Effects of prior ethanol exposure on ethanol self-administration in a continuous access situation using retractable drinking tubes.

To examine whether exposure to ethanol influences subsequent ethanol consumption using a continuous access procedure, two groups of rats were given differing initial exposure to ethanol. One group underwent a sucrose-substitution initiation procedure. The second group received abbreviated initiation consisting of one-session exposure to each ethanol/sucrose combination used in standard initiation. The animals were then provided with 23 h/day access to ethanol (10%, v/v) from a retractable drinking tube. Food pellets were available following a single-lever press, and water was available from a sipper tube. After 5 weeks, the data indicated that few significant differences existed between the groups on total ethanol (g/kg), food or water consumed. The overall intake (g/kg/day), number of ethanol bouts per day, and amount consumed per bout (g/kg/bout) were substantially lower than observed in previous research using ethanol presented in a dipper. However, differences in g/kg per ethanol bout did differ significantly between the two groups with the group receiving standard initiation showing more ethanol consumed per bout. These data agree with our previous work indicating that initiation results in larger drinking bouts.

Chronic ethanol self-administration in a continuous-access operant situation: the use of a sucrose/ethanol solution to increase daily ethanol intake.

The addition of sucrose to an ethanol solution increases both limited- and continuous-access ethanol consumption. The present study examined if the increased intakes in a continuous-access condition could produce withdrawal signs indicating physical dependence on ethanol. Rats were maintained in a continuous-access operant situation in which one lever press on one lever resulted in the presentation of a food pellet, whereas one lever press on a second lever presented 0.1 ml of fluid in a dipper. Water was available from a drinking spout. Ten rats received a 10% sucrose/20% ethanol mixture in the dipper and six rats 10% sucrose. After 30 days the animals were tested for withdrawal signs after 8 h without ethanol using an activity test and response to key shaking. They were then given an additional 30 days of access to the solutions and retested for withdrawal. This was followed by a final 30 days of access and a third withdrawal test. Over the 90 days, the sucrose/ethanol group consumed 8-10 g of ethanol per kilogram of body weight per day. Over this time both groups gained weight. At the third withdrawal test, a significant reduction in activity occurred in the ethanol-drinking group, compared with the sucrose group. No severe withdrawal effects were observed to the key shake test. The results suggest that the higher ethanol intakes previously observed using this sucrose/ethanol solution can be maintained over long periods of time. Although this intake was not sufficient to produce severe withdrawal signs, the results suggest that longer exposure might result in more severe ethanol dependence.

Effects of the atypical antipsychotic remoxipride on alcohol self-administration.

Remoxipride is a dopamine (DA) D2 antagonist that produces fewer of the side effects normally associated with chronic DA antagonist administration. It has been demonstrated that DA antagonists can reduce the desire for a second drink in alcoholics. However, because of the usual side effects associated with DA antagonist administration, chronic use as an adjunct to alcoholism treatment has not been considered. Because the DA D2 antagonist haloperidol reduces ethanol self-administration in an operant animal model of ethanol self-administration, this study was designed to determine whether remoxipride would produce similar results. Six Long-Evans rats were initiated to self-administer ethanol in daily 30-min operant sessions using a sucrose-substitution procedure. Following establishment of ethanol-reinforced lever pressing, remoxipride (0.5, 1.0, 5.0, or 10.0 mg/kg) or haloperidol (0.01, 0.05, or 0.1 mg/kg) were injected 30 min prior to the sessions. Remoxipride produced an approximate 50% reduction in the number of ethanol presentations per session at the highest dose tested (10.0 mg/kg) and did so by terminating the ethanol-drinking bout earlier in the session. Haloperidol also decreased ethanol presentations with the highest dose tested (0.1 mg/kg) producing the largest effect. These data indicate that remoxipride produces reductions in ethanol-reinforced responding similar to those observed with another DA antagonist. Because remoxipride produces fewer of the side effects commonly observed with chronic DA antagonist administration, it could prove to be a useful adjunct in the treatment of excessive alcohol consumption.

Comparison of alcohol-preferring and nonpreferring selectively bred rat lines. I. Ethanol initiation and limited access operant self-administration.

