Voluntary Ethanol Intake In Rats Research Articles

Repeated Light–Dark Phase Shifts Modulate Voluntary Ethanol Intake in Male and Female High Alcohol‐Drinking (HAD1) Rats

Chronic disruption of sleep and other circadian biological rhythms, such as occurs in shift work or in frequent transmeridian travel, appears to represent a significant source of allostatic load, leading to the emergence of stress-related physical and psychological illness. Recent animal experiments have shown that these negative health effects may be effectively modeled by exposure to repeated phase shifts of the daily light-dark (LD) cycle. As chronobiological disturbances are thought to promote relapse in abstinent alcoholics, and may also be associated with increased risk of subsequent alcohol abuse in nonalcoholic populations, the present experiment was designed to examine the effects of repeated LD phase shifts on voluntary ethanol intake in rats. A selectively bred, high alcohol-drinking (HAD1) rat line was utilized to increase the likelihood of excessive alcoholic-like drinking. Male and female rats of the selectively bred HAD1 rat line were maintained individually under a LD 12:12 cycle with both ethanol (10% v/v) and water available continuously. Animals in the experimental group were subjected to repeated 6-hour LD phase advances at 3 to 4 week intervals, while control rats were maintained under a stable LD cycle throughout the study. Contact-sensing drinkometers were used to monitor circadian lick patterns, and ethanol and water intakes were recorded weekly. Control males showed progressively increasing ethanol intake and ethanol preference over the course of the study, but males exposed to chronic LD phase shifts exhibited gradual decreases in ethanol drinking. In contrast, control females displayed decreasing ethanol intake and ethanol preference over the course of the experiment, while females exposed to experimental LD phase shifts exhibited a slight increase in ethanol drinking. Chronic circadian desynchrony induced by repeated LD phase shifts resulted in sex-specific modulation of voluntary ethanol intake, reducing ethanol intake in males while slightly increasing intake in females. While partially contrary to initial predictions, these results are consistent with extensive prior research showing that chronic stress may either increase or decrease ethanol intake, depending on strain, sex, stressor type, and experimental history. Thus, repeated LD phase shifts may provide a novel chronobiological model for the analysis of stress effects on alcohol intake.

The impact of emotional stress early in life on adult voluntary ethanol intake-results of maternal separation in rats

The combination of genetic and environmental factors determines the individual vulnerability for excessive ethanol intake, possibly leading to dependence. The environmental influences early in life represent examples of determinant factors for adult behaviour and can be protective as well as risk factors. Maternal separation is one model to examine the long-term consequences of early environmental experiences on neurochemistry and behaviour, including drug-taking behaviour in experimental animals. In the present review, findings from studies using repeated short and prolonged periods of maternal separation, with emphasis on effects on voluntary ethanol intake in rats with or without a genetic predisposition for high voluntary ethanol intake, are summarized. Despite some contradictory results, the general picture emerging shows that short periods of maternal separation during the postnatal period result in a lower adult voluntary ethanol intake in male rats. Prolonged periods of maternal separation were found to induce a high voluntary ethanol intake in male rats, including rats with a genetic predisposition for high ethanol intake. Results from the literature also show that changes were not just related to time of separation but were also related to the degree of handling. Interestingly, in terms of voluntary ethanol intake, female rats were generally not affected by postnatal maternal separation. The reasons for these sex differences need further investigation. In terms of neurobiological consequences of maternal separation, conclusive data are sparse and one of the future challenges will, therefore, be to identify and characterize underlying neurobiological mechanisms, especially in the individual animal.

Strychnos nux-vomica extract and its ultra-high dilution reduce voluntary ethanol intake in rats.

