Effects of self-administered ethanol or water preloads on appetitive and consummatory behavior in the alcohol-preferring (P) rat

OBJECTIVE: Ethanol intake control in the selected alcohol-preferring lines of rats appeared to have shifted in some lines for both increased ethanol seeking and increased consumption once ethanol was available. It was unknown whether a small preload of ethanol would alter either the seeking or the consumption in a selected line. This study examined this issue. METHOD: Alcohol-preferring (P) rats from Indiana University School of Medicine were initiated to drink ethanol using a sucrose-substitution procedure and a single daily limited-access trial. Following 30 responses on a lever, a sipper tube containing 10% ethanol extended into the operant chamber for 20 minutes. Self-administered ethanol and water preloads were tested prior to either a regular session or an extinction session. In extinction sessions, no access to the sipper tube occurred, and the number of responses occurring during 20 minutes was taken as a measure of ethanol seeking. RESULTS: The ethanol and water preloads had no effect on the following ethanol consumption at any time during the experiment. However, the first two ethanol preloads significantly reduced extinction responding, which did not recover to the levels observed prior to the preload tests. CONCLUSIONS: The data support the conclusion that ethanol seeking in the P rat can be influenced by environmental history, whereas consummatory behavior appears to be under more explicit genetic control. This gene-environment interaction suggests that, in the P rat, seeking behavior, initially set at higher levels than observed for nonselected lines, can be modified by certain environmental experiences.     

Individual differences in the priming effect of ethanol in social drinkers

OBJECTIVE: Alcohol-dependent individuals frequently report increased desire for alcohol and exhibit increased alcohol-seeking behaviors following a single drink. The phenomenon, known as priming, has been demonstrated in the laboratory in alcohol-dependent humans and in nonhumans, but the effect is inconsistently observed in nonproblem social drinkers. The current experiment examined this effect in healthy, nonproblem social drinkers across a range of preload doses. METHOD: Using a repeated-measures design, 12 social drinkers were given ethanol (0.2, 0.4 or 0.8 g/kg) or placebo preloads. Various subjective effects measures were obtained at regular intervals. In addition, before and after consuming, the preload subjects performed an operant task on which they made repeated choices for either ethanol or money. RESULTS: Ethanol dose-dependently increased subjective reports of drug liking and desire to take more ethanol. When data from all subjects were examined, ethanol did not affect choices for ethanol on the choice task. However, in subjects who reported the greatest positive mood effects from ethanol (0.8 g/kg), the ethanol preload increased choices for ethanol over money on the choice task. CONCLUSIONS: These findings provide evidence for a priming effect of ethanol in social drinkers as measured by increased subjective desire for drug. The findings also suggest that the priming effects may be strongest in individuals who experience the greatest subjective positive mood effects from ethanol.     

The influence of early postweaning ethanol exposure on oral self-administration behavior in the rat

The effects of three early ethanol home cage consumption procedures on the maintenance of operant lever responding reinforced by ethanol presentation were examined in the rat. Two groups of rats, 25 and 31 days of age, were exposed to 10% (v/v) ethanol as the only fluid in the home cage for 3 or 10 days. A third group, 31 days of age, were exposed to 10% ethanol or tap water for 24 h, with the fluid alternating daily for 18 days. All animals were subsequently trained to lever press using 10% ethanol reinforcement under a decreasing water restriction schedule. All three groups were found to have substantial ethanol consumption levels during the initial exposure in the home cage, ranging from 11.2 to 11.9 g/kg/day. The animals were all successfully trained to lever press in the operant chamber with ethanol as the reinforcer when limited to 15 ml/day of water in the home cage. The average number of reinforcements per day ranged from 29 to 43.5, yielding ethanol intakes from 1.06 to 1.97 g/kg in the 30-minute operant session. However, when 50 ml/day of water was available in the home cage, ethanol reinforcements were substantially reduced, with intakes which ranged from 0.14 to 0.18 g/kg/day. The data suggest that early exposure does not enhance ethanol's reinforcing properties later in the animal's life. These results were discussed in terms the effect of early ethanol exposure on later ethanol consumption and the role of ethanol initiation procedures in oral self-administration.     