Several lines of alcohol-preferring and alcohol-nonpreferring rats have been developed using selective breeding based on 24-hr homecage ethanol consumption. However, it remains unclear if the selection based on two-bottle choice resulted in similar ethanol self-administration when measured using an operant procedure. In this paper, we compare our previous work using alcohol-accepting (AA) and alcohol-nonaccepting (ANA) rats with data obtained using the identical procedures in the (P) and (NP) rat lines, and both replicate lines of the high alcohol drinking (HAD1 and HAD2) and low alcohol drinking (LAD1 and LAD2) lines. All rats from each line were initiated to self-administer 10% ethanol using the sucrose fading procedure. After initiation, increasing concentrations of ethanol up to 30% ethanol were tested. The results indicated that only in the LAD1 and LAD2 lines was ethanol presentation not able to maintain lever pressing after initiation. Compared with the AA line, the P, HAD1, HAD2, and NP lines all self-administered more ethanol in the operant paradigm after initiation. The ANA line self-administered less ethanol than the AA line, but more than the LAD lines. Correlational analysis of homecage consumption with operant ethanol self-administration suggested that approximately 62% of the genetic variance in operant self-administration resulted from genes selected for the homecage drinking. At the same time, it was clear that there were genetic influences on operant self-administration that were not selected for by homecage ethanol drinking.

Comparison of alcohol-preferring and nonpreferring selectively bred rat lines. II. Operant self-administration in a continuous-access situation.

Several rat lines have been developed using preference/nonpreference and daily ethanol intake in the homecage as criteria for selective breeding. Using these lines, behavioral and neural factors that may underlie the genetic basis for the control of ethanol consumption have been examined. In this paper, we report data from eight of these selected lines: the Alcohol-Preferring (P) and Alcohol-Nonpreferring (NP), the Alcohol-Accepting (AA) and Alcohol-Nonaccepting (ANA), and the High Alcohol Drinking (HAD1 and HAD2) and Low Alcohol Drinking (LAD1 and LAD2) rats. All lines were tested using operant procedures and the same protocols for both the ethanol self-administration initiation and measurement of continuous-access ethanol consumption. During continuous access, the animals were housed in operant chambers with access to 10% (v/v) ethanol after responses on one lever, food pellets (45 mg) after responses on a second lever, and water in a drinking tube that was connected to a drinkometer circuit. Under these procedures, both similarities and differences among the selected lines on continuous-access operant ethanol intake were observed. For example, overall total homecage ethanol drinking was similar for the AA and both HAD lines. When examined in the operant continuous-access situation, however, the AA rats displayed a different consumption pattem, compared with the HAD lines. Data suggest that the frequency of drinking bouts was a primary factor in the phenotypic homecage selection of the preferring lines that was revealed by the use of the continuous-access operant procedure. In general, data suggest that genes related to ethanol preference and intake in homecage continuous-access situations may not be identical to those related to ethanol's reinforcing function in operant continuous-access conditions. Because ethanol consumption appears to be controlled by different drinking patterns across lines, the selected lines provide for a variety of models to understand how varying genotypes can impact ethanol consumption.

Effects of sucrose-substitution initiation on patterns of drinking by Lewis rats during continuous alcohol access.

Initiation of alcohol drinking using the sucrose-substitution procedure was studied in inbred Lewis rats. One group of animals was initiated to self-administer alcohol prior to being placed in the continuous-access condition, whereas the second group of animals did not undergo initiation. During the continuous-access period, the animals were housed in operant chambers where they had continuous access to alcohol (10% v/v), food, and water during daily 23-h experimental sessions. After 5 weeks of baseline conditions, the response, requirement for food was increased over weeks. This was followed by weekly increases in the ethanol response requirement with the food response requirement returned to baseline conditions. In the continuous-access condition, both groups consumed similar amounts of alcohol by the end of the 4-week baseline period and showed similar numbers of dippers presented per alcohol bout and number of alcohol bouts per day. During the food response requirement manipulation, alcohol consumption increased for both groups but intake increased significantly more for the noninitiated group. The difference between groups was accounted for by a larger number of alcohol drinking bouts per day for the noninitiated group. Alcohol consumption decreased at each increase in ethanol reinforcement response requirement for both groups. Alcohol-reinforced responding per session increased for the noninitiated animals but remained unchanged for the initiated group during this condition. Responding increased substantially for both groups when the alcohol reinforcement response requirement was returned to baseline conditions. These results suggest that alcohol may serve more as a food source for noninitiated animals during the food reinforcement manipulation and that initiation may result in more resistance to change during the alcohol reinforcement manipulation. These data show that the type of initial exposure to alcohol can impact future drinking patterns.

