Ethanol-reinforced Behavior Research Articles

Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol

The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol. The study further reveals that URB597 specifically acts through FAAH and that cannabinoid-1 (CB(1)) receptor is critical for N-arachidonoyl ethanolamide (AEA) mediated ethanol-reinforced behavior as revealed by lack of URB597 effect in both FAAH and CB(1)-/- mice compared with vehicle-treated -/- mice. The FAAH -/- mice displayed a lower sensitivity to hypothermic and sedative effects to acute ethanol challenge. The FAAH -/- mice also exhibited a reduction in the severity of handling-induced convulsions following withdrawal from chronic ethanol exposure. The CB(1) receptor and proenkephalin gene expressions, and CB(1) receptor and mu-opioid (MO) receptor-mediated G-protein activation were found to be significantly lower in the caudate-putamen, nucleus accumbens core and shell of FAAH -/- than +/+ mice. Interestingly, the MO receptor-stimulated G-protein signaling was greater in the striatum of FAAH -/- than +/+ mice following voluntary ethanol consumption. These findings suggest that an elevation in the AEA content and its action on the limbic CB(1) receptor and MO receptor might contribute to ethanol-reinforced behavior. Treatment with drugs that decrease AEA tone might prove useful in reducing excessive ethanol consumption.

κ-Opioid receptor modulation of accumbal dopamine concentration during operant ethanol self-administration

Our study examined ethanol self-administration and accumbal dopamine concentration during κ-opioid receptor (KOPr) blockade. Long-Evans rats were trained to respond for 20 min of access to 10% ethanol (with sucrose) over 7 days. Rats were injected s.c. with the long-acting KOPr antagonist, nor-binaltorphimine (NOR-BNI; 0 or 20 mg/kg) 15–20 h prior to testing. Microdialysis revealed a transient elevation in dopamine concentration within 5 min of ethanol access in controls. NOR-BNI-treated rats did not exhibit this response, but showed a latent increase in dopamine concentration at the end of the access period. The rise in dopamine levels correlated positively with dialysate ethanol concentration but not in controls. NOR-BNI did not alter dopamine levels in rats self-administering 10% sucrose. The transient dopamine response during ethanol acquisition in controls is consistent with previous results that were attributed to ethanol stimulus cues. The altered dopamine response to NOR-BNI during ethanol drinking suggests that KOPr blockade temporarily uncovered a pharmacological stimulation of dopamine release by ethanol. Despite these neurochemical changes, NOR-BNI did not alter operant responding or ethanol intake, suggesting that the KOPr is not involved in ethanol-reinforced behavior under the limited conditions we studied.

Relationship between dopamine D2 receptor-associated responses and operant ethanol self-administration in the rat: a factor analysis.

To characterize the relationship between dopamine D(2) receptor-associated responses and operant ethanol self-administration in Wistar rats. Thirty-two rats were first tested for apomorphine-induced sniffing and raclopride-induced catalepsy. Subsequently, the same subjects were initiated to lever press for ethanol in the sucrose-fading procedure. The subjects were allowed to respond for 8% v/v ethanol for 20 days. A factor analysis was used to characterize the relationship between D(2)-associated responses and parameters of sucrose and ethanol self-administration. The analysis revealed three factors accounting for 88.3% of the total variability. The first factor comprised only parameters of ethanol-reinforced behaviour. Parameters of sucrose self-administration and cataleptic responses to raclopride loaded heavily on the second and third factors, respectively. None of the factors comprised apomorphine-induced stereotypy. It appears that there is no relationship between apomorphine-induced sniffing, raclopride-induced catalepsy and operant responding for ethanol in Wistar rats. Our results, combined with previous reports, suggest that D(2) receptors are not primarily involved in the regulation of ethanol reinforcement.

Sucrose self-administration predicts only initial phase of ethanol-reinforced behaviour in Wistar rats.

To characterize the relationship between the sucrose- and ethanol-reinforced behaviour in Wistar rats. Subjects (n = 31) were trained to lever press for 8% (v/v) ethanol in an operant procedure where increasing concentrations of ethanol were introduced in the presence of 8% (w/v) sucrose. The sucrose concentration was subsequently decreased from 8 to 0%. Subjects were allowed to stabilize their intake of 8% ethanol over the next 20 days. Self-administration of 8% sucrose (ml/kg) significantly correlated with ethanol consumption (g/kg) on days 1-5 of the 8% ethanol self-administration period. This relationship completely disappeared during the subsequent weeks of ethanol self-administration (days 6-20). The results of the present study, combined with our previous findings, may indicate that self-administration of sucrose predicts only the initial phase of ethanol-taking behaviour in Wistar rats.