To see whether Strychnos nux-vomica extract (mother tincture [MT]), its potency Nux 30c, and its principal alkaloid, strychnine, could reduce voluntary ethanol intake in rats. To analyze the solution structure of Nux MT, Nux 30c, 90% ethanol, and ethanol 30c by means of electronic (ES) and nuclear nuclear magnetic resonance (NMR) spectra. Potentially alcoholic rats were first given 20% ethanol and then kept on a two-choice bottle, one with 20% ethanol and another with tap water. These rats were given the following oral treatments for 15 days: group 1, control; group 2, strychnine at 0.36 mg/kg per day; group 3, ethanolic extract of S. nux-vomica seeds (Nux MT) at 3.6 mg/kg per day; and group 4, Nux 30c at 0.05 mL/d per rat. Nux 30c was prepared by successive dilution of Nux MT and 90% ethanol (1:100) and sonication at 20 kHz for 30 seconds in 30 steps. Both Nux MT and Nux 30c significantly reduced ethanol intake and increased water intake in rats. ES of two dilutions of Nux MT and Nux 30c showed intersections at more than one point suggesting existence of molecular complexes. ES of Nux MT in CCl4 showed a red shift when 90% ethanol was added indicating molecular complexation and charge transfer interaction between ethanol and Nux compounds. NMR spectra of Nux MT, 90% ethanol, ethanol 30c, and Nux 30c indicated a change in solution structure of the medium (90% ethanol) of Nux 30c. Nux MT and Nux 30c could reduce ethanol intake in rats. The altered solution structure of Nux 30c is thought to mimic Nux MT and produce ethanol aversion in rats.

Naltrexone Blocks Acquisition of Voluntary Ethanol Intake in Rats

The effects of naltrexone (NTX) on the acquisition of ethanol drinking was assessed in rats. NTX (0, 2.5, 5.0, or 10.0 mg/kg) was administered to rats presented with an ascending series of ethanol concentrations (2%, 4%, 6%, and 8% v/v) and water. The 2.5 and 10 mg/kg doses of NTX attenuated the acquisition of voluntary drinking of 8% ethanol, but the 5.0 mg/kg dose of NTX had no effect on ethanol intake. The acquisition paradigm was repeated in experiment 2 with naïve animals that received 0, 5.0, or 7.5 mg/kg of NTX. Neither dose of NTX affected ethanol intake, preference for alcohol, or water intake. Total fluid intake was suppressed in the NTX groups, but only on the second presentations of the 2% and 6% concentrations of ethanol. We suggest that the 2.5 and 10 mg/kg doses of NTX may have attenuated the acquisition of ethanol drinking by at least two different behavioral mechanisms.

Naltrexone Blocks Acquisition of Voluntary Ethanol Intake in Rats

Naltrexone Blocks Acquisition of Voluntary Ethanol Intake in Rats

Harman-induced changes of extracellular concentrations of neurotransmitters in the nucleus accumbens of rats

Several β-carbolines, including harman, induce voluntary ethanol intake in rats. It is not clear yet which mechanisms cause these effects. One possibility is the stimulation of the mesolimbic reward system. In vivo microdialysis was used to investigate the effects of acute injections of harman (1-methyl-β-carboline) on extraneuronal concentrations of dopamine and 5-hydroxytryptamine in the nucleus accumbens, which is part of the mesolimbic reward system. Administration of harman (2.27 μmol/kg, intraperitoneal application) elicited an increase of the dopamine efflux by 72% which returned to basal levels after approximately 300 min. In contrast, administration of an intermediate dose of harman (13.65 μmol/kg, intraperitoneal application) caused a significant decrease in efflux, to 76% of basal levels. Still higher doses induced again an increased extracellular dopamine concentration. This change was statistically significant in only a subgroup of rats, possibly because individual animals reacted differently to the high doses. Extracellular 5-hydroxytryptamine in the nucleus accumbens was increased during the first 2 h after the administration of high doses (40.94 and 81.93 μmol/kg, intraperitoneal application). These findings indicate that harman affects the activity of mesolimbic dopaminergic neurons following a U-shaped dose-response relationship.