Ethanol-reinforced responding by AA and ANA rats following the sucrose-substitution initiation procedure.

Ethanol-reinforced responding was initiated in male AA and ANA rats using the sucrose-substitution procedure. Before the initiation procedure, a homecage, two-bottle preference test was conducted. The rats were then trained to respond on an Fixed-Ratio 1 schedule with sucrose reinforcement. Over sessions, ethanol was added gradually to the sucrose solution as the concentration of sucrose was reduced until 10% ethanol (v/v) alone functioned as the reinforcer for lever pressing. The schedule of reinforcement was then increased to Fixed-Ratio 4. Next, the ethanol concentration presented as the reinforcer was increased over weeks to 15%, 20%, 30%, and then returned to 10%. A second homecage test was then performed. The results showed that the AA and ANA lines differed significantly on preference and intake (g/kg) during the homecage preference tests. There was a significant increase in preference during the second homecage test. During sucrose substitution, initial large differences in responding were observed between the lines. When the ethanol concentration was increased, intake (grams per kilogram) increased for the AA line but not for the ANA line. These effects were a function of no change in responding by the AA rats as concentration was increased and a decrease in responding by the ANA rats at the higher concentrations (20% and 30%). Taken together, data indicate that ethanol can function as a positive reinforcer for the behavior of AA and ANA rats. Even though 10% ethanol functioned as a reinforcer similarly for the two lines, ethanol intake in the AA line was significantly greater at the higher concentrations of ethanol, suggesting that ethanol functioned as a qualitatively different reinforcer for the AA rats, compared with the ANA rats.

Initiation of ethanol self-administration by the sucrose-substitution method with HAS and LAS rats.

This study was performed to examine ethanol self-administration in rats bred for different sensitivities to the sedative effects of alcohol [the Colorado High Alcohol Sensitive (HAS) and Low Alcohol Sensitive (LAS) rats]. Four rats from each replicate line of the HAS and LAS rats (n = 16) were obtained from the University of Colorado, and initiation to self-administer ethanol by the sucrose-substitution procedure was attempted. Before the initiation procedure was conducted, home-cage ethanol intake and preference ratio did not differ between LAS and HAS rats. During the initiation procedure, the LAS rats came to self-administer 10% ethanol (v/v) at similar levels as outbred Wistar rats initiated with the same procedure (approximately 0.4 g/kg/session). The HAS rats, however, failed to initiate (approximately 0.08 g/kg/ session after completing the sucrose-substitution procedure) and lever pressing was reduced even more in the HAS rats when the ethanol concentration presented was > 10% (v/v). Three of the eight HAS rats stopped lever pressing completely when the ethanol concentration was raised to 15%. After initiation, home-cage preference ratio differed significantly between the LAS and HAS rats (LAS > HAS, p < 0.03). That the LAS rats did not consume greater amounts of ethanol compared with outbred Long-Evans or Wistar rats is contrary to our hypothesis, based on recent human data suggesting that a lower sensitivity to ethanol could result in increased alcohol intake. The finding that the HAS rats could not be initiated, while selectively bred ethanol nonpreferring rats can, is also contrary to our hypothesis. Further studies related to ethanol self-administration with the HAS line could provide important information related to the genetics of alcohol nonacceptance.

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.

Effects of continuous versus limited access to ethanol on ethanol self-administration.

Eight male, experimentally naive Long-Evans rats were housed in operant chambers 23 h per day following initiation to self-administer ethanol. While housed in the chambers, the animals had continuous access to food pellets according to a fixed ratio 1 schedule of reinforcement, 10% ethanol (v/v) according to a fixed ratio 4 schedule of reinforcement and water in a drinking tube with licks recorded via a drinkometer. Over a series of experimental phases, daily availability of the ethanol solution was limited to 16, 6, 4, 2, or 1 30-min period per day. The 1 30-min period access was examined during the 12th hour or the second hour of the daily sessions. Over the course of the experiment, total responses on the lever that operated the dipper, g/kg per day and number of ethanol drinking bouts per day decreased significantly as the number of daily access periods decreased. On the other hand, the number of dippers presented per ethanol bout, g/kg per ethanol bout and ethanol bout duration increased, with significant increases in dippers per bout occurring when one 30-min access period per day was provided. These data indicate that the size of a single ethanol drinking bout can be increased somewhat by limiting the opportunity to obtain ethanol reinforcement and agrees with earlier research that has shown similar effects.

