Effects of MDL 72222, a serotonin3 antagonist, on operant responding for ethanol by alcohol-preferring P rats

BACKGROUND: Previous studies indicated that, under continuous access conditions, the 5-HT3 antagonist MDL 72222 (MDL) effectively reduced ethanol drinking of alcohol-preferring P rats. However, MDL was without effect when similar doses were tested under scheduled access conditions, unless the ethanol access period was randomly presented. This study examined the effects of MDL on operant responding for ethanol and water by adult male alcohol-preferring P rats. METHODS: During the dark cycle, subjects in the first experiment were trained to respond concurrently for 15% ethanol and water on a fixed-ratio 5 (FR-5) and FR-1 schedule of reinforcement, respectively. Approximately 30 min before the 4-hr operant session, rats were injected subcutaneously (sc) with saline or MDL (1, 3, or 5 mg/kg). A second experiment tested the effects of 1 mg/kg MDL on operant responding for 15% ethanol in 1-hr sessions when operant access was given at a fixed time each day (fixed scheduled access, FSA group) or at variable time periods throughout the dark cycle (variable scheduled access, VSA group). RESULTS: In the first experiment, only the 5 mg/kg dose of MDL decreased responding for ethanol (approximately 20%) during the first 30 min of the 4-hr session. This dose also reduced total 4-hr responding for ethanol and water. In the second experiment, the 1 mg/kg dose of MDL had no effect on operant responding by the FSA group, but significantly reduced ethanol responding by the VSA group. CONCLUSIONS: These results suggest that 5-HT3 receptors may be involved in mediating the reinforcing effects of ethanol, and that temporal-environmental cues associated with the presentation of ethanol may be one factor involved in reducing the effectiveness of 5-HT3 antagonists to attenuate ethanol intake.     

Effects of acamprosate on ethanol-seeking and self-administration in the rat

BACKGROUND: Acamprosate (calcium acetyl homotaurinate) has been used clinically to treat relapse in alcoholics. In rats, it has been shown to decrease ethanol, but not water, self-administration after ethanol deprivation. METHODS: To further investigate the effect of acamprosate on reinforced behaviors in rats, the present experiment used: (1) both ethanol and sucrose reinforcer solutions to better assess the distinct effects of acamprosate on ethanol-directed behaviors, and (2) an operant model that procedurally separates the "cost" to begin drinking from consuming the reinforcer solutions to dissociate the effects of acamprosate on appetitive versus consummatory processes. In daily sessions (5 days/week), rats (n = 6/group) were trained to make 30 lever-press responses to gain access for 20 min to a sipper tube containing either ethanol (10%) or sucrose (3%). After stable responding, acamprosate treatment was given. Three doses were tested (50, 100, and 200 mg/kg/injection, intraperitoneally), one dose per week. Each week, a total of four injections were given (21 and 2 hr before the operant sessions over 2 consecutive days). RESULTS: At these doses, acamprosate had no effect on the measures of appetitive responding for either solution. However, all doses reliably decreased ethanol consumption on the 2nd day of treatment (from an average of 0.83 to 0.63 g/kg). Analysis of the pattern of ethanol consumption showed that the effects of acamprosate occurred after the onset of a normal pattern of intake, as measured by lick rate and size of the initial bout of drinking, which suggested that acamprosate is most effective when combined with the pharmacological effects of ethanol. Sucrose intake was unaffected by all acamprosate treatments, which indicated that the treatment effects were specific to ethanol and not due to a general decrease in consummatory behavior. CONCLUSIONS: Overall, these results suggest that acamprosate is effective at reducing total ethanol intake, but may not reliably alter subjects propensity to begin a drinking bout as measured by this model. However, whether this applies to the clinical use of acamprosate, where other types of reinforcement may also precipitate relapse drinking, is not certain.     

