Cocaine self-administration in Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats

Individuals prone to drug self-administration may be vulnerable not only to a single drug reinforcer but to a variety of drug reinforcers. It has been shown that two thirds of alcoholics regularly use drugs other than ethanol (alcohol). Up to 30% of alcohol-dependent patients report concurrent misuse of cocaine. The aim of the present study was to investigate intravenous cocaine self-administration in selectively bred, alcohol-preferring WHP (Warsaw high-preferring) and non-preferring WLP (Warsaw low-preferring) rats. It was hypothesized that WHPs could be more prone to cocaine self-administration in comparison to WLPs. Rats from both lines were allowed to nose-poke for cocaine infusions (0.33 mg/kg/infusion) under the FR-1, FR-2, and FR-3 schedule of reinforcement. Dose-response curves were assessed with increasing doses of cocaine (0.03, 0.1, 0.33, 1.0mg/kg/infusion). The WHP and WLP rats did not differ in cocaine self-administration. Both groups quickly acquired nose-poke responding for cocaine, presented a similar response profile when the schedule of reinforcement was increased from FR-1 to FR-3, and similar sensitivity to cocaine in the dose-response test. The present results may indicate that the selective breeding of alcohol-preferring WHP and alcohol non-preferring WLP rats did not lead to differences in cocaine's rewarding effects as assessed in the self-administration procedure.     

Effects of voluntary alcohol intake on nicotine-induced behavioural sensitisation in rats

Behavioural sensitisation has been suggested to play a role in the acquisition and maintenance of addictive behaviour. The aim of the present study was to assess nicotine-induced behavioural sensitisation in chronic voluntary alcohol drinking rats. Subjects had free access to alcohol/water or glucose/water solutions since weaning. Rats were pretreated after 2 months of voluntary alcohol drinking. Pretreatment consisted of once-daily intraperitoneal injection of nicotine (0.5 mg/kg) or saline administered for five consecutive days. The nicotine-induced behavioural sensitisation of locomotor activity was tested 3 weeks latter. Horizontal motor activity was monitored for 30 min and expressed as distance travelled (in centimetres). During all the experimental procedure, the animals were maintained under 1-h limited access to alcohol. In glucose-drinking animals, results indicated that nicotine induced locomotor activity sensitization: The locomotor effects of nicotine challenge in the nicotine-pretreated group of rats were significantly enhanced as compared with the saline-pretreated group (Duncan, P<.01). Instead, in the alcohol-drinking animals, no significant differences were observed between the nicotine- and saline-pretreated groups. Thus, chronic alcohol consumption at mild doses prevented the development and/or the long-term expression of the nicotine-induced sensitisation at the doses tested.     

Operant self-administration of ethanol in Warsaw high-preferring (WHP) and Warsaw low-preferring (WLP) lines of rats

The results of the present experiment demonstrate that ethanol-preferring line of rats (WHP), and ethanol-nonpreferring line of rats (WLP) are able to acquire and maintain lever pressing reinforced by EtOH (oral operant EtOH self-administration) under FR-1 and FR-2 schedule of reinforcement. On the other hand, WHP rats but not WLP rats, displayed the high ability to acquire and maintain robust lever pressing for EtOH under FR-3 procedure. These data suggest that EtOH possesses stronger reinforcing properties in WHP rats. Nevertheless, WLP rats are able to acquire operant self-administration of EtOH when response demand of the reinforcement schedule is lower. Thus, both lines of rats can differ substantially in the amount of EtOH intake when its access is continuous and freely available, but less fundamentally when they respond for EtOH reward under low-demand schedules of partial reinforcement.     

The beta adrenergic agonist isoproterenol suppress voluntary alcohol intake in rats

The effects of isoproterenol on alcohol consumption were examined to investigate whether beta adrenergic stimulation can reduce voluntary alcohol intake. Two and one-half, 5 and 10 micrograms/kg isoproterenol administered subcutaneously (SC) just prior to alcohol availability produced a dose-dependent reduction in alcohol intake and elevation in water intake. Blood alcohol levels measured subsequent to a SC injection of 5 micrograms/kg isoproterenol or vehicle followed by an intraperitoneal injection of 2.5 g/kg alcohol showed that the adrenergic agonist did not alter the distribution or metabolism of alcohol. Since beta adrenergic agonists such as isoproterenol are potent releasers of renin, these findings support previous work showing that different kinds of interventions which share the common property of elevating activity in the renin-angiotensin system (beta adrenergic stimulation in the present case) consistently result in the reduction of voluntary alcohol intake.     