Lack of operant ethanol self-administration in dopamine D2 receptor knockout mice

RATIONALE: Dopamine D2 receptors are postulated to play an important role in modulating the reinforcing effects of abused drugs including ethanol. OBJECTIVES: This experiment examined operant ethanol self-administration in dopamine D2 receptor knockout (KO) mice and wild-type (WT) mice using a continuous access procedure. METHODS: Adult male KO and WT mice were trained in 30-min sessions to perform a lever press response for access to 10% v/v ethanol. After training, the mice were placed in test chambers on a continuous (23 h/day) basis with access to food (one lever press, i.e., FR1), 10% v/v ethanol (four lever presses, i.e., FR4), and water from a sipper tube (phase 1). After 30 consecutive sessions, response patterns were determined for 0, 5, 10, 20 and 30% v/v ethanol (phase 2). Saccharin (0.2% w/v) was subsequently added to the ethanol mixture and responding was examined for 0, 5, 10 and 20% ethanol (phase 3). RESULTS: During phase 1, WT mice displayed higher ethanol-lever responding compared to KO mice. Food lever responding and water intake was the same in both genotypes. During phase 2, WT mice displayed concentration-dependent ethanol lever responding, whereas KO mice responded at low rates regardless of ethanol concentration. WT mice also responded more for food compared to KO mice. Each genotype showed similar water intakes except at the 20% ethanol concentration, where WT mice had lower intakes. During phase 3, WT mice continued to show higher responding for all concentrations including saccharin alone. WT mice also continued to respond more for food compared to KO mice, but drank less water. In each phase, WT mice displayed episodic (bout) responding on the ethanol lever. KO mice did not respond for ethanol in bouts. CONCLUSIONS: Reduced responding in the KO mice for several reinforcers including ethanol indicates a more general role for dopamine D2 receptors in motivated responding rather than a specific role in ethanol reinforcement.     

Induction and maintenance of ethanol self-administration without food deprivation in the rat

Rats were trained to lick at a drinking tube containing 5% ethanol to obtain access to a 0.1-ml dipper containing 20% sucrose. Following 20 of these drinking sessions, a lever press response was shaped and maintained with ethanol presentation in the dipper. This induction procedure resulted in rats responding on a FR 8 schedule of reinforcement to receive 40% (v/v) ethanol. Ethanol intakes over 0.5 g/kg in 30 min were obtained when ethanol concentrations over 10% were available. These intakes frequently resulted in blood ethanol levels over 100 mg ethanol/dl blood. This contingent sucrose induction procedure did not use food deprivation at any time. It is suggested that this procedure can be used to investigate the processes involved with the initiation of ethanol as a reinforcer independent of food restriction procedures.     

Increased ethanol choice in social drinkers following ethanol preload

This study showed that normal social drinkers were more likely to consume ethanol after receiving a "priming" (preload) dose of ethanol. Twenty-eight non-problem drinkers (average consumption 9 drinks/week) participated in a six-session, double-blind choice procedure. On the first two sessions they sampled beverages containing ethanol (0.8g/kg) or placebo (mix alone), between which they would choose on subsequent choice sessions. On the third session ("dummy" choice session) subjects were first asked to indicate verbally which beverage they preferred. If they chose the ethanol-containing beverage the experimenter negotiated with each subject to determine the minimum amount of money (from $1 to $30) needed to switch his or her choice from ethanol to placebo. Once this amount was determined it remained fixed for the subsequent three preload/choice sessions. Thus, on choice sessions subjects chose between the beverage which contained ethanol, and placebo plus the amount of money established in Session 3. On the preload/choice test sessions (Sessions 4-6) subjects received preloads of ethanol (0, 0.25 or 0.5g/kg) 1h before being given the choice between the sampled ethanol beverage and the placebo beverage plus money. The frequency of ethanol choice was the primary dependent variable. Subjective drug effects, including ratings of desire for the sampled substances, were also measured. Twenty subjects initially chose ethanol on Session 3 and switched their choice with a monetary incentive. Of these 20 subjects, four chose ethanol after the placebo preload, seven chose ethanol after the low-dose ethanol preload, and 11 chose ethanol after the higher ethanol preload (significant linear trend, Mantel-Haenszel test, p < 0.03). Ratings of desire for the ethanol-containing beverage increased after the higher preload. These results suggest that ingestion of a moderate dose of ethanol increases the tendency to continue drinking, even among normal social drinkers.     