Elevated Concentrations of Ethanol in Plasma Do Not Suppress Voluntary Ethanol Consumption in C57BL Mice

The 24-hr patterns of ethanol intake and resulting concentrations of ethanol in plasma are described for male C57BL/6J mice given free access to water and a 10% v/v solution of ethanol. Animals treated with the alcohol dehydrogenase inhibitor 4-methylpyrazole developed peak plasma concentrations of 116 +/- 20 mg/100 ml, while controls given daily injections of saline exhibited peak plasma concentrations of 11 +/- 7 mg/100 ml. Ethanol consumption as measured by total daily intake and preference was not significantly different in the two groups of mice. The absence of an effect on ethanol consumption despite a tenfold difference in peak plasma levels suggests that concentrations of circulating ethanol within the range observed do not limit voluntary consumption of ethanol.     

Effects of concurrent access to multiple ethanol concentrations and repeated deprivations on alcohol intake of alcohol-preferring rats

BACKGROUND: The alcohol deprivation effect (ADE) is a temporary increase in the voluntary intake of ethanol solutions following a period of alcohol deprivation. Multiple deprivations can prolong the expression of an ADE. This study examined the effects of initial deprivation length, concurrent exposure to multiple ethanol concentrations, and number of deprivation exposures on the magnitude and duration of the ADE in alcohol-preferring (P) rats. METHODS: Adult female P rats received 24-hr free-choice access to 10, 20, and 30% ethanol and water for 6 weeks. Rats were then randomly assigned to three groups; one group served as a nondeprived control, whereas the other two groups were initially deprived of ethanol for 2 or 8 weeks. The ethanol solutions were restored to both deprived groups for 2 weeks before the groups were deprived of ethanol for another 2 weeks. This cycle was repeated three times for a total of four deprivations. RESULTS: After the initial ethanol deprivation period, both deprived groups displayed a similar 2-fold increased ethanol intake (g/Kg/day) during the initial 24-hr period when ethanol was restored. Both deprived groups showed greater than 2-fold increases in intake of the 20 and 30% ethanol solutions after re-exposure. Ethanol consumption returned to baseline levels within 2 weeks, before the subsequent deprivation period. Multiple deprivations increased the magnitude of the ADE over that observed in the first deprivation during the initial 24-hr period of re-exposure and prolonged the duration of the ADE. In addition, repeated deprivations increased ethanol intake in the first 2-hr period of re-exposure and produced blood ethanol levels in excess of 150 mg/100 ml. CONCLUSIONS: Alterations in the reinforcing and/or aversive effects of alcohol occurred after a single prolonged deprivation and were enhanced with repeated deprivations.     

Effects of Pregnanolone and Dehydroepiandrosterone on Ethanol Intake in Rats Administered Ethanol or Saline during Adolescence

Background: Adolescent alcohol use may contribute to long‐term changes in the receptors and neuroactive steroids that may mediate its effects and to subsequent alcohol abuse and dependence as an adult. Therefore, in this study, ethanol preference and intake as an adult were examined after adolescent ethanol or saline administration. In addition, ethanol intake in the same groups was examined after administration of 2 neuroactive steroids with modulatory effects at GABA_A receptors. Methods: Two groups of male Long‐Evans rats were administered 15 intraperitoneal (i.p.) injections of either ethanol (2 g/kg, 20% v/v) or saline between postnatal days 35 and 63. Starting on postnatal day 75, both groups were trained to consume 10% ethanol using a saccharin‐fading procedure, and ethanol intake and preference were measured after a series of manipulations involving food deprivation, changes in the duration of access to ethanol, and changes in the concentrations of ethanol presented. Following these manipulations, pregnanolone (1 to 10 mg/kg) and dehydroepiandrosterone (DHEA, 1 to 100 mg/kg) were administered prior to preference sessions with an 18% ethanol solution. Results: Adult ethanol preference and intake did not differ significantly in subjects treated with either saline or ethanol as adolescents during training, the substitution of other ethanol concentrations (3.2 to 32%), ad‐lib feeding, or moderate food deprivation. Pregnanolone administration altered the intake of both adolescent‐treated groups after the first injection of 3.2 mg/kg and after repeated injections with 10 mg/kg, a dose that produced sedation. In contrast, multiple doses of DHEA consistently decreased intake of an 18% ethanol concentration in both groups after repeated injections and 3 doses of DHEA (10, 32, and 56 mg/kg) administered with various ethanol concentrations dose‐dependently shifted the ethanol‐concentration curves for the volume and dosage of ethanol consumed downward. Conclusions: These results indicate that chronic intermittent ethanol (CIE) administration of 2 g/kg during adolescence did not alter preference or overall consumption of ethanol in outbred rats trained to drink ethanol as an adult under the conditions tested, and that DHEA may be more effective than pregnanolone at significantly decreasing ethanol consumption.     