Oral drug self-administration in the home cage of mice: alcohol-heightened aggression and inhibition by the 5-HT1B agonist anpirtoline.

In order to model heightened aggression after alcohol consumption and to study the inhibitory influence of 5-HT1B receptors on drinking and fighting, an experimental procedure should enable self-administration of precise amounts of alcohol in a limited period of time before an aggressive confrontation. To design a new device that can reinforce operant responding by the delivery of sweet alcohol in the resident mouse home cage, where aggressive behavior toward an intruder can subsequently be examined, and to demonstrate inhibition of alcohol-heightened aggression by 5-HT1B receptor agonist treatment. Within one experimental session, all singly housed CFW male mice (n=26) performed a nose-poke response that was reinforced by 0.05 ml sucrose. Using the sucrose fading technique, eventually the mice consumed a 6% ethanol/4% sucrose solution after each fifth nose poke during daily 15-min experimental sessions. The number of ethanol reinforcements was adjusted so that 0.6, 1.0, 1.7, and 3.0-g/kg doses were consumed in 15 min or less. Assays confirmed blood alcohol levels at 68.1 mg/dl for intake of 1.0 g/kg. After consuming a specific dose of ethanol in the form of a fixed number of response-dependent deliveries, the response panel was removed from the home cage and, 15 min later, the resident confronted a male intruder. Anpirtoline was administered either before alcohol self-administration or before the aggressive confrontation. After being reinforced with 1.0 g/kg or 1.7 g/kg sweet ethanol, the mice significantly increased attack and threat behavior relative to their aggressive behavior following sucrose or water consumption only. Treatment with the 5-HT1B receptor agonist anpirtoline (0.125, 0.25, 0.5 mg/kg, i.p.) before the confrontation decreased alcohol-heightened aggression and species-typical aggression in the absence of changes in other elements of the behavioral repertoire. Anpirtoline affected ethanol-reinforced behavior only at doses that were 5-10 times higher than those producing anti-aggressive effects. Self-administration of alcohol in the home cage of mice is readily accomplished with the aid of a simple, removable panel. The effective inhibition of high levels of aggressive behavior due to alcohol consumption after anpirtoline treatment confirm the 5-HT1B receptor as a critical site in the termination of aggression.

Ethanol-reinforced behaviour in the rat: effects of naltrexone

It has been repeatedly reported that endogenous opioid pathways play an important role in ethanol drinking behaviour. In line with these findings, a non-selective opioid receptor antagonist, naltrexone, seems to reduce relapse rates in detoxified alcoholics. The aim of the present study was to evaluate the effects of naltrexone on (i) ethanol self-administration; (ii) extinction of responding for ethanol; (iii) reinstatement of ethanol-seeking induced by non-contingent presentations of ethanol-associated stimuli. Male Wistar rats were trained to lever-press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of naltrexone's actions was assessed by studying its effects on water-reinforced behaviour in separate control experiments. Acute injections of naltrexone (1 or 3 mg/kg) did not alter ethanol self-administration. Repeated treatment with naltrexone (3 mg/kg, before three consecutive self-administration sessions) progressively reduced ethanol intake. In the extinction procedure, acute administration of 3 mg/kg naltrexone suppressed responding previously reinforced with ethanol. Similarly, naltrexone (1–3 mg/kg) potently and dose-dependently inhibited reinstatement of ethanol-seeking produced by non-contingent deliveries of the liquid dipper filled with 8% ethanol. In the control experiments, lower doses of naltrexone (1–3 mg/kg) did not exert any effect on either reinforced or non-reinforced (extinction) lever-pressing for water. These results indicate that: (i) subchronic treatment with naltrexone leads to progressive reduction of ethanol self-administration; (ii) single doses of naltrexone may increase extinction and attenuate cue-induced reinstatement of ethanol-reinforced behaviour.