Effects of manipulating food availability on ethanol self-administration by P rats in a continuous access situation.

Male rats from the alcohol-preferring (P) line were housed in operant chambers in which food, water, and ethanol (10% v/v) were available continuously 23 hr per day. Over a period of weeks, the fixed ratio (FR) requirement for food reinforcement was gradually increased from FR 1 to FR 64. The response requirements for water and ethanol remained constant throughout the experiment. As the FR requirement for food reinforcement increased, the total number of food-reinforced responses increased significantly, whereas the total number of food pellets delivered per day and total calories per day decreased significantly. Conversely, ethanol intake (g/kg) and the percentage of total calories from ethanol increased significantly as the response requirement for food reinforcement increased. The increase in ethanol intake was accounted for largely by an increase in the number of ethanol drinking bouts per day rather than an increase in the number of dippers presented per bout. The results support the hypothesis that the manipulation of environmental variables, such as FR requirement for food reinforcement, can influence the ethanol self-administration of P rats; an effect observed previously with nonselected Long-Evans rats.

Ethanol self-administration by alcohol-nonpreferring (NP) rats in a continuous access situation.

Male rats, from the alcohol nonpreferring (NP) line, were studied in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 h/d. The NP rats consumed less ethanol per day following 7 weeks under these conditions than did either alcohol-preferring (P) rats or Long-Evans (LE) studied previously under the same conditions for 4 weeks. The NP rats consumed 0.2 g/kg per day during the first week of the experiment, 0.72 g/kg per day during the fourth week, and 1.03 g/kg per day during the seventh week compared to 2.2 g/kg per day for LE rats and 4.8 g/kg per day for P rats following 4 weeks. These data indicate that NP rats will slowly initiate ethanol self-administration under continuous access conditions, but to a lesser extent and at a slower rate than other lines of rats studied previously.

Effects of ethanol concentration and fixed-ratio requirement on ethanol self-administration by P rats in a continuous access situation.

Rats, from the alcohol preferring (P) line, were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. During Experiment 1, the effects of changing ethanol concentration and response requirement for ethanol were examined. Ten percent and 20% ethanol (v/v) were available on two fixed ratio (FR) schedules, FR 1 and FR 4, for 2 weeks each. During Experiment 2, the effects of increasing the response requirement for ethanol were investigated. Starting with FR 4, the FR requirement for ethanol doubled during 2-week intervals until FR 32 was in effect. For the final phase of these studies, water was placed in the dipper for 1 week followed by a return to 10% ethanol in the dipper. The results from Experiment 1 indicated that when the FR requirement was decreased from FR 4 to FR 1, ethanol-reinforced responding decreased but total daily intake increased. Lowering the FR requirement did not affect the number of ethanol bouts per day but bout size increased. Ethanol concentration had no effect on bout size but the number of bouts per day decreased when the concentration was increased to 20%. Since bout size was unchanged by increasing the ethanol concentration, intake per bout increased at 20% ethanol. The results from Experiment 2 indicated that increasing the response requirement for ethanol decreases ethanol intake. When water was placed in the dipper, responding decreased to the lowest levels observed in the experiment. When ethanol was returned to the dipper, responding returned to baseline levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol drinking patterns in a continuous-access operant situation: effects of ethanol concentration and response requirements.

Rats, initiated to self-administer ethanol with either a sucrose-substitution procedure or a secondary-conditioning procedure, were maintained in a continuous-access environmental system in which operant lever press responses were required to receive 10% ethanol and food reinforcement. Water available from a drinking tube was electronically monitored to detect licks. Total daily consumption and patterns of food, water, and ethanol responding were analyzed under conditions in which the concentration of ethanol presented as a reinforcer was either 10% or 20%, and the response requirement for ethanol reinforcement was either a fixed ratio 4 schedule or a fixed ratio 1 schedule. Either increasing the ethanol concentration or decreasing the response requirement resulted in an increase in total daily ethanol intake. There was no significant difference between initiation procedures. These results are similar to observations in studies using a limited-access operant situation. This increased ethanol intake resulted from a complex alteration in the daily ethanol drinking pattern. The greatest ethanol intakes were observed when both the ethanol concentration was increased and response requirement was decreased. This was predominantly the result of increasing the number of ethanol drinking bouts per day when the response requirement was decreased, and by decreasing individual bout size by less than half when the ethanol concentration was doubled. These studies indicate that concentration of the ethanol presented as the reinforcer and the response cost required for reinforcement are involved in regulating ethanol consumption in the continuous-access condition. Type of initiation did not appear to interact with these variables.