The Alcohol Deprivation Effect in the Alcohol-Preferring P Rat under Free-Drinking and Operant Access Conditions

The alcohol-deprivation effect (ADE) was examined under 4-hr operant and 24-hr free-choice alcohol access in the alcohol-preferring (P) rat after deprivation intervals from 2 to 4 weeks. Results indicated that adult male P rats responding for 6 weeks on a concurrent FR-5/ FR-1 schedule of reinforcement for alcohol and water, respectively, and then deprived of alcohol for 2 weeks, demonstrated a 40% increase in alcohol responding during the first 60 min of alcohol reinstatement. The alcohol deprivation effect was temporary, however, as responding did not differ from baseline levels on the second day of reinstatement. In a second experiment, weanling male and female P rats received 7 weeks of continuous access to alcohol, beginning at 21 days of age, and were then deprived of alcohol for 4 weeks. On the first day of alcohol reinstatement, P rats exhibited a 40% to 45% increase from baseline alcohol drinking levels, with alcohol intake returning to baseline levels by the 3rd day of reinstatement. Although alcohol intake was higher in females than in males when adjustment was made for body weight, there were no gender differences in the magnitude of the alcohol deprivation effect. Taken together, these results indicate that the ADE is a long-lasting phenomenon that occurs under both operant and continuous access conditions in the P rat, and thus these rats may be useful models for the study of factors involved in relapse of alcohol drinking.     

Patterns of Ethanol Intake in Preadolescent, Adolescent, and Adult Wistar Rats Under Acquisition, Maintenance, and Relapse-Like Conditions

Background: Animal behavioral models of voluntary ethanol consumption represent a valuable tool to investigate the relationship between age and propensity to consume alcohol using an experimental methodology. Although adolescence has been considered as a critical age, few are the studies that consider the preadolescence age. This study examines the ethanol consumption/preference and the propensity to show an alcohol deprivation effect (ADE) after a short voluntary ethanol exposure from a developmental perspective. Methods: Three groups of heterogeneous Wistar rats of both sexes with ad libitum food and water were exposed for 10 days to 3 ethanol solutions at 3 different ontogenetic periods: preadolescence (PN19), adolescence (PN28), and adulthood (PN90). Ethanol intake (including circadian rhythm), ethanol preference, water and food consumption, and ADE were measured. Results: During the exposure, the 3 groups differed in their ethanol intake; the greatest amount of alcohol (g/kg) was consumed by the preadolescent rats while the adolescents showed a progressive decrease in alcohol consumption as they approached the lowest adult levels by the end of the assessed period. The pattern of ethanol consumption was not fully explained in terms of hyperphagia and/or hyperdipsia at early ages, and showed a wholly circadian rhythm in adolescent rats. After an abstinence period of 7 days, adult rats showed an ADE measured both as an increment in ethanol consumption and preference, whereas adolescent rats only showed an increment in ethanol preference. Preadolescent rats decreased their consumption and their preference remained unchanged. Conclusions: In summary, using a short period of ethanol exposure and a brief deprivation period the results revealed a direct relationship between chronological age and propensity to consume alcohol, being the adolescence a transition period from the infant to the adult pattern of alcohol consumption. Preadolescent animals showed the highest ethanol consumption level. The ADE was only found in adult animals for both alcohol consumption and preference, whereas adolescents showed an ADE only for preference. No effect of sex was detected in any phase of the experiment.     