Neuronal spike activity in the nucleus accumbens of behaving rats during ethanol self-administration

Many lines of evidence support the importance of the nucleus accumbens (NAC) for ethanol-reinforced behavior. The nature of the neuronal activity that occurs in this region during ethanol self-administration is not known. We recorded from ensembles of single-units primarily located within the shell of the NAC during operant responding for oral ethanol solutions by well-trained rats. Of 90 units recorded from seven sessions from seven rats, 41 (46%) did not exhibit significant changes in relation to the experimental events. Of the 49 units (54%) that did exhibit significant phasic changes, alterations in firing rate occurred in relation to the following experimental events: operant response (63%), tone stimulus (20%), and ethanol delivery (63%). In addition, changes in spike activity during the intervals between the three experimental events were noted in 33% of the units. Most units (55% of responsive units) responded to multiple experimental events. Thus different but overlapping populations of neurons in the NAC represent each event that occurs along the temporal dimension of a single trial performed to obtain ethanol reward. The data suggest that the NAC plays a crucial role in linking together conditioned and unconditioned internal and external stimuli with motor plans to allow for ethanol-seeking behavior to occur.

Suppression of Ethanol-Reinforced Behavior by Naltrexone Is Associated with Attenuation of the Ethanol-Induced Increase in Dialysate Dopamine Levels in the Nucleus Accumbens

The opiate antagonist naltrexone suppresses ethanol-reinforced behavior in animals and decreases ethanol intake in humans. However, the mechanisms underlying these actions are not well understood. Experiments were designed to test the hypothesis that naltrexone attenuates the rewarding properties of ethanol by interfering with ethanol-induced stimulation of dopamine activity in the nucleus accumbens (NAcc). Simultaneous measures of the effects of naltrexone on dialysate dopamine levels in the NAcc and on operant responding for oral ethanol were used. Male Wistar rats were trained to self-administer ethanol (10-15%, w/v) in 0.2% (w/v) saccharin during daily 30 min sessions and were surgically prepared for intracranial microdialysis. Experiments began after reliable self-administration was established. Rats were injected with naltrexone (0.25 mg/kg, s.c.) or saline and 10 min later were placed inside the operant chamber for a 20 min waiting period with no ethanol available, followed by 30 min of access to ethanol. A transient rise in dialysate dopamine levels was observed during the waiting period, and this effect was not altered by naltrexone. Ethanol self-administration reliably increased dopamine levels in controls. Naltrexone significantly suppressed ethanol self-administration and prevented ethanol-induced increases in dialysate dopamine levels. Subsequent dose-effect analyses established that the latter effect was not merely a function of reduced ethanol intake but that naltrexone attenuated the efficacy of ethanol to elevate dialysate dopamine levels. These results suggest that suppression of ethanol self-administration by opiate antagonists is the result of interference with dopamine-dependent aspects of ethanol reinforcement, although possible additional effects via nondopaminergic mechanisms cannot be eliminated as a factor in opiate antagonist-induced reduction of ethanol intake.

Ethanol-reinforced behaviour in rats: effects of memantine

Ethanol-reinforced behaviour in rats: effects of memantine

Ethanol-reinforced behaviour in the rat: effects of uncompetitive NMDA receptor antagonist, memantine

Ethanol has been reported to alter NMDA receptor-mediated biochemical and electrophysiological responses in vitro. The aim of the present study was to evaluate the effects of an uncompetitive NMDA receptor antagonist memantine, in animal models of alcoholism. Male Wistar rats were trained to drink 8% ethanol in a free-choice, limited access procedure. A separate group of animals was trained to lever press for 8% ethanol in an operant procedure where ethanol was introduced in the presence of sucrose. The selectivity of memantine's actions was assessed by studying its effects on food or water consumption in separate control experiments. Memantine (4.5–24 mg/kg) significantly, but not dose dependently, affected ethanol drinking in the limited access procedure. However, only 6 mg/kg memantine selectively decreased ethanol drinking. Memantine did not alter ethanol intake in rats trained to lever press for ethanol in the operant procedure. Only 9 mg/kg memantine reduced operant responding in the extinction procedure in the rats trained to lever press for ethanol. The same dose of memantine significantly reduced the operant behaviour of rats trained to respond for water. These results indicate that: (i) single doses of memantine only moderately and not dose dependently reduce alcohol drinking in the limited access procedure; (ii) memantine produces non-selective effects on operant behaviour in rats trained to lever press for ethanol in an oral self-administration procedure.