Long-Evans Rats Acquire Operant Self-Administration of 20% Ethanol Without Sucrose Fading

A major obstacle in the development of new medications for the treatment of alcohol use disorders (AUDs) has been the lack of preclinical, oral ethanol consumption paradigms that elicit high consumption. We have previously shown that rats exposed to 20% ethanol intermittently in a two-bottle choice paradigm will consume two times more ethanol than those given continuous access without the use of water deprivation or sucrose fading (5–6 g/kg every 24 h vs 2–3 g/kg every 24 h, respectively). In this study, we have adapted the model to an operant self-administration paradigm. Long-Evans rats were given access to 20% ethanol in overnight sessions on one of two schedules: (1) intermittent (Monday, Wednesday, and Friday) or (2) daily (Monday through Friday). With the progression of the overnight sessions, both groups showed a steady escalation in drinking (3–6 g/kg every 14 h) without the use of a sucrose-fading procedure. Following the acquisition phase, the 20% ethanol groups consumed significantly more ethanol than did animals trained to consume 10% ethanol with a sucrose fade (1.5 vs 0.7 g/kg every 30 min) and reached significantly higher blood ethanol concentrations. In addition, training history (20% ethanol vs 10% ethanol with sucrose fade) had a significant effect on the subsequent self-administration of higher concentrations of ethanol. Administration of the pharmacological stressor yohimbine following extinction caused a significant reinstatement of ethanol-seeking behavior. Both 20% ethanol models show promise and are amenable to the study of maintenance, motivation, and reinstatement. Furthermore, training animals to lever press for ethanol without the use of sucrose fading removes a potential confound from self-administration studies.     

Increased expression of the 5-HT6 receptor by viral mediated gene transfer into posterior but not anterior dorsomedial striatum interferes with acquisition of a discrete action-outcome task

Serotonin plays a role in reinforcement learning; however, it is not known which serotonin receptors mediate these effects. Serotonin 6 (5-HT(6)) receptors are abundant in the striatum, a brain area that is involved in reinforcement learning. We previously found that 5-HT(6) receptors in the dorsomedial striatum (DMS) affect reinforcement learning or consolidation over several days. We use viral-mediated gene transfer to discern the role that 5-HT(6) receptors play in mediating post-synaptic responses in anterior versus posterior DMS. Male Long-Evans rats were used to study learning acquisition during a single session of 100 trials on a fixed interval of 20 seconds. In a discrete action-outcome learning task, rats had 10 seconds to press a lever to induce lever retraction and sucrose pellet delivery. In another group of rats, the task had a lever that was continuously extended but only active every 20 seconds, allowing for repetitive, mostly non-reinforced, lever pressing. Results demonstrate that increased expression of 5-HT(6) receptors in the posterior DMS interferes with earning sucrose pellets in only the former task. We take this to indicate that 5-HT(6) receptor signaling in the posterior DMS interferes with acquisition of discrete action-outcome responding.     

