Impairment of acquisition of a DRL schedule following prolonged ethanol consumption

Two groups of male hooded rats (N = 9) were given either ethanol or sucrose solutions as their only source of fluid for six months. Thirty days after the ethanol treatment, the rats were reduced to 85% of their free-feeding weights and allowed to obtain 45 mg of food pellets on an FR 1 schedule fof five consecutive days. Subsequently, the rats were tested on four DRL schedules (6. 12, 18, 24 sec). There was no difference between the two groups on FR 1 or DRL 6 sec schedules; however, when the DRL interval was lengthened to 12, 18, and 24 sec, the ethanol group required more sessions than the sucrose group to reach criterion performance. After increases in the DRL interval, the modal interresponse time of the ethanol group shifted more slowly than that of the sucrose group.     

Effect of exposure to high concentrations of toluene on ethanol preference of laboratory rats

Male and female Holtzman Sprague Dawley rats were given 10-minute exposures to high concentrations of toluene twice a week at 10–30 days of age. The rate of acquisition of ethanol preference for these rats did not differ significantly from litter-mate sham exposed controls. Once ethanol preference curves were established, the rats were exposed daily over a 5-day period to high concentrations of toluene. An increase in ethanol intake occurred in most of the rats irrespective of early toluene exposures at 10–30 days of age.     

Lever press responding as a measure of ethanol preference in rats

Preference for ethanol in rats, overcoming the problem of a position habit, was assessed in a one-lever and two-liquid chamber. Performance in lever pressing for ethanol of different concentrations (2.5%, 5.0%, and 15.0%) and for water, as well as the amount of liquid intake, were recorded. Evidence of ethanol preference was observed by both the lever press and consumption measures when the concentration was 2.5%. Water preference was evident at higher concentrations. The present method proved to be a useful method for studying ethanol preference in rats.     

Rapid establishment of ethanol as a reinforcer for rats

Daily 6-h sessions were run during which each lever press by rats produced brief access to water, or to 8?/0 (W/V) ethanol on experimental days. Food pellets were presented noncontingently on a 1 min fixed-time schedule during the last, 4 h of each session. A stable baseline of water responding developed, characterized by little or no responding during the first 2 h followed by high rates and schedule-induced polydipsic drinking during the last 4 h. Following the development of a stable water baseline, 8% (W/V) ethanol was substituted for water on alternate days. After one previous session with ethanol, rats' responding for ethanol during the first 2 h of a session substantially exceed water baseline rates, indicating that ethanol had been established as a reinforcer. Subsequently, when food pellet presentations were discontinued, and the ethanol concentration was increased from 8 to 16 to 32% (W/V), ethanol intake persisted at values exceeding water control levels; these results confirm that ethanol was functioning as a reinforcer.     

Flavor preference conditioning by oral self-administration of ethanol

 Oral self-administration and operant tasks have been used successfully to confirm ethanol′s positive reinforcing effects in rats. However, in flavor conditioning tasks, ethanol is typically found to have aversive effects. The present studies explored this apparent paradox by examining the change in value of a flavor paired with orally self-administered ethanol in two different limited-access procedures. Rats were food-deprived and trained to drink (experiment 1) or to barpress for (experiment 2) 10% (v/v) ethanol during daily 30-min sessions using prandial initiation techniques. All rats were then exposed to a differential flavor conditioning procedure in which banana or almond extract was added to the drinking solution. One flavor (counterbalanced) was always mixed with ethanol (CS+), whereas the other flavor was mixed with water (CS–). By the end of conditioning, rats in both experiments drank more flavored ethanol than flavored water, confirming ethanol’s efficacy as a reinforcer. Moreover, barpress rates for CS+ exceeded those for CS– in the operant task. Ethanol doses self-administered in final sessions averaged about 1 g/kg. The effect of the flavor-ethanol contingency was assessed in preference tests that offered a choice between the two flavor solutions without ethanol. In both experiments, subjects developed a preference for the flavor that had been paired with ethanol. Thus, the outcome of flavor conditioning was consistent with that of the oral self-administration tasks in providing evidence of ethanol’s rewarding effects. These experiments confirm and extend previous studies showing that flavor aversion is not the inevitable result of flavor-ethanol association in rats. It seems likely that ethanol’s nutrient and pharmacological effects both contributed to the development of conditioned flavor preference. Received: 15 February 1997 / Final version: 11 June 1997     