Ethanol self-administration is genetically independent of locomotor stimulation in fast and slow mice

One substance abuse hypothesis proposes that rewarding effects of drugs are causally related to their psychostimulant effects. We examined this hypothesis by comparing operant self-administration of ethanol in mice selectively bred for either high (Fast) or low (Slow) locomotor stimulation response to ethanol. Mice were trained to lever press for ethanol using postprandial induction and were then tested over a range of conditions to determine the degree of self-administration. There were no significant differences between Fast and Slow mice in either the amount of work produced to obtain ethanol or the amount of ethanol consumed. In general, none of the groups of mice showed robust ethanol-reinforced behavior. This is in contrast with C57BL/6J mice tested concurrently, which showed substantial ethanol-reinforced behavior. Further analysis revealed individual differences in responding within each of the selected lines. However, there was no systematic pattern within or between groups for these individual differences, suggesting that the genes mediating ethanol-reinforced behavior are segregating in a manner independent from genes mediating the locomotor stimulant response to ethanol, and thus, the mechanistic processes mediating reinforcement from ethanol are distinct from those that influence the psychomotor stimulant response to this drug.

Selective serotonin reuptake inhibitors: effects of chronic treatment on ethanol-reinforced behavior in mice

Several lines of evidence suggest that aspects of ethanol drinking are mediated, at least in part, by serotonergic (5-HT) neurotransmitter systems. Ethanol-preferring animals show decreases in serotonin function and receptor densities. In addition, serotonin uptake inhibitors have been shown to decrease ethanol consumption in animal models and in humans. However, the time course of these effects and their duration remain undetermined. In the present studies, C57BL/6J male mice were treated with one of three selective 5-HT reuptake inhibitors (SSRIs): fluoxetine, sertraline, or paroxetine. All three drugs produced initial decreases in operant lever pressing behavior for ethanol followed by a return to baseline on subsequent days. Immediately following 14 days of this initial treatment, subsequent treatment with higher SSRI doses was ineffective in decreasing ethanol-reinforced behavior. However, after a several week “washout period,” SSRI pretreatment again produced an initial decrease in responding for ethanol, again followed by a return to baseline. Thus, suppression of ethanol drinking may be related to immediate changes in 5-HT function following treatment with SSRIs, and tolerance to this effect appears to develop rapidly.

Regulation of operant ethanol-reinforced behavior is genetically independent of regulation of withdrawal severity in WSP and WSR mice

Selectively bred withdrawal seizure prone (WSP1 and WSP2) and withdrawal seizure resistant (WSR1 and WSR2) mice were used to test the extent to which severity of ethanol withdrawal response is predictive of the reinforcing effects of ethanol. Mice were systematically introduced to ethanol under a fixed ratio 1 (FR 1) schedule using adjunctive drinking methods. There were no significant differences in ethanol consumption between the lines during training. Subsequently, responding for ethanol concentrations of 8%, 0% (vehicle control), and 8% retest under a FR 1 schedule in the absence of food induction was measured. Group data showed that ethanol did not serve as a reinforcer in the test phase within any of the four lines, and there were no significant line differences in rate of responding, intake, or blood ethanol concentrations (BEC). Mice were next tested for responding for ethanol under a FR 4 schedule. Again, ethanol did not serve as a reinforcer for any of the four groups, and there were no significant differences between the lines. However, further analysis showed that there were individual differences in responding within each group, some animals were apparently reinforced by ethanol, while others showed no reinforcement and some appeared to avoid ethanol. There was no systematic pattern within or between groups for these individual differences in responding. Thus, both the group results as well as the behavior patterns of individual animals are consistent with the conclusion that genes regulating rewarding effects of ethanol appear to be segregating randomly across groups and are independent of genes mediating ethanol withdrawal severity. These findings indicate a lack of association between propensity to develop physical dependence on ethanol and propensity to find this drug reinforcing.

Ethanol-reinforced behavior in P, NP, HAD and LAD rats: differential genetic regulation of reinforcement and motivation.