Preference for saccharin-sweetened alcohol relative to isocaloric sucrose

 This experiment tested the reinforcing efficacy of a saccharin-sweetened alcohol solution relative to an isocaloric sucrose drink in rats. One dipper served 10% alcohol plus 0.25% saccharin, and a second, concurrently available, dipper served 14.2% sucrose. During the course of the experiment, access to the two drinks was challenged by increasing the schedule requirement (variable-interval) that determined when a lever press would operate the dipper. There were two main findings. First, the rats continued to consume significant amounts of alcohol despite access to the isocaloric sucrose solution. Second, schedule-requirement increases that decreased sucrose-reinforced responding failed to decrease saccharin-sweetened alcohol reinforced responding. These results extend and replicate earlier findings from studies in which alcohol was mixed with sucrose, and the alcohol mixtures held a caloric advantage over the competing sucrose solutions. The experiment also included controls for differences in baseline response rates and for the influence of saccharin on preference. In the baseline response-rate control conditions, the two reinforcers were 10% sucrose and a mixture of 10% sucrose-plus-quinine. The results showed that the persistence of sweetened-alcohol reinforced responding could not be explained by differences in baseline response rates or the reinforcing properties of saccharin. Rather, the findings were consistent with the idea that the rats were defending baseline levels of alcohol-plus-saccharin consumption. Received: 15 June 1996 / Final version: 13 August 1996     

Comparison of reinstatement of ethanol- and sucrose-seeking by conditioned stimuli and priming injections of allopregnanolone after extinction in rats

Rationale and objectives Understanding the mechanism of relapse provoked by conditioned and unconditioned stimuli is critical to improving treatments for alcoholism. This study compared the reinstatement of alcohol- or sucrose-seeking by conditioned stimuli and priming injections of the neuroactive steroid, allopregnanolone (ALLO). Methods Rats were trained to lever-press for 0.1 ml of 10% ethanol or 5% sucrose solutions. Responding was then extinguished, and subjects were tested for reinstatement of lever-press responding. The effects of priming injections of 0, 1.0, 3.0 and 7.5 mg/kg ALLO were determined in subjects trained to self-administer ethanol, and the response-reinstating effects of priming injections of 3.0 mg/kg ALLO were compared with those of conditioned cue presentation in subjects trained to self-administer either ethanol or sucrose. Results Priming injections of ALLO dose-dependently reinstated previously extinguished responding for ethanol, as shown by increased responding on the active (ethanol) lever. Contingent presentation of cues previously associated with the reinforcer increased the number of active lever-presses for both ethanol- and sucrose- trained subjects. In contrast, pretreatment with 3.0 mg/kg ALLO increased the number of active lever-presses for subjects that were trained to self-administer ethanol, but not sucrose. Conclusions ALLO promotes responding for ethanol, but not sucrose, following a period of abstinence, suggesting that GABA_A receptor modulation may contribute to processes involved in reinstatement of ethanol-seeking behavior. In contrast, conditioned stimuli reinstate previously extinguished ethanol- and sucrose-seeking behavior, indicating that the mechanisms that subserve cue-induced reinstatement do not depend upon the nature of the positive reinforcer.     

Ro 15-4513 selectively attenuates ethanol,but not sucrose,reinforced responding in a concurrent access procedure: comparison to other drugs

The experiments described in this report used a concurrent access procedure to study ethanol reinforcement. Rats were trained to lever press for a 10% sucrose solution and a 10% ethanol/10% sucrose mixture, and both reinforcers were available on variable-interval 5-s schedules. In baseline and vehicle injection sessions, the animals distributed their responding between both solutions. When injected with the partial inverse benzodiazepine agonist Ro 15-4513 (3, 9, and 18 mg/kg), responding for the ethanol solution decreased while responding for sucrose remained intact. Ethanol injections (0.5 and 1.0 g/kg) engendered a similar profile. Chlordiazepoxide led to an increase in ethanol mix responding at 2 mg/kg and a decrease in ethanol mix responding at higher doses; no dose affected sucrose responding. Morphine (0.5–16 mg/kg) decreased responding for both the ethanol mix and sucrose solutions, more or less simultaneously. Naloxone (0.125–20 mg/kg) selectively reduced ethanol mix responding at low doses, and decreased responding for both reinforcers at high doses. In another group of animals, isocaloric alternatives were concurrently available: 10% ethanol/0.25% saccharin versus 14% sucrose. Injections of Ro 15-4513 and chlordiazepoxide produced similar results as in the first group of rats: an increase in ethanol mix responding with low dose chlordiazepoxide, and a decrease in ethanol mix responding with Ro 15-4513. However, naloxone injections did not selectively affect responding for either of the reinforcers when they were isocaloric. These results are discussed in terms of ethanol's neuropharmacological actions.     

Erucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats

Aim： Brucine （BRU） extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse. Methods： Alcohol-preferring Fawn-Hooded （FH/Wjd） rats were administered BRU （10, 20 or 30 mg/kg, sc）. The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference （CPP） was conducted to assess conditioned reinforcing effect. Results： In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU （30 mg/kg） administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose （10%） responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU （30 mg/kg） completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU （10, 20, and 30 mg/kg） did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion. Conclusion： BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.     

Effects of cocaine on responding for ethanol or sucrose under a progressive ratio schedule

Progressive ratio (PR) schedules have been increasingly used to study motivation for self-administered drugs of abuse, such as psychostimulants and ethanol. In these and other studies, the breaking point (BP) is thought to be a measure of the motivation of the animal to work for a particular reward. Ethanol, a highly abused drug, maintains only low BPs. The present experiment was designed to examine if the low BP achieved by animals working for ethanol could be increased by the administration of a psychostimulant. A group working for a sucrose reinforcer was included for comparison. Rats previously trained to lever press under a PR schedule for 0.1 ml aliquots of 10% ethanol or 5% sucrose reinforcers were dosed once a week with cocaine (0, 5 and 15 mg/kg intraperitoneally) 30 min prior to their daily operant session using a Latin square design. Vehicle and 5 mg/kg cocaine had no effect on BP for any reinforcer, but 15 mg/kg cocaine produced a significantly higher BP (P<0.05) for animals working for either ethanol or sucrose. The same doses of cocaine decreased consumption of, and preference for, a 5% sucrose solution. These results indicate that, although cocaine administration does not increase sucrose preference, it may increase BP values in PR schedules. It is therefore unlikely that the increases in BP reflect cocaine-induced increased motivation, and they may be due to cocaine's stimulant or other properties. These data reinforce opinions that PR schedules may be unsuitable for assessing the effects of experimental manipulations on motivation for drugs with stimulant actions.     

Reinstatement of ethanol and sucrose seeking by the neurosteroid allopregnanolone in C57BL/6 mice

Rationale  Recent work in our laboratory documented that the “sipper” method of operant ethanol self-administration produced high ethanol intake and blood ethanol concentrations as well as the typical extinction “burst” in responding under nonreinforced conditions in male C57BL/6 mice. However, the neurochemical basis for reinstatement of responding following extinction has not been examined in mice with this model. Objectives  Based on findings that the GABAergic neurosteroid allopregnanolone (ALLO) significantly increased the consummatory phase of ethanol self-administration, the present study determined the effect of ALLO on the reinstatement of extinguished ethanol-seeking behavior and compared this effect to the reinstatement of responding for sucrose reward. Materials and methods  Separate groups of male C57BL/6 mice were trained to lever press for access to a 10% ethanol (10E) or a 5% sucrose (5S) solution. A single response requirement of 16 presses (RR16) on an active lever resulted in 30 min of continuous access to the 10E or 5S solution. After the animals responded on the RR16 schedule for 14 weeks, mice were exposed to 30 min extinction sessions where responding had no scheduled consequence. Once responding stabilized below the preextinction baseline, mice received an intraperitoneal injection of ALLO (0, 3.2, 5.6, 10, or 17 mg/kg) 15 min prior to the extinction session in a within-subjects design. Results  ALLO produced a dose-dependent increase in responding under nonreinforced conditions in both the 10E and 5S groups. Additional work documented the ability of a conditioned cue light or a compound cue (light+lever retraction) to reinstate nonreinforced responding on the previously active lever. Conclusions  These findings definitively show that conditioned cues and priming with ALLO are potent stimuli for reinstating both ethanol- and sucrose-seeking behavior in C57BL/6 mice.     