Influence of age at drinking onset on long-term ethanol self-administration with deprivation and stress phases

BACKGROUND: Onset of alcohol use during adolescence has potentially long-lasting consequences, e.g., prospective alcohol dependence. To obtain new insight into the effects of early chronic ethanol consumption, we compared the drinking behavior of two adult male Wistar rat groups: one that initiated alcohol consumption during adolescence (adolescent group) and the other that initiated their drinking during adulthood (adult group) in a model of long-term alcohol self-administration. We investigated the magnitude of the effects of deprivation and stress on alcohol intake and the influence of these events on the alcohol drinking behavior across time. METHODS: Heterogeneous Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as 5% and 20% ethanol solutions during an observation period of 30 wk. A deprivation phase of 14 days was instituted after eight wk of access to alcohol. After 16 and 26 wk of alcohol access, all animals were subjected for three consecutive days to forced swimming and electric foot shocks, respectively. RESULTS: At the onset of drinking, adolescent animals consumed less alcohol and showed lower preference than adults. The deprivation phase was followed by increased intake of highly concentrated ethanol solution without appreciable differences between age groups. Repeated swim stress produced a slight increase in ethanol consumption in both animal groups; however, alcohol intake was not significantly different between groups, whereas the foot shock stress-induced increase in alcohol intake was significantly higher in the animal group that initiated alcohol consumption during adolescence. After swim stress, the drinking behavior of the adolescent group resembled that of the adult group. In particular, the adolescent group increased their preference for 20% ethanol solution for the remainder of the experiment. CONCLUSIONS: Age of voluntary alcohol drinking onset does not appear to be a strong predictor for prospective alcohol intake and relapse-like drinking behavior under the present experimental conditions. However, male Wistar rats that initiated alcohol consumption during adolescence seem to be more susceptible to acute stressor-specific effects in terms of alcohol consumption.     

Intermittent access to 20% ethanol induces high ethanol consumption in Long-Evans and Wistar rats

Background: There has been some difficulty getting standard laboratory rats to voluntarily consume large amounts of ethanol without the use of initiation procedures. It has previously been shown that standard laboratory rats will voluntarily consume high levels of ethanol if given intermittent‐access to 20% ethanol in a 2‐bottle‐choice setting [ Wise, Psychopharmacologia 29 (1973), 203 ]. In this study, we have further characterized this drinking model. Methods: Ethanol‐naïve Long–Evans rats were given intermittent‐access to 20% ethanol (three 24‐hour sessions per week). No sucrose fading was needed and water was always available ad libitum. Ethanol consumption, preference, and long‐term drinking behaviors were investigated. Furthermore, to pharmacologically validate the intermittent‐access 20% ethanol drinking paradigm, the efficacy of acamprosate and naltrexone in decreasing ethanol consumption were compared with those of groups given continuous‐access to 10 or 20% ethanol, respectively. Additionally, ethanol consumption was investigated in Wistar and out‐bred alcohol preferring (P) rats following intermittent‐access to 20% ethanol. Results: The intermittent‐access 20% ethanol 2‐bottle‐choice drinking paradigm led standard laboratory rats to escalate their ethanol intake over the first 5 to 6 drinking sessions, reaching stable baseline consumption of high amounts of ethanol (Long–Evans: 5.1 ± 0.6; Wistar: 5.8 ± 0.8 g/kg/24 h, respectively). Furthermore, the cycles of excessive drinking and abstinence led to an increase in ethanol preference and increased efficacy of both acamprosate and naltrexone in Long–Evans rats. P‐rats initiate drinking at a higher level than both Long–Evans and Wistar rats using the intermittent‐access 20% ethanol paradigm and showed a trend toward a further escalation in ethanol intake over time (mean ethanol intake: 6.3 ± 0.8 g/kg/24 h). Conclusion: Standard laboratory rats will voluntarily consume ethanol using the intermittent‐access 20% ethanol drinking paradigm without the use of any initiation procedures. This model promises to be a valuable tool in the alcohol research field.     