Conditioned taste aversion and place preference induced by the calcium channel antagonist nimodipine in rats

It has become clear that various calcium channel antagonists are able to suppress excessive intake of ethanol in rats. With respect to these findings, it has become of interest whether these drugs can act as rewarding and/or aversive stimulus. Therefore, such affective stimulus effects of the L-type calcium channel antagonist nimodipine and its enantiomers were studied in Wistar rats in a series of conditioned taste aversion (CTA; two-bottle choice procedure) and conditioned place preference (CPP; two-compartment procedure) experiments. Racemic nimodipine (0.95–15 mg/kg IP) was found to induce a dose-dependent CTA, 7.5 mg/kg being the lowest effective dose. Subsequent studies with both enantiomers revealed that the CTA effects of nimodipine are completely dependent on the activity of (−)-nimodipine. With (+)-nimodipine (0.25–90 mg/kg IP), none of the doses tested induced a significant CTA, whereas with (−)-nimodipine clear and dose-dependent CTA effects were noted (0.5–30 mg/kg IP). For this enantiomer, the lowest effective dose was 15 mg/kg. In additional CPP experiments, it was confirmed that (±)-nimodipine and (−)-nimodipine have affective stimulus properties, whereas (+)-nimodipine was again an ineffective stimulus (dose used for all drugs: 15 mg/kg IP). Interestingly, the affective stimulus effects as measured with CPP of (±)- and (−)-nimodipine turned out to be rewarding, as it was found that both drugs produced a significant place preference. It is concluded from these studies that nimodipine possesses intrinsic affective stimulus effects which are rewarding in nature. Furthermore, these stimulus effects are mediated by the activity of the (−)-enantiomer. Possibly, these rewarding effects of nimodipine may play a role in the reported attenuating effects of this drug on voluntary ethanol intake in rats.

Effect of the 5-HT3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure

The effect of the 5-HT3 antagonist ondansetron on ethanol self-administration was examined in a limited access paradigm. Acute administration of ondansetron (0.01 and 0.1 mg/kg) reduced ethanol intake in male Wistar rats by 35%, whilst water intake was unaffected. Both a lower (0.001 mg/kg) and higher dose (1 mg/kg) of ondansetron failed to modify ethanol consumption. Ondansetron did not, however, alter the pharmacokinetic profile of an orally administered dose of ethanol (1 g/kg) over the same dose range. To examine the generality of these findings and to determine if tolerance would develop to the suppressant effects of ondansetron on ethanol intake, male C57BL/6 mice were treated with ondansetron (0.001, 0.01 and 0.1 mg/kg) over 22 days, 30 min prior to scheduled access to ethanol. Both 0.01 and 0.1 mg/kg doses reduced ethanol intake; however, water intake was not altered by either dose. This finding confirms and extends the generality of the effects of 5-HT3 receptor antagonists on ethanol intake across different species and different paradigms of ethanol consumption. More importantly, the present study shows that the reduction in ethanol intake induced by ondansetron was maintained even after a prolonged period of treatment and is not due to an alteration in the absorption or metabolism of ethanol.

Bidirectional effects of GABAergic agonists and antagonists on maintenance of voluntary ethanol intake in rats

The effects of THIP (GABA A agonist) and picrotoxin (GABA antagonist) on the maintenance of voluntary ethanol ingestion were examined. Thirty-three male Long-Evans rats were initially exposed to a screening procedure in which increasing concentrations of ethanol (from 2% to 9%) were presented in a free choice with water, on an alternate day schedule. Following the screening procedure, the rats were exposed to five ethanol presentations at a concentration of 9%, which constituted the baseline period, and five additional ethanol presentations during which the effects of the GABAergic manipulations were determined (test period). During the test period, the animals received IP injections of either 16 mg/kg of THIP, 2 mg/kg of picrotoxin or saline. The results suggested that the differential GABA manipulations resulted in bidirectional effects on the consumption of ethanol. More specifically, the GABA A agonist THIP increased the intake of ethanol as compared to baseline measures, while the GABA antagonist picrotoxin decreased ethanol intake. Similarly, the administration of THIP increased ethanol preference. In contrast, preference for ethanol over water was decreased following the administration of picrotoxin. It appears that the effects of these GABAergic manipulations are specific to ethanol, since total fluid intake was not influenced by the administration of eitherr drug (i.e., THIP or picrotoxin). In light of the literature suggesting that THIP and picrotoxin are active at different sites within the GABA A chloride-ionophore receptor complex, the present findings would suggest that the GABA A receptor may play a role in regulating the voluntary intake of ethanol.