Reduced alcohol drinking in adult rats exposed to sucrose during adolescence

Intake of sweet-alcoholic drinks during adolescence is believed to favor alcohol abuse and dependence in adulthood. This study examined the influence of early exposure to ethanol with or without sucrose on the consumption of sweet or alcoholic solutions in adulthood. Adolescent rats (from post-natal day 30-46) were given continuous free access to tap water and either 5% sucrose, 5% ethanol or mixed 5% sucrose-5% ethanol. The control group was given access to water only. Upon reaching adulthood (post-natal day 60), rats were tested for saccharin (sweet), quinine (bitter) and ethanol consumption using a two-bottle free-choice paradigm. The results indicated that pre-exposure to ethanol did not alter the intake of sweet or ethanol solutions in adulthood. However, rats exposed to sucrose during adolescence showed a decreased consumption of both sweet and ethanol solutions. Because alcohol has a sweet taste component, an additional group of rats, pre-exposed to either 5% sucrose or water during adolescence, was tested for intravenous ethanol self-administration (preventing oral sensory stimulation) and in a new model of simultaneous access to oral saccharin and intravenous ethanol that results in higher total ethanol intake. Relative to controls, sucrose-exposed rats showed reduced operant self-administration of saccharin, yet no differences were found for intravenous ethanol self-administration. Altogether, these findings indicate that sucrose exposure during adolescence persistently affected the perception of sweet taste reward and thereby alcohol’s acceptance in adulthood.     

Characterization of the Enhanced Responsiveness to Postingestive Satiety Signals in 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-Treated Han / Wistar Rats

Abstract: Previous studies have shown that under free-feeding conditions, TCDD-treated Han/Wistar (H/W) rats consume less sucrose solution but ingest more saccharin solution than their controls thus implying hyperresponsiveness to postingestive satiety signals. In this study, nutrient preloads were employed to further elucidate this phenomenon. Male H/W rats were given a single high but usually non-lethal intraperitoneal dose (1000 g?/kg) of TCDD. Feed intake was stimulated by 24 hr feed deprivation at various time points after TCDD exposure. When TCDD-dosed rats were allowed to drink either a 20% sucrose or a 0.25% saccharin solution and then given access to feed, those that had had sucrose ate only about 50% of the amount consumed by the saccharin group. Although the preloads were similar in control rats, no such difference in subsequent feeding occurred. The sucrose solution also produced a longer-lasting suppression of feed intake in TCDD-treated compared with control rats when infused directly into the stomach. By contrast, TCDD-treated H/W rats failed to exhibit an augmented satiety response to parenterally applied glucose independent of testing time. Oral corn oil reduced feed intake in both control and TCDD-exposed rats, but the inhibition was slightly larger in TCDD-treated animals. TCDD did not markedly affect the responsiveness of H/W rats to the suppression of feeding by CCK-8 or bombesin. It is concluded that gastrointestinal factors appear critical to the exaggerated response of TCDD-treated H/W rats to nutrient energy.     

Ethanol-maintained behavior in a foraging context: effects of search and procurement cost

In a simulated foraging procedure, the effects of manipulating search and procurement costs of access to ethanol, food, and water on ethanol self-administration were determined in rats. Completion of a response ratio on one lever (search) resulted in the opportunity to complete a high- or low-cost response ratio on one of three other levers (procurement). Each procurement lever was exclusively associated with access to ethanol, food, or water, and the six procurement opportunities occurred in random order. Any procurement opportunity could be rejected, and a new search subsequently initiated. Percent acceptance of high-cost opportunities varied directly with increases in search cost and inversely with increases in high procurement cost. When search cost was increased, daily water and food consumption decreased, whereas daily ethanol consumption was unaffected. Regardless of these manipulations, rats consumed 1.0–2.0 g/kg ethanol daily. Ethanol consumption also was unaffected by increases in low or high food procurement cost values. These results indicate that ethanol self-administration can be analyzed within a foraging environment in which the animal initiates and determines the length and size of all drinking bouts and meals. Within this environment, patterns of ethanol self-administration were orderly and distinguishable from patterns of food- and water-maintained behavior.     