Genetic differences exist in whether animals find ethanol or other drugs positively reinforcing. Through the use of P, NP, HAD and LAD rats, animals selectively bred for high (P, HAD) or low (NP, LAD) ethanol consumption in a two-bottle choice procedure, the present results show that multiple factors determining ethanol consumption can be identified. Ethanol-preferring P rats consumed more ethanol across all conditions involving fixed ratio or progressive schedules than did non-preferring NP, preferring HAD or non-preferring LAD rats. In both non-preferring NP and preferring HAD rats, responding decreased similarly as fixed ratio size was increased. However, under a progressive ratio schedule, NP rats responded to higher break points than did HAD rats. In LAD rats, ethanol has not consistently been shown to be a reinforcer and these rats exhibited the lowest levels of responding for ethanol across all conditions. These findings extend the conditions under which P rats have been shown to consume substantial amounts of ethanol. In addition the results illustrate genetic differences with regard to the propensity of animals to maintain ethanol-reinforced behaviors under different schedules of intermittent reinforcement, and provide further evidence that ethanol drinking in a preference paradigm is not highly predictive of whether or to what extent ethanol may come to serve as a positive reinforcer. The results suggest that the phenomenon of ethanol drinking is a composite of at least three genetically independent factors governing different aspects of ethanol-seeking behavior: (1) a permissive factor allowing animals to readily overcome the aversive sensory effects of ethanol; (2) a reinforcement factor that determines whether a substance can come to serve as a positive reinforcer; and (3) a motivational factor related to the subjects' drive state with regard to drug seeking.

Effect of dopamine agonists and antagonists on ethanol-reinforced behavior: The involvement of the nucleus accumbens

Rats initiated to self-administer 10% ethanol (v/v) in an operant situation using the sucrose-substitution technique received bilateral n. accumbens or caudate nucleus microinjections of d-amphetamine (4, 10, and 20 μg/brain), quinpirole (4 μg/brain), and/or raclopride (0.1, 0.5, and 1.0 μg/brain). Only microinjections into the n. accumbens produced changes in rate and pattern of responding. With d-amphetamine, an increase in total responding and a slowing of initial response rate was seen, whereas with raclopride administration a dose-related decrease in total responding was observed with no alteration in momentary response rates. Drug-dependent behavioral rate and pattern differences suggest that DA activity in the n. accumbens influences ethanol reinforced behavior.

Effect of naltrexone on alcohol consumption during chronic alcohol drinking and after a period of imposed abstinence in free-choice drinking rhesus monkeys

Relapse into problematic alcohol drinking is a serious problem in the treatment of alcoholism. Free-choice drinking rhesus monkeys show relapse-like behaviour after imposed abstinence of alcohol, by immediately reinitiating ethanol intake at an increased level. The relapse-like behaviour of the monkeys seems not induced by physical withdrawal, but rather argues for a resistance to extinction of ethanol-reinforced behaviour. It has been suggested that endogenous opioids play a role in the positive reinforcing effect of ethanol. In this study, the effect of the opiate antagonist naltrexone was investigated in eight adult male rhesus monkeys (Macaca mulatta) who had about 1 year experience with alcohol drinking, under two conditions: 1) (expt 1) during continuous and concurrent supply of drinking water and two ethanol/water solutions (16% and 32% (v/v], and 2) (expt 2) after 2 days of alcohol abstinence. In both experiments, each monkey received six doses of naltrexone (0.02, 0.06, 0.17, 0.5, 1.0, 1.5 mg.kg-1); each dose was paired with a placebo injection (im) in a cross-over design. Consumption was measured from 16.00 hours in the afternoon (30 min after injection) to 9.00 hours the next morning. In experiment 1 naltrexone reduced total net ethanol intake in a graded dose-dependent manner. The effect of naltrexone was apparent shortly after injection, and lasted until the following day. Consumption of drinking water was reduced only shortly after injection. In expt 2, reduction of net ethanol intake was largely restricted to the first few hours of reinitiation of alcohol drinking, i.e. the period in which the abstinence-induced increase was manifest. Consumption of drinking water was not affected by naltrexone. Naltrexone hardly influenced consumption of the non-preferred ethanol solution of 32%. It is postulated that the opioid modulation specifically interacted with positively reinforced behaviour. In expt 2 naltrexone reduced ethanol intake at a lower dose (0.17 mg.kg-1) compared to expt 1 (0.50 mg.kg-1), but net ethanol intakes however remained higher. It might be that alcohol abstinence resulted in altered opioid activity, leading to increased ethanol-seeking behaviour. The renewed presentation of ethanol solutions (also) might have stimulated reinitiation of alcohol drinking, representing conditioned incentive stimuli. The reported monkey model of relapse in alcohol drinking could be a useful tool to evaluate new hypotheses and experimental treatments with respect to human alcoholism.