Effects of naloxone on ethanol dependence in rats

Adult male Long-Evans rats were maintained on an ethanol-containing liquid diet. During development of ethanol dependence, the rats were given daily i.p. injections of either naloxone (2 mg/kg) or saline daily. At the beginning of ethanol withdrawal, the rats were injected with either naloxone (10 mg/kg) or saline i.p. Rats injected with naloxone during the development of ethanol dependence consumed significantly more of the ethanol diet and therefore more ethanol than rats injected with saline. Rats treated with naloxone throughout both the development of ethanol dependence and during ethanol-withdrawal showed delayed or reduced withdrawal symptomatology compared to rats injected with only saline, naloxone only during the development of dependence and naloxone only during ethanol withdrawal. These results indicate that naloxone can alter the effects of chronic ethanol exposure and further suggest that ethanol may exert some of its actions via the brain opioid system.     

The effect of phenobarbital and carbamazepine on the ethanol withdrawal reaction in the rat

The effects of phenobarbital (PB) and carbamazepine (CZ) on the ethanol withdrawal reaction in the rat were investigated in a blind study including an untreated control group. Physical ethanol dependence was established by intragastric intubation during a 4-day period. Both the degree of intoxication and the withdrawal reaction were assessed by standardised assessment instruments. Treatment with PB (40–60 mg/kg) and CZ (80–120 mg/kg) was initiated 10 h after the last ethanol dose and continued during the first 24 h of withdrawal. Serum concentrations of the drugs were measured.Both PB and CZ significantly reduced the ethanol withdrawal reaction compared to controls, and PB was significantly more effective than CZ. The degree of drug intoxication signs assessed by the same rating scale as the degree of ethanol intoxication indicated that maximum tolerable drug doses were used.PB probably exerts its treatment effect through the mechanism of cross dependence with ethanol, while CZ may exert a more specific effect on limbic structures responsible for central nervous system excitability.Abbreviations ANOVA analysis of variance - BEC blood ethanol concentration - CIS cumulated intoxication score - CZ carbamazepine - ICS incomplete clonic seizure - PB phenobarbital     

Chlordiazepoxide''s interaction with ethanol intake in the rat: Relation to ethanol exposure paradigms

Chlordiazepoxide's interaction with ethanol (5% v/v) intake was assessed in rats on a feeding regimen producing high daily quantities of ethanol intake (schedule-induction procedure with intermittent feeding), more moderate amounts of ethanol intake (a single daily feeding), and small amounts of ethanol intake (free feeding). Six days of twice daily sham injections (IP) were followed by 12 days of 0 (vehicle), 5, 10, or 15 mg/kg (twice daily) chlordiazepoxide, and finally six days of the saline (vehicle) injections. Rats in the intermittent feeding daily consumed 9.9–12.3 g/kg (80–95 ml) of ethanol on baseline which was reduced 15 to 33% by the drug. In the single feed condition most rats were drinking 70 to 85 ml (8.8–10.3 g/kg) of ethanol and this was reduced 15–40% by the drug. During the six days after drug, intake in both of these feeding regimens returned to the baseline level. Ethanol intake of rats under the free feeding condition (48 ml, 3.5 g/kg on average) was not affected by the drug, nor was water intake under any of the three feeding regimens.     