Effect of toluene on ethanol preference in rats

The effect of toluene on the preference of ethanol was studied in rats. Toluene was administered orally by stomac tube in doses of 200, 400 or 800 mg/kg daily for 5 weeks or by inhalation at a concentration of 2000 p.p.m. 6 or 8 hr daily for 5 or 6 days per week for 2 weeks in rats of different age. During toluene inhalation exposure the rats had access to either tap water or ethanol-containing water (6 or 10%). After the exposure and during oral administration the rats had access to both ethanol-free and ethanol-containing water. Toluene inhibited the body weight gain in the highest oral dose group and in rats exposed to toluene and forced to drink ethanol in the inhalation experiments. In these experiments, the intake of fluid was reduced in the exposure period in rats forced to drink ethanol-containing water and further reduced in rats exposed to both ethanol and toluene. Exposure to toluene alone increased the fluid consumption. The preference of ethanol defined as consumed ethanol-containing water in per cent of the total water intake was not influenced by oral administration of toluene. It was, however, reduced by toluene given by inhalation to rats forced to drink ethanol-containing water during the exposure period. Toluene exposure alone or forced ethanol intake alone caused in these experiments a short-lasting reduction of the ethanol preference. It is concluded that toluene decreases the preference of ethanol in rats forced to drink ethanol during exposure to toluene.     

Oral self-administration of sweetened nicotine solutions by rats

Oral self-administration of sweetened nicotine solutions in rats was studied in two ways. In the first experiment, one group had continuous access to a water bottle containing a sucrose solution and nicotine (10 μg/ml), while another group had access to an identical sucrose solution without nicotine. All rats had continuous access to water. While consumption of nicotine increased with increasing concentrations of sucrose, consumption of the sucrose + nicotine solution never exceeded the intake of sucrose alone. In subsequent experiments, the delivery of the solutions was made contingent upon an operant response. The sucrose + nicotine solution was found to maintain responding to higher response/reinforcer ratiosthan the sucrose only solution. These data demonstrate that rats will self-administer sweetened nicotine solutions and that sucrose + nicotine solutions are more reinforcing than sucrose solutions alone. Free accessconsumption is not a good predictor of the response maintaining properties of nicotine solutions.     

High alcohol/sucrose consumption during dark circadian phase in C57BL/6J mice: involvement of hippocampus,lateral septum and urocortin-positive cells of the Edinger-Westphal nucleus

Abstract Rationale. Identification of the neuroanatomical substrates regulating alcohol consumption is important for the understanding of alcoholism. Previous studies mapping changes in brain activity used rodent models of alcohol drinking with relatively low alcohol intakes. Objectives. This study was aimed to identify brain regions changing activity after high voluntary intake of alcohol-containing solutions. Methods. Adult male C57BL/6J mice were trained to drink a 10% ethanol/10% sucrose solution in daily 30-min limited-access sessions during the dark phase of the circadian cycle. Control groups of animals consumed 10% sucrose or water. Analysis of c-Fos immunohistochemistry (as a marker for neuronal activity) was performed at 90 min after the last alcohol drinking session. Results. The limited access procedure led to high intakes (2.9±0.3 g/kg) and blood alcohol concentrations of 251±46 mg%. Expression of c-Fos was significantly higher in the alcohol/sucrose group than both the water and sucrose groups in the Edinger-Westphal nucleus, and significantly lower in the alcohol/sucrose group than two control groups in hippocampal subregions, posterior hypothalamus and dorsal lateral septum. Double immunohistochemistry showed that alcohol-induced c-Fos-positive cells in the Edinger-Westphal nucleus co-localized with the neuropeptide urocortin. In addition, intake and/or blood alcohol concentrations correlated with c-Fos expression in specific subregions of the hippocampus, hypothalamus, prefrontal cortex, lateral septum and midbrain. Conclusions. The dark phase voluntary limited-access procedure in mice leads to intakes of alcohol-containing solutions that are considered highly intoxicating. Brain regions showing alcohol-specific changes in c-Fos expression after this procedure can be connected into a novel neurocircuit, including lateral septum, hippocampus, hypothalamus, and the Edinger-Westphal nucleus. Electronic Publication