Effect of topiramate treatment on ethanol consumption in rats

Rationale  

Results from clinical studies have shown that topiramate effectively reduces alcohol consumption in a population of heavy-drinking alcohol-dependent humans.     

Effect of acute administration of ethanol on beta-endorphin plasma level in ethanol preferring and non-preferring rats chronically treated with naltrexone

An ample support can be found in professional literature for the hypothesis that the endogenous opioid system plays an important role in developing a craving for alcohol. It is well established that people with a genetic deficit of beta-endorphin are particularly susceptible to alcoholism. In our study, we looked into the beta-endorphin plasma level of animals with high- and low-risk of alcohol dependency after repeated treatment with naltrexone, the opioid antagonist known to be effective in the treatment of alcoholism. We used the Warsaw High Preferring (WHP) and Warsaw Low Preferring (WLP) rats and treated them for 10 days with naltrexone in a dose of 2 mg/kg i.p. One hour before blood collection the rats were injected with a single dose of ethanol. A prolonged naltrexone treatment or a single application of ethanol resulted in the increase of the beta-endorphin plasma level. In the WLP rats repeated naltrexone treatment prevents the ethanol-induced increase in beta-endorphin plasma level. In the WHP rats the level of this peptide was similar to it while they were undergoing the naltrexone treatment or had received a single alcohol injection. This finding supports the proposition that the endogenous opioid system plays an important role in developing a craving for alcohol. It is likely that effectiveness of naltrexone in reducing craving for alcohol results from the attenuation of the rewarding properties of ethanol and restoring the beta-endorphin deficit in reward system.     

Effect of nociceptin on alcohol intake in alcohol-preferring rats

The present study investigated the effect of nociceptin (NC), the endogenous ligand of the opioid-like orphan receptor ORL1, on ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Acute intracerebroventricular (ICV) injection of 250 or 500 ng/rat of NC, just before access to 10% ethanol (offered 2 h/day), significantly increased ethanol intake. Subchronic (7 days) ICV injection of 500 ng/rat of NC, given just before access to 10% ethanol (for 30 min/day), resulted in a progressive decrease in ethanol consumption. After the end of NC treatment, rats progressively recovered their usual ethanol intake. When NC, 500 or 1000 ng/rat, was tested versus the effect of ethanol in the place conditioning paradigm, NC significantly reduced the increase in time spent in the ethanol-paired compartment after conditioning. This finding suggests that NC reduces the rewarding properties of ethanol in msP rats; thus, they may respond to the acute NC administration by increasing their ethanol intake in an attempt to achieve the usual reinforcing effect of ethanol, whereas subchronic NC treatment may result in extinction of ethanol drinking. The results of the present study suggest that the brain NC mechanisms may represent an interesting target of pharmacological interventions for the treatment of alcoholism. Received: 11 August 1998/Final version: 15 October 1998     

Tolerance and sensitization to the hypnotic effects of alcohol induced by chronic voluntary alcohol intake in rats

The effect of a chronic alcohol exposure on the development of tolerance to the depressive effects of alcohol were examined in male Wistar rats that voluntary self-administered alcohol. A free-choice drinking procedure based on the limited access paradigm and the addition of glucose that implies an early availability of the alcoholic solution was used (Alcoholism Primary Praecox procedure). Alcohol induced sleep time (3.5 g alcohol per kg i.p.) was measured at 90 days (after 2 months of alcohol consumption) or at 60 + 90 days old (1 or 2 months of alcohol consumption). The psychomotor performance was also evaluated by means of an 80 degrees inclined screen test. Subjects that had been tested for the hypnotic effects at both 60 and 90 days showed a higher intake of alcoholic solution than the animals only tested at 90 days. The same consumption increase was observed in the glucose group. No significant differences between groups were observed in the inclined screen test. Tolerance to the hypnotic effects of alcohol was observed at 90 days. On the other hand, no significant differences between alcohol and control groups (glucose or water) were observed in the sleep time at 60 days. In the alcohol-drinking rats tested for two trials (60 and 90 days), sensitization instead of tolerance to the second hypnotic alcohol injection was seen. Tolerance to the hypnotic effects of alcohol observed after chronic voluntary alcohol consumption may provide animal models of alcoholism based on limited access to sweetened alcoholic solutions with construct validity.     