Effects of duration and timing of environmental enrichment on voluntary ethanol intake in rats

The effects of exposure to five environmental rearing conditions on subsequent voluntary ethanol intake was examined. Male weanling rats were reared for 60 days in either an enriched environment, individually, or in a smaller enriched environment (quasienriched). The quasienriched environment was employed to allow for a group measurement of ethanol intake. Following the initial 60-day environmental exposure period, the three initial groups (Enriched, Isolation, Quasienriched) were randomly subdivided into five groups (Enriched/Isolation, Isolation, Isolation/Quasienriched, Quasienriched, Quasienriched/Isolation) and exposed to increasing concentrations of ethanol (3–9% v/v) in a free choice with water. Results indicated that exposure to an enriched environment for 60 days does not alter ethanol intake. In contrast, rats exposed to the quasienriched environment while having access to ethanol demonstrated a significant increase in voluntary ethanol intake as compared to all other groups. Exposure to different environmental conditions while having access to ethanol was not by itself sufficient to alter ethanol intake. These data are discussed in terms of the amount and timing of exposure to an enriched environment necessary to alter voluntary ethanol intake.

Suppression of ethanol intake in ethanol-preferring rats by 1,4-butanediol

The oral administration of 1,4-butanediol (1,4-BD) at doses ranging from 100 to 300 mg/kg, twice daily, produced a dose-dependent reduction (40 to 85%) in the voluntary ethanol intake in rats selectively bred for high preference for ethanol. Treatment with 1,4-BD did not reduce total fluid intake. Repeated 1,4-BD administration (300 mg/kg twice daily for 7 days) suppressed ethanol intake almost completely. After suspension of 1,4-BD treatment, the inhibitory effect on ethanol intake remained significantly low for 2 days. 1,4-BD failed to inhibit aldehyde dehydrogenase to a concentration of 10 mM in rat liver homogenate.

Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference

The effect of naloxone on voluntary ethanol intake was examined in rats which were selectively bred for oral ethanol preference (High Alcohol Drinking or HAD line). Rats of the HAD line were treated with naloxone in doses of 0.05–18.0 mg/kg b.wt. before access to water alone or to a free-choice between a 10% (v/v) ethanol solution and water. Naloxone suppressed water intake when water was presented as the sole source of fluid. In contrast, naloxone produced a dose-dependent decrease in ethanol consumption, without altering water intake, when rats were given a free-choice between the ethanol solution and water. Selective suppression of ethanol consumption by naloxone was not attributable to changes in blood ethanol concentrations or ethanol elimination rates following naloxone treatment. It appears that although naloxone may attenuate the positively reinforcing properties of both ethanol and water, ethanol drinking is a subset of consummatory behaviors that is particularly sensitive to opioid receptor blockade. The results suggest that activation of the endogenous opioid system may be an important mechanism which serves to maintain continued ethanol drinking.