Patterns of ethanol and water consumption as a function of restricted ethanol access and feeding condition

Sixteen male albino rats were divided into two groups of eight animals and maintained at either their free-feeding or at 80% of their free-feeding weight. For four animals, access to 8% ethanol was unrestricted, for the remaining four, access was restricted to eight 20-min access periods per day. Mean amounts of ethanol consumed per bout were greater during restricted access than during unrestricted access for food-deprived animals but not for free-feeding animals. Total daily ethanol consumption was greatest when animals were food deprived and access to ethanol unrestricted. Total fluid consumption and the within session distribution of water and ethanol responding were affected by feeding condition. For food-deprived animals, the amount of water consumed per session remained relatively constant. The increase in ethanol consumption over sessions resulted in an increase in total fluid consumption. For the free-feeding animals, increases in ethanol consumption resulted in decreases in water consumption so that total fluid consumption remained constant. In addition, food-deprived animals consumed all their daily water intake at the beginning of each session when food was present. Free-feeding animals consumed water throughout the session.     

Failure to establish a conditioned place preference with ethanol in rats

Previous studies have demonstrated that many drugs of abuse are able to produce a conditioned place preference in rats. We sought to determine if ethanol, injected in a wide range of doses, could also produce a conditioned place preference. Statistical analysis of our results indicated that the IP administration of the drug (50, 100, 150, 300, 600, 800, or 1000 mg/kg) failed to produce either a conditioned place preference or aversion compared to vehicle injected control rats. Under similar testing conditions a conditioned place preference was obtained with amphetamine (2 mg/kg) and this preference was not secondary to conditioned hyperactivity. In another experiment, rats were injected with ethanol through indwelling jugular cannulae at doses similar to those reported [24,26] to support (1, 2 mg/kg) or not to support (8 mg/kg) self-administration by rats. We also failed to obtain a conditioned place preference using these doses. Blood and brain ethanol levels, determined 1, 2 or 5 minutes after the administration of 2 mg/kg (IV) indicated very low ethanol levels. These results may suggest that rats do not self-administer ethanol for its intoxicating properties, and that the affective state produced by ethanol administration per se is not readily conditionable to environmental cues.     

Apomorphine increases ethanol discrimination

Rats were trained to discriminate between the stimulus properties of 600 mg/kg ethanol and saline in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower ethanol doses and analysis of the dose-response curve indicated an ED50 of 372 mg/kg. Pretreatment with 0.16 mg/kg apomorphine produced increased discriminative performance at each ethanol dose and the combination generated a dose-response curve parallel to ethanol administered alone with an ED50 of 232 mg/kg. This significant shift to the left of the ethanol dose-response curve after apomorphine administration is discussed in relation to dopaminergic neuronal systems and the clinical use of apomorphine alcoholics.     

Effects of acute ethanol intoxication,chronic ethanol intoxication,and ethanol withdrawal on magnesium and calcium metabolism in the rat

Effects of ethanol intoxication and withdrawal on magnesium and calcium metabolism were studied in rats. During acute ethanol intoxication, plasma [Mg²⁺] was increased and plasma [Ca²⁺] decreased. During chronic intoxication, plasma [Mg²⁺] was normalized whereas plasma [Ca²⁺] was persistently subnormal. Ethanol withdrawal was followed by a decrease in plasma [Mg²⁺] and a normalization of plasma [Ca²⁺]. These various changes are probably related to changes in systemic pH and to the biochemical effects of ethanol and ethanol withdrawal on intermediary metabolism. Cerebrospinal fluid [Mg²⁺] was unchanged during intoxication and withdrawal and it was concluded that no etiological role can presently be ascribed to the magnesium ion as far as cerebral signs of ethanol intoxication and withdrawal in the rat are concerned. No consistent changes in erythrocyte [Mg²⁺] were encountered during ethanol intoxication and withdrawal in rats.     

Increasing the rate of ethanol consumption in food- and water-satiated rats.