Genetic, sex, and early environmental effects on the voluntary alcohol intake in Wistar rats

The aim of this study was to investigate the effects of genetic, sex, and early environmental factors on the voluntary alcohol intake in Wistar rats. Genetic correlates were examined by comparing animals pharmacogenetically selected for high susceptibility to apomorphine (APO-SUS) with animals selected for low susceptibility (APO-UNSUS). Early environmental factors were investigated through postnatal manipulations (cross-fostering in APO-SUS and maternal deprivation in APO-UNSUS). Voluntary alcohol intake was measured using a two-bottle, free-choice protocol, in which animals could choose either water or an ascending series of alcohol concentrations every second day. Genetic correlates were only observed in male rats, with APO-UNSUS animals consuming more alcohol than APO-SUS animals. No effect of the early postnatal manipulations was detected: neither cross-fostering nor maternal deprivation influenced the voluntary alcohol intake. As for the influence of gender on ethanol self-administration, APO-SUS females consume more alcohol than APO-SUS males, while no sex differences were observed in APO-UNSUS animals.     

Effect of cued and uncued inescapable shock on voluntary alcohol consumption in rats

Rats were given cued and uncued inescapable shock; their voluntary alcohol intake was compared to a group given a yoked cue but no shock. Results suggested that, unlike uncued inescapable shock, cued inescapable shock caused an increase in voluntary alcohol intake, although the increase was insufficient to produce overt inebriation. It was suggested that the increase which occurred was due to a combination of adjunctive drinking and a gustatory and olfactory discrimination breakdown, both occurring in direct response to shock.     

Effects of estradiol treatment on voluntary and forced alcohol consumption in male rats.

Estrogens have been related to alcohol as a dependent variable, but scarcely as a causal variable, that affects the alcohol consumption. The scope of the present work was to study the effect of estrogens on both the amount and the pattern of alcohol consumption. Male Wistar rats were individually exposed to forced alcohol consumption (FAC) and voluntary alcohol consumption (VAC) in each of the following four periods: precastration (PreC), postcastration (PosC) or post-sham castration, estradiol (E) treatment (5 microg of estradiol benzoate/day/rat) and postestradiol (PosE). Estrogenic treatment reduced significantly the alcohol consumption with respect to the PreC and PosE periods in castrated (C) males during VAC. E treatment showed the lowest value of alcohol intake in FAC, but differences were significant only with respect to PreC regardless of the male gonadal condition. E treatment decreased food intake regardless of the male gonadal condition in both FAC and VAC. Castration and E treatment modified differentially the patterns of alcohol consumption depending on the volitive characteristics of alcohol intake. Castration reduced the size of the licking rates without affecting the number of drinking bouts in FAC. This pattern was maintained in the E and PosE periods of C males. Castration did not affect the pattern of alcohol consumption in VAC, but estrogen reduced both the bout size and the number of bouts during the day, which gave an additional support to the inhibitory effect of estrogens on VAC. Results are discussed in terms of a possible inhibitory action of estrogens on the opioid system, which possibly reduces the rewarding properties of alcohol.     