Effects of environmental enrichment on voluntary ethanol intake in rats

The effects of exposure to four environmental rearing conditions on subsequent voluntary ethanol intake were examined. Male weanling rats were were reared in either an enriched environment or individually for 90 days. After the 90-day environmental exposure period, the initial groups (Enriched and Isolated) were randomly subdivided into four groups (Enriched, Enriched/Isolated, Isolated, and Isolated/Enriched) and exposed to increasing concentrations of ethanol (3% to 9% v/v) in a free choice with water. Therefore, half the animals raised in the enriched environment were permanently placed into individual cages (Enriched/Isolated) for the remainder of the study. Likewise, half of the animals previously reared individually were exposed daily (0900-1700) to the enriched environment (Isolated/Enriched). Results indicated that the enriched animals consumed greater amounts of ethanol as compared to all other groups. In contrast, rats placed in isolation following 90 days of enrichment demonstrated significant reductions in voluntary ethanol intake. The data suggest that rearing in an enriched environment for 90 days and continued exposure following 111 days of age, are necessary to enhance voluntary ethanol consumption.

Relation between voluntary ethanol intake in rats and changes in striatal muscarinic binding sites seen after induction of stable ethanol intake by an intermittent ethanol treatment

Male rats were treated with ethanol (2.0 g/kg i.p.) once a week for approximately a year. They also had a choice between an ethanol solution (10%) and water as drinking fluid for 24 h prior to the injection. During the following evaluation period lasting around 40 weeks the rats had a continuous choice between ethanol and water as the drinking fluid. The ethanol concentration was varied with 10% as a standard. At sacrifice, muscarinic binding sites in the brain were determined. During the evaluation period the daily dose of ethanol varied considerably but the intake in each individual was remarkably stable independent of offered ethanol concentration. A highly significant regression was found between voluntary ethanol intake and muscarinic binding sites in the striatum ( b = −0.003, r = −0.87, df= 8, P < 0.005).

An indian herbal formula (skv) for controlling voluntary ethanol intake in rats with chronic alcoholism

Chronic ethanol ingestion in rats showed metabolic and physiological changes similar to alterations reported in human alcoholics. There was a lowering of blood glucose concentration, urea and plasma proteins and elevated concentrations of serum γ-glutarnyl transpeptidase. Administration of SKV, an Ayurvedic formula produced by fermentation of cane sugar with raisins and 12 herbal ingredients brought down voluntary ethanol ingestion in the rats and increased food intake. ECG and EEG studies in alcoholic rats showed cardiac depression, augmentation of frequency and amplitude of the alpha, delta and theta waves and weakness in the beta waves. These changes were reversed during SKV-induced voluntary alcohol restriction. The involvement in the ECG and EEG wave patterns was associated with improvement in blood glucose, plasma protein levels and reduction in gamma glutamyl transpeptidase activities. SKV appeared to have no adverse reaction with ethanol (it contains 1—2% ethanol) and appears to be a promising way to combat alcoholism.

Effects of Thiamin Deprivation and Antagonism on Voluntary Ethanol Intake in Rats

Effects of Thiamin Deprivation and Antagonism on Voluntary Ethanol Intake in Rats

Voluntary ethanol intake in rats following exposure to ethanol on various schedules.

Voluntary intake of 20% (v/v) ethanol solutions was assesed in groups of male Wistar rats following various forms of ethanol exposure. Some animals were first exposed to gradually increasing weak solutions of ethanol (acclimation); while others were given 20% solutions from the start. Some were given ethanol every day (continuous schedule); others were given ethanol every other day (intermittent schedule). Some were given ethanol solutions with plain water also available (free-choice); others were given ethanol solutions as the only fluid available (forced-choice). The animals on intermittent schedules for a 30 day period developed a slight preference for 20% ethanol solutions; they came to drink an average of over 9 g/kg/day of absolute ethanol when tested in free choice conditions. Previous acclimation did not add significantly to this effect. The effect held whether the animals received their ethanol in free- or forced-choice conditions. Forced-choice experience inhibited subsequent free-choice intake in the continuous-exposure group, but forced-choice coupled with intermittent exposure led to the highest intake levels in the shortest total ethanol exposure. The intake levels of these animals are encouraging for those interested in developing animal analogues for human ethanol abuse.