Alcohol self-administration in a nonrestricted access situation with alcohol-preferring (P) rats.

Genetic variables have been implicated as contributing factors in the development of alcoholic behavior. Rats bred selectively for alcohol preference have been used in laboratory studies to investigate the role of such variables. In the present study, rats from the alcohol preferring (P) line were placed in operant chambers in which food pellets, water, and 10% ethanol (v/v) were available continuously for 23 hr/day. Food pellets (45 mg) were presented on an FR 1 schedule of reinforcement, while ethanol was presented in a 0.1 ml dipper on an FR 4 schedule of reinforcement. Water was available in a drinking tube with licks monitored by a drinkometer. Data were analyzed in terms of both total daily intakes and computer defined bouts. The P rats showed greater daily ethanol intakes compared with Long-Evans (LE) animals previously studied under similar access conditions. The major difference in intake was a result of the P rats having a greater number of daily ethanol drinking bouts, while having only a slight increase in individual bout size. These data indicate that genetic selection for ethanol preference may result in the regulation of ethanol intake by means of changes in the frequency of ethanol drinking bouts but not by changes in bout size.

Effects of morphine and naloxone on ethanol- and sucrose-reinforced responding in nondeprived rats.

In the following series of experiments, effects of morphine (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) and naloxone (0.1, 0.3, and 1.0 mg/kg) were assessed in nondeprived rats trained to leverpress with 10% ethanol, sweetened ethanol, or 5% sucrose and water as the reinforcers. Morphine, at doses of 0.1, 0.3, and 1.0 mg/kg had little effect on responding with ethanol or sweetened ethanol available on a fixed ratio 4 (FR4) schedule of reinforcement, but at the 3.0 mg/kg dose, morphine suppressed responding to near zero. Similar results were obtained when 10% ethanol and water were available on a concurrent FR4 FR4 schedule of reinforcement. When 5% sucrose and water were available concurrently, morphine suppressed responding at 3.0 and 10 mg/kg. Naloxone (0.1, 0.3, and 1.0 mg/kg) decreased responding for ethanol, sweetened ethanol, and sucrose solutions in a dose-dependent manner. Naloxone decreased total number of responses/session by shortening the duration of responding without affecting momentary rate. Overall, the data suggest that the endogenous opioid system plays a role in the ability of ethanol to reinforce operant behavior. However, this role does not appear to be specific to ethanol because similar results were observed with sucrose reinforcement. Failure to find enhanced ethanol intakes following morphine injections in the operant situation suggests that the method used to measure ethanol self-administration makes a difference in assessing the effects of drugs on ethanol intake.

Effects of methylphenidate on responding under extinction in the presence and absence of conditioned reinforcement.

Pigeons pecked a key during sessions that began with a variable number of reinforcers under a second-order schedule of food presentation. Every 30sec, on the average, a key peck was followed immediately by one of two consequences: (a) food presentation, accompanied by a stimulus complex that consisted of houselight off, key color change, tone presentation, and hopper-light illumination, or (b) the stimulus complex alone. Following the last food presentation, 20min of one of two types of extinction began. The two types of extinction were: (a) standard extinction (key pecks had no consequence) and (b) key pecks produced, on a variable-interval schedule, the stimulus complex previously paired with food. Consequently, it was possible to study performance under extinction during which responses either did or did not result in occasional presentation of a food-paired stimulus complex. Methylphenidate (5, 10 and 20mg/kg) occasionally was administered before sessions containing each type of extinction. At moderate doses methylphenidate produced higher response rates during extinction when the stimulus complex was presented than when it was not. These results support previous findings with rats that stimulant drugs can enhance responding during extinction when responding produces conditioned reinforcers, and illustrate this effect in a novel, within-subject design.