 1st series, the reinforcing properties of exogenous opioids were investigated in 112 5-day-old pups. Ss' ability to associate the novel taste of saccharin, received while suckling, with intraperitoneal morphine injections was assessed. Results show that Ss that received 0.5 ml of saccharin prior to morphine administration ingested considerably more saccharin on Day 10 than did control rats. The 2nd set of experiments was conducted to determine whether 144 rat pups could associate a novel odor with morphine administration. Five days after conditioning, that stimulus was highly preferred by morphine-treated Ss compared with saline control Ss. Thus positive associations were formed with either a novel taste stimulus experienced while suckling or with an odor experienced during social isolation. Conditioning was cue specific and was retained for at least 5 days. The formation of these associations was blocked with opioid antagonists given prior to conditioning. Data suggest behaviorally functional opioid receptors and raise the possibility of a functional role of the endogenous opioids in motivational processes in infant rats. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)