The effects of food satiation, ethanol concentration, and the schedule of ethanol availability on the rate of ethanol consumption were investigated in rats. In Experiment 1 separate groups were exposed to 6.2 or 12.5% w/v ethanol and unlimited access to food. The food and ethanol were available concurrently for one to three hours daily. After approximately 15 sessions unlimited food was available whenever ethanol was not available. The rate of ethanol consumption was positively related to ethanol concentration and negatively related to duration of ethanol availability. In Experiment 2 similar procedures were followed, except rats had unlimited access to food throughout the experiment. The results were similar to Experiment 1. In Experiment 3 separate groups were exposed to 6.2 and 12.5% w/v ethanol for one hour every other day; unlimited food was available throughout the experiment. The results were similar to the one-hour availability groups in Experiments 1 and 2. In all experiments ethanol consumption rates increased to levels above baseline and above the usual ethanol metabolic rate found in rats. The results demonstrated new combinations of ethanol availability and non-availability durations that were sufficient to significantly increase the rate of ethanol consumption.     

Ethanol as a reinforcer for rats: Effects of concurrent access to water and alternate positions of water and ethanol

Water and ethanol solutions were concurrently made available on a continuous reinforcement schedule to 4 food-deprived male albino rats during daily 1-hr sessions in an operant conditioning chamber equipped with 2 levers and 2 liquid dippers. The number of ethanol reinforcements substantially exceeded the number of water reinforcements for each rat at each concentration studied (8, 16, and 32% w/v). Water reinforcements were low in number and did not vary with ethanol concentration. As the ethanol concentration was increased, the number of ethanol reinforcements obtained decreased, while the quantity consumed (mg/100 g of body weight/hr) increased. The highest rate of responding occurred at the beginning of the session.     

Oral ethanol self-administration in the rat: effect of naloxone

Rats responding on a two lever concurrent for ethanol and water, were injected with 5, 10, or 20 mg/kg naloxone hydrochloride 30 min prior to a 30 min session. Only the 20 mg/kg dose had any effect, a decrease in responding for ethanol of up to 50% compared to saline control injection sessions. There were no systematic effects upon water responding. An additional study using sucrose and water as the fluid concurrently available failed to find any effects of naloxone on sucrose responding at the same doses. The effect upon ethanol responding was found not to resemble a pattern of extinction, but rather was best described as a general overall reduction in responding. The relation of these findings to the direct involvement of the endogenous opiate system in ethanol reinforcement is discussed.     

Alcohol-deprivation effect in rats genetically selected for their ethanol preference

Alcohol deprivation and alternate-day access increase voluntary alcohol drinking by normal rat strains in a consistent manner. In contrast, the ANA strain developed by selective outbreeding for low alcohol intake during continuous access showed no increase in their alcohol drinking during alternate-day access and only a small increase after a week of deprivation. The AA strain developed for high alcohol intake showed an increase after a week of deprivation similar in magnitude to that of normal rats but persisting much longer. In order to have been selected, these deviant reactions to deprivation must have been related to deviant baseline levels of alcohol drinking during continuous access, but presently even the AAs with the lowest baselines show the persistent increase and the ANAs with the highest baselines show only small increases. Strain differences were also found in spontaneous alternation in a T-maze. A modification of Pinel and Huang's inhibitory factor model accounting for these results is presented.     

Consumption of intoxicating beverages by rats and mice exhibiting high and low preferences for ethanol

Lines of rats selectively bred for alcohol consumption or avoidance (AA and ANA, ALKO, Finland) as well as inbred strains of mice (C57/BL/6J and DBA/2J) and common female Wistar rats (Charles River) exhibiting high and low preferences for ethanol were tested under free-choice conditions for their consumption of solutions of ethanol (5, 10, or 15 g/100 ml tap water), sodium pentobarbital (0.19, 0.038, 0.076 g/100 ml tap water), and different beverages containing ethanol in the range of 8.1–9.6% (red and white wine, Scotch, ethanol in Hawaiian Punch). The Wistar rats and the mice classified as alcohol-preferring also tended to consume more of the pentobarbital solution than did alcohol-avoiding animals. Alcohol-nonaccepting (ANA) rats, however, consumed considerably more of all three pentobarbital solutions than did the alcohol-accepting (AA) rats. The intake of pentobarbital by the ANA rats and C57/BL/6J mice was in the range of 25–40 mg/kg/day, quantities that might be expected to produce pharmacological effects discriminable by those animals. The intake of ethanol by ANA rats was markedly elevated when the ethanol was contained in white wine or in punch.     

