Reduce Alcohol Drinking Research Articles

Specific and Nonspecific Effects of Naltrexone on Goal-Directed and Habitual Models of Alcohol Seeking and Drinking

The opioid-receptor antagonist naltrexone (NTX) reduces goal-directed alcohol drinking in rats presumably by blunting alcohol reward. However, different operant conditioning behavior can be produced by different reinforcement schedules, with goal-directed operant behavior being more sensitive to changes in reward value than less flexible, habit-associated models. We tested the