Orally delivered cocaine functions as a positive reinforcer in C57BL/6J mice

Cocaine serves as a reinforcer across several routes of administration and species. However, whether orally delivered cocaine serves as a positive reinforcer has not been systematically established. We determined the extent to which contingent access to orally delivered cocaine would maintain lever pressing behavior in C57BL/6J mice who had a prior history of operant ethanol-reinforced behavior. The findings presented in this report demonstrate that orally delivered cocaine can serve as a reinforcer of operant behavior. A drug substitution procedure where cocaine was substituted for gradually decreasing ethanol concentrations was successful in inducing pharmacologically significant intakes of cocaine under a fixed ratio (FR) schedule of drug access. When ethanol was removed, responding for cocaine continued. As FR size was increased, proportionate increasesin responding occurred except at the highest FR value. Responding maintained by cocaine significantly exceeded responding maintained by vehicle, with the mice typically consuming 6–10 mg/kg cocaine per 30-min session. The utilization of inbred strains and the procedures followed in the present studies should prove useful in determining the extent of both genetic and environmental influenes on various behavioral effects of cocaine and their mechanisms of action.

Antagonism of ethanol-reinforced behavior by the benzodiazepine inverse agonists Ro15-4513 and FG 7142: Relation to sucrose reinforcement

The partial inverse benzodiazepine agonist Ro15-4513 has been shown to antagonize many of ethanol's actions, including the reduction of behavior reinforced with ethanol presentation. The studies reported here compared the effects of the Ro compound on sucrose reinforcement alone and concurrently available with ethanol reinforcement. Also, a second inverse agonist, FG 7142, was tested. The result indicated that ethanol reinforcement was more sensitive to the inverse agonists compared to sucrose reinforcement. This was seen as a graded effect upon ethanol responding at doses which failed to have any effect upon sucrose-reinforced behavior. The Ro compound was approximately three times more potent than the FG compound in suppressing ethanol-reinforced responding. Possible explanations for the greater sensitivity of ethanol reinforcement compared to sucrose reinforcement was discussed in terms of ethanol's potential actions at the benzodiazepine-GABA receptor complex.

Ethanol self-administration in ALKO rats: II. Effects of selection and fixed-ratio size

The ethanol-reinforced behaivor of ALKO Alcohol Accepting (AA) rats was studied as a function of fixed-ratio (FR) size (1, 2, 4, 8 and 16) across several ethanol concentrations (8, 16 and 32% w/v). A comparison was also made with ethanol-reinforced behavior of Sprague-Dawley (SD) rats. Ethanol, previously shown to serve as a reinforcer in AA and SD rats, maintained responding in these animals under conditions of intermittent reinforcement. SD rats exhibited higher response rates than AA rats to obtain 8% ethanol concentrations as fixed-ratio size was varied in these experiments. These results confirm that, for AA rats, the selection for preference in a two-bottle choice situation did not include the selection for those biological factors which maximize ethanol-reinforced behavior under conditions of intermittent reinforcement. These experiments suggest the existence of distinct, biologically influenced components of ethanol drinking behavior, and have demonstrated several similarities as well as differences between two-bottle choice preference tests and operant studies of ethanol-reinforced behavior.

Ethanol self-administration in ALKO rats: I. Effects of selection and concentration

The ALKO Alcohol Accepting (AA) rats and Alcohol Non-Accepting (ANA) rats were used to study the relationship between ethanol preference in a two-bottle choice paradigm and oral ethanol self-administration in an operant conditioning paradigm. Ethanol served as a positive reinforcer in the preferring AA line. Under a continuous reinforcement schedule (FR 1), ethanol deliveries were consistently greater than water (vehicle) deliveries and varied as an orderly inverted U-shaped function of ethanol concentration. Conversely, in nonpreferring ANA animals, ethanol did not serve as a reinforcer. Findings obtained with the AA rats were compared with those obtained with Sprague-Dawley rats. Sprague-Dawley rats maintained higher levels of responding and greater ethanol intake, relative to AA rats, at all concentrations of ethanol tested. The data are consistent with evidence that genotype is a critical factor in determining the extent to which ethanol serves as a reinforcer. The results also suggest that ethanol preference and the maintenance of ethanol reinforced behavior under operant conditions appear to have some common mechanisms. However, since the selection for ethanol preference in AA rats apparently did not maximize the maintenance of ethanol-reinforced behavior in an operant paradigm, ethanol drinking behavior in the preference paradigm may not be completely generalizable to that observed in the operant model.