Neonatal clomipramine treatment, alcohol intake and circadian rhythms in rats

Neonatal exposure to antidepressant monoamine re-uptake inhibitors produces a wide variety of effects on the behavior and physiology of adult rats which are consistent with features of clinical depression. Since depressed patients show characteristic alterations in circadian rhythmicity, our laboratory has examined free-running circadian drinking rhythms in this putative animal depression model. Previously, neonatal desipramine treatment was shown to lengthen free-running period, and increase circadian amplitude, spectral magnitude, and voluntary alcohol intake (10% ethanol v/v) of male rats. The purpose of the present study was to examine the effects of neonatal clomipramine treatment (25 or 30 mg/kg SC, postnatal days 8–21) on circadian drinking rhythms and alcohol intake of both male and female rats. In addition, effects of alcohol exposure on circadian rhythmicity were also examined. Contrary to expectations, free-running period of clomipramine-treated rats did not differ from saline-treated controls in either constant darkness (DD) or constant light (LL), but spectral magnitude was increased in clomipramine-treated males and females, and circadian amplitude was increased in clomipramine-treated females. Neonatal clomipramine also increased voluntary alcohol intake, and both clomipramine- and saline-treated groups displayed significant period-shortening during alcohol exposure. Taken together, these results suggest that alterations in the amplitude and coherence of circadian rhythmicity may be more consistent than alterations in free-running period in animal depression models, as has been suggested previously for depressed patients. Received: 29 July 1997 / Final version: 18 November 1997     

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.     

The role of the gastric and hepatic vagus in voluntary alcohol intake

The present study investigated a possible role for neural signals sent from the liver and stomach to the brain in the regulation of alcohol intake. Experiment 1 showed that gastric vagotomy (GVX) reduced the intake of 3% alcohol and 6% alcohol, while water intake was increased. This effect was not due to an alteration in pharmacokinetics, although an alteration in taste function could not be ruled out. Angiotensin II reduced the intake of 6% alcohol and stimulated the intake of water similarly in both GVX and sham groups. In Experiment 2 rats were subjected to hepatic vagotomy or sham laparotomy and then offered a choice between an alcohol solution and tap water for 40 min each day. Although hepatic vagotomy (HVX) did not alter the intake of 3% alcohol or water, 6% alcohol intake was significantly reduced. Angiotensin II decreased 6% alcohol intake and increased water intake similarly in both groups. These experiments indicated that interrupting information from the liver and stomach to the brain by selective gastric and hepatic vagotomy can decrease voluntary alcohol intake. Since vagal afferent nerves are thought to participate in the control of food intake, the present findings support the hypothesis that the "food-like" qualities of alcohol, i.e., calories and taste, can contribute to the regulation of alcohol intake.     

Lack of changes in beta-endorphin plasma levels after repeated treatment with fluoxetine: possible implications for the treatment of alcoholism--a pilot study

Clinical and animal studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may help to reduce alcohol intake but investigations led to conflicting results. A few studies indicated that serotonin (5-HT) may modulate the brain beta-endorphin level, which plays an important role in the development of alcohol craving. Our study examined the influence of fluoxetine on the endogenous opioid system. We investigated plasma levels of beta-endorphin in rats with either high alcohol preference (Warsaw High-Preferring; WHP) or low alcohol preference (Warsaw Low-Preferring; WLP) after repeated treatment with fluoxetine (5 mg/kg i.p. for 21 days). We examined the rats 24 hours after fluoxetine treatment in order to determine whether chronic fluoxetine produces a long-term change in the beta-endorphin levels. The animals received either a single dose of ethanol (2 g/kg) or an identical single dose of saline one hour before blood collection. While a few studies observed an increase in the level of beta-endorphin after a single fluoxetine injection, we did not observe any increase in beta-endorphin plasma levels after repeated fluoxetine treatment. We also did not observe any changes in beta-endorphin levels of rats treated with fluoxetine and injected with ethanol. A lack of increase of beta-endorphin levels may explain why fluoxetine has a limited value in the prevention of craving for alcohol.     

Induction of high voluntary ethanol intake in dependent rats

The experimental conditions under which oral high intake may be induced in previously intoxicated rats have been investigated. Seventeen rats were administered intragastrically with 10 g/kg/day of ethanol for 15 days. At cessation of treatment, they were presented a single bottle of alcoholic solution (10% v/v) during 24 hr. For the following 6 days, they received either an ethyl alcohol solution or water in alternation for 8 hours each. Ethanol treated rats exhibited a high oral intake of ethanol equivalent to the previously injected doses. Controls displayed a significantly lower intake of ethanol. It is concluded that the suppression of the withdrawal state by an initial priming oral intake of ethanol in physically dependent rats is a condition for the development of a conditioned taste preference for ethanol as a basis for the behavioral dependence.