A critical evaluation of tetrahydroisoquinoline induced ethanol preference in rats

It has been reported [30] that certain tetrahydroisoquinoline compounds, especially salsolinol and tetrahydropaveroline (THP) when infused into the lateral ventricle of rats' brains results in increased preference for alcohol solutions. The effect is reported to be long-term, in that animals do not return to baseline drinking even months later. The current report provides a replication of the original experiments and also extension of the work to complete dose-response curves for salsolinol and THP. Generally we have confirmed that rats of the Sprague-Dawley and Long-Evans strains do increase their alcohol intake in response to infused THP or salsolinol and that the effect is long lasting, up to 10 months. Such animals consume less alcohol at concentrations above 20% than below, in contrast to the previous reports where drinking was maintained at high concentrations of alcohol. While the animals will select alcohol in the face of a saccharin choice, they will not drink alcohol adulterated with quinine. We have failed to observe signs of dependence or withdrawal by these techniques and suggest that the original reports of these signs may have been a result of cellular damage caused by the long-term infusions. Additionally we have carried out extensive dose-response experiments with both salsolinol and THP. Doses of THP of 104 nmoles/day were inhibitory to alcohol drinking. We conclude that these compounds do shift these animals preference for alcohol relatively permanently, but not to the point of gross intoxication nor into the highly aversive range of alcohol concentration. We cannot confirm the reports that salsolinol or THP produce withdrawal symptoms when infused.     

Changes in serum LH and FSH following preovulatory administration of ethanol in rats

The effect of different single doses of ethanol (1.0, 2.0 and 4.0 g/kg) on serum LH and FSH has been studied in rats treated during preovulatory periods (18th h of diestrous). High doses of ethanol (2.0 and 4.0 g/kg) decreased serum LH levels at the 18th h of proestrous, 24 h after ethanol administration, inhibiting the preovulatory LH surge. No changes were observed in FSH levels. These effects could be mediated through the inhibition of the hypothalamic releasing factors.     

Environmental context conditioning with ethanol reduces the aversive effects of ethanol in the acquisition of self-administration in rats

RATIONALE: Many recent theoretical approaches to drug-taking behavior feature a role for Pavlovian conditioning. Despite growing evidence for that role, the particular contributions of Pavlovian conditioning to self-administration are not clear. For example, few studies have addressed the effects of Pavlovian conditioning on the acquisition of self-administration. OBJECTIVES: The purpose of this study was to test the effect of Pavlovian conditioning with an environmental conditioned stimulus and an ethanol unconditioned stimulus on the acquisition of self-administration reinforced by ethanol. METHODS: Rats were either given ethanol by gastric gavage in a distinctive context or in their home cage. All animals were then trained to bar press on a variable interval schedule for a sweetened ethanol solution in the distinctive context. RESULTS: Animals that had received ethanol associated with the training context maintained a higher level of bar press behavior for ethanol as the reinforcing solution. This effect developed only after the first session and resulted from differences in response rates, but did not affect the rate of reinforcement. CONCLUSIONS: This study demonstrates that an environmental context signaling the effects of ethanol maintains a higher operant response rate when ethanol is used subsequently as a reinforcer. This finding replicates previous reports of Pavlovian conditioning effects on ethanol consumption. The specific pattern of results suggests that conditioned tolerance modifies the reinforcing impact of ethanol. Context conditioning with ethanol reduces the aversive impact of initial ethanol consumption and maintains the reinforcing value of the ethanol solution.