Differences in Free-Choice Ethanol Acceptance between Taste Aversion-Prone and Taste Aversion-Resistant Rats

Taste aversion (TA)-prone (TAP) and TA-resistant (TAR) rats were tested for naive, nonforced acceptance of ethanol. Ethanol acceptance had played no role in line development. Rather, the lines had been developed via bidirectional, nonsibling matings based on susceptibility to develop cyclophosphamide-induced conditioned TAs to a 0.1% saccharin solution (at cyclophosphamide doses of 12.5 mg/kg for males and 15.0 mg/kg for females, ip). Rats from the 23rd selectively bred generations, with no prior exposure to ethanol, were given 24-hr access to a two-bottle choice between plain tap water and a solution of ethanol in water. Rats were initially given access to 1% ethanol in water, and the ethanol concentration was increased by 1% every 3 days to a maximum of 10%. Ethanol consumption (g ethanol consumed/kg body weight) and preference scores (volume ethanol solution consumed/total fluid intake) were determined by daily bottle weighings. At 1% ethanol concentration, there were no differences between the rat lines in terms of ethanol consumption or preference. At concentrations of 2 to 10%, TAP rats consumed less ethanol and showed a decreased preference for the ethanol solutions than TAR rats. Maximum ethanol consumption was reached at the 6% concentration for both lines. The mean (±SE) values of consumption at 6% ethanol were 1.8 (±0.8) and 5.6 (±0.5) g of ethanol/kg body weight for TAP and TAR rats, respectively. Mean (±SE) preference scores at 6% ethanol were 26 (±12) and 76 (±6) for TAP and TAR rats, respectively. These findings indicate that differences in TA conditionability may be associated with the propensity of rats to be high or low consumers of ethanol. Based on these data, it is hypothesized that high susceptibility for TA conditionability may deter many individuals from consuming the high levels of ethanol that usually precede alcohol tolerance and dependence.     

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 -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.     

Effects of alcohol deprivation on alcohol consumption using a sipper-tube procedure

BACKGROUND: When rats with prior experience drinking ethanol solutions are deprived of ethanol for various time periods, a transitory increase in alcohol consumption is observed when ethanol solutions are again made available. This has been termed the alcohol deprivation effect (ADE). The ADE has been observed in limited-access operant procedures in which small dippers of ethanol are presented following completion of a lever press requirement. However, it has not been determined if the effect occurs in an operant model of ethanol self-administration that separates the ethanol-seeking responding from the consummatory drinking (the sipper procedure). METHODS: Rats were initiated to drink ethanol from a sipper tube using the sucrose-substitution procedure. Once initiated, the rats had to make 30 lever presses to gain access to a sipper-tube containing the ethanol solution for 20 min. The effects of 2-3 days, 7 days, and 14 days of ethanol deprivation were examined on ethanol consumption and extinction responding (seeking response). RESULTS: There were no effects of deprivation on intake at any deprivation period examined. Contrary to expectations, the alcohol-seeking response as measured by extinction responding was decreased after 7 and 14 days of deprivation. CONCLUSIONS: The data from this study and others using the limited access operant procedures suggest that the ADE may be more related to consummatory control (i.e., loss of control) and not to ethanol-seeking behaviors (i.e., craving).     

Ethanol Reinforcement in the Alcohol Nonpreferring Rat: Initiation using Behavioral Techniques without Food Restriction

Genetic selection of rats can markedly alter their ethanol consumption. The manner in which environmental factors interact in these genetically selected animals to influence ethanol consumption has not been thoroughly investigated. Using the alcohol-nonpreferring (NP) line of rats selectively bred at the Indiana University School of Medicine, alcohol self-administration in an operant situation was initiated using either a sucrose-fading or a secondary-conditioning procedure. These initiation procedures do not require any food or fluid restriction. Initiation was successful in 10 out of 12 NP animals, with the initiated rats self-administering ethanol at concentrations as high as 40%. Following initiation, a retest of home-cage ethanol preference found increases in ethanol acceptability. When tested in a concurrent operant situation, the initiated NP rats also chose ethanol over water. However, the NP rats had lower alcohol intakes and a different pattern of drinking over time when compared to that of nonselected Long-Evans rats. While the NP rats could be initiated to lever-press for ethanol, at no time did their intake approach that of the selected line of alcohol-preferring (P) rats. Thus, while an upward shift from the genetic baseline in ethanol preference and intake can result from the environmental initiation manipulations employed in these studies, genetic factors would appear to limit the extent to which ethanol ingestion can be increased.     

Effect of naloxone on appetitive and consummatory phases of ethanol self-administration

BACKGROUND: The opioid system has been implicated in ethanol self-administration. Morphine, an opiate agonist, can sometimes increase the amount of ethanol consumed, and opiate antagonists such as naloxone and naltrexone decrease the amount of ethanol consumed in both animals and humans. The objective of this study was to examine the effect of naloxone on appetitive (or seeking) and consummatory behaviors by using an operant model developed to separate these two phases of self-administration. METHODS: Intraperitoneal injections of naloxone (0.3-10 mg/kg) or vehicle were given before operant self-administration sessions to assess the effect on lever pressing (appetitive behavior) and subsequent consumption. Effects were measured in two groups of rats: one self-administered a 3% sucrose solution and the other a 10% ethanol solution. RESULTS: Naloxone dose-dependently decreased ethanol and sucrose consumption by an earlier cessation of drinking in the session compared with vehicle injection days. There were some effects on appetitive responding after treatment with naloxone, but none was statistically significant. CONCLUSIONS: Naloxone may decrease ethanol self-administration by decreasing the postingestive or pharmacological effects of alcohol. This model provides a new method for examining the effects of potential pharmacotherapeutics on alcohol self-administration behavior.     

Effects of Neonatal Ethanol Exposure on Saccharin Consumption

Prenatal ethanol exposure has been associated with alterations in a variety of sexually dimorphic behaviors in rats. This study examined the effects of neonatal ethanol exposure on saccharin consumption, a sexually dimorphic behavior in rats. Subjects were Sprague-Dawley rats that were artificially reared (AR) from postnatal day (PN) 4-PN12 through gastrostomy tubes with ethanol exposure limited to PN4-PN10. The AR groups included two ethanol doses (6 g/kg/day and 4 g/kg/day) and an isocaloric maltose-dextrin control. A sham surgery control group was also included. The AR subjects were returned to their dams on PN13. At 21 days of age, subjects were housed with one same-sex sibling and free access to rat chow and water until testing. Subjects were tested for saccharin preference and consumption at 110 days of age. Typically, male rats consume less saccharin than females, and this was evident in the 4 g/kg ethanol group and both control groups. However, this was not apparent among the 6 g/kg ethanol-exposed males. Furthermore, saccharin preference seemed to be reduced in the females exposed to 6 g/kg ethanol. These data suggest that the "sensitive period" for ethanol's effects on sex differences in saccharin consumption extends into postnatal life.     

Early Social Isolation in Male Long-Evans Rats Alters Both Appetitive and Consummatory Behaviors Expressed During Operant Ethanol Self-Administration

Background: Postweaning social isolation in rats produces profound and long‐lasting cognitive and behavioral deficits in adult animals. Importantly, this housing manipulation alters sensitivity to a number of drugs of abuse including ethanol. However, most studies with ethanol have utilized continuous or limited home‐cage access to examine interactions between juvenile social experience and drinking. More recently, social isolation was shown to increased ethanol responding in a “dipper” model of self‐administration ( Deehan et al., 2007 ). In the current study, we utilize a “sipper” operant self‐administration model to distinguish the effects of isolation rearing on ethanol seeking‐ and drinking‐related behaviors. Methods: Postweaning juvenile male Long‐Evans rats were placed into 2 housing groups for 6 weeks: one group consisted of individually housed animals; the second group was housed 4 animals per cage. Following the isolation period, anxiety‐like behavior was assessed to confirm the efficacy of the isolation procedure. In some animals, ethanol drinking in the home cage was assessed using a continuous access, 2‐bottle choice paradigm. All animals were then individually housed and trained to lever‐press for a sipper tube containing either an ethanol solution or a sucrose solution. Results: Postweaning social isolation increased the expression of anxiety‐like behavior in the elevated plus maze but not the light‐dark box. Ethanol consumption was also increased during continuous home‐cage access with the 2‐bottle choice paradigm. During operant self‐administration, isolation housing increased the response rate and increased ethanol consumption but did not alter responding for or consumption of sucrose. The housing manipulation did not change the total number of lever responses during extinction sessions. Paired‐pulse inhibition deficits that are characteristic of juvenile isolation remained intact after prolonged experience with sucrose self‐administration. Discussion: The effects of postweaning social isolation on ethanol drinking in the home cage are also manifest during operant self‐administration. Importantly, these alterations in adult operant self‐administration are ethanol‐specific.     

Central nervous system mechanisms in alcohol relapse

BACKGROUND: Alcohol relapse is a major problem in the treatment of alcohol abuse and alcoholism. Understanding the long-term neuronal alterations that promote relapse of alcohol drinking is critical for the development of pharmacotherapies to treat alcoholism and alcohol abuse. The major objectives of this workshop were to present recent findings, by using rodent models, on behavioral and neurobiological factors that may underlie alcohol relapse and the results of clinical and pharmacological treatment strategies for preventing relapse. METHODS: Prolonged ethanol drinking and repeated periods of alcohol deprivation were studied in nonselected rats and in rats selectively bred for high alcohol preference (P rat). The expression of a robust alcohol deprivation effect (ADE) was used as a model for alcohol relapse in rodents. Operant techniques were used to examine responding for ethanol after deprivation in both rats and C57BL/6J mice. Environmental cues and stress were used to assess their effects on reinstatement of alcohol responding. Microdialysis and [14C]-2-deoxyglucose techniques were used to examine neuronal alterations associated with alcohol relapse. RESULTS: Prolonged free-choice ethanol drinking followed by deprivation produced an ADE in both stock and P rats. These rats demonstrated loss of control on reinstatement after chronic drinking and after prolonged deprivation. Acamprosate and naltrexone effectively reduced the ADE in stock rats. Stress reinstated operant responding for alcohol, and rats trained to associate a cue with ethanol presentation increased responding on the ethanol-associated lever in the absence of ethanol. After repeated deprivations, P rats shifted their preference toward drinking higher concentrations of ethanol, which increased the magnitude and duration of the ADE. Stock rats also shifted their preference toward solutions with higher ethanol concentrations and demonstrated a loss of control after prolonged ethanol drinking and deprivation. Long-lasting alterations in neuronal activity, serotonin-3 receptor function, and dopamine neurotransmission within the mesolimbic system were evident after chronic drinking that followed a prolonged deprivation period. CONCLUSIONS: The ADE is a useful model for studying alcohol relapse in both rats and mice. The potential validity of this model is supported by the findings that acamprosate and naltrexone are effective in preventing the ADE in rodents, and both compounds have gained recognition for their therapeutic effects in clinical populations. Genetics, stress, and environmental cues are all important factors that influence alcohol relapse. Long-term alterations in neuronal activity within the mesolimbic system, which possibly involve dopamine and serotonin, may underlie alcohol relapse.     

Patterns of Ethanol Consumption in a Continuous Access Situation: The Effect of Adding a Sweetener to the Ethanol Solution

The effect of the addition of sucrose to an ethanol solution upon daily intake patterns was examined in a continuous-access operant situation with Wistar rats. Rats were first initiated to self-administer orally a 10% ethanol (v/v) solution using the sucrose-substitution procedure in 30-min limited-access conditions. When then studied in a continuous-access operant situation (23 hr ethanol access), substantial increases in ethanol consumption were found when varying concentrations of sucrose were added to the ethanol solutions presented. This increased consumption was found to be a complex function of both an increase in the number of drinking occurrences each day and in the size of each drinking occurrence. When 2% sucrose was compared with 2% sucrose/10% ethanol, the consumption of the sweetened ethanol was greater than consumption of the sweetener alone, suggesting that the ethanol added to the ability of the solution to maintain behavior beyond that of the sucrose alone. This study supports the use of sweetened ethanol solutions for the study of ethanol drinking patterns, and as a model system for examining factors involved in the regulation of ethanol consumption.     

The Effects of Ethanol Initiation Procedures on Ethanol Reinforced Behavior in the Alcohol-Preferring Rat

Rats from the alcohol preferring (P) line developed at Indiana University were initiated to self-administer ethanol orally without food or water restriction using either a sucrose-fading or a secondary-conditioning procedure. Following initiation, they were tested under a variety of operant conditions to examine the ability of ethanol to reinforce lever pressing behavior. Regardless of initiation procedure, the animals maintained lever pressing behavior with ethanol reinforcement, even at ethanol concentrations as high as 40% (v/v). Slightly higher daily session intakes (g/kg) were found at the higher ethanol concentrations following the secondary-conditioning initiation procedure compared with the sucrose-fading technique. When both ethanol and water were concurrently available, the rats showed a high preference for ethanol reinforcement. When varying concentrations of sucrose were substituted for water, the amount of ethanol ingested decreased as the concentration of the alternative sucrose increased. However, if the response requirement for the sucrose was substantially greater than that for ethanol, the rats shifted their responding to the lever associated with ethanol presentation. The results are discussed in relation to prior work using similar procedures with Long-Evans non-selected rats and with the alcohol non-preferring (NP) rat line.     

Effects of long-term episodic access to ethanol on the expression of an alcohol deprivation effect in low alcohol-consuming rats

Background: The alcohol‐preferring (P) and ‐nonpreferring (NP) and high alcohol–drinking (HAD) and low alcohol–drinking (LAD) rats have been selectively bred for divergent preference for ethanol over water. In addition, both P and HAD rats display an alcohol deprivation effect (ADE). This study was undertaken to test whether the NP, LAD‐1, and LAD‐2 lines of rats could display an ADE as well. Method: Adult female NP, LAD‐1, and LAD‐2 rats were given concurrent access to multiple concentrations of ethanol [5, 10, 15% (v/v)] and water in an ADE paradigm involving an initial 6 weeks of 24‐hr access to ethanol, followed by four cycles of 2 weeks of deprivation from and 2 weeks of re‐exposure to ethanol (5, 10, and 15%). A control group had continuous access to the ethanol concentrations (5, 10, and 15%) and water through the end of the fourth re‐exposure period. Results: For NP rats, a preference for the highest ethanol concentration (15%) was evident by the end of the fifth week of access (～60% of total ethanol fluid intake). Contrarily, LAD rats did not display a marked preference for any one concentration of ethanol. All three lines displayed an ADE after repeated cycles of re‐exposure to ethanol, with the general ranking of intake being LAD‐1 > NP > LAD‐2 (e.g., for the first day of reinstatement of the third re‐exposure cycle, intakes were 6.5, 2.9, and 2.4 g/kg/day compared with baseline values of 3.1, 2.0, and 1.3 g/kg/day for each line, respectively). By the 13th week, rats from all three lines, with a ranking of LAD‐1 > NP > LAD‐2, were drinking more ethanol (3.3, 2.2, and 2.0 g/kg/day, respectively) compared with their consumption during the first week of access (～1.1 g/kg/day for all three lines). Conclusion: These data indicate that access to multiple concentrations of ethanol and exposure to multiple deprivation cycles can partially overcome a genetic predisposition of NP, LAD‐1, and LAD‐2 rats for low alcohol consumption. In addition, the findings suggest that genetic control of low alcohol consumption in rats is not associated with the inability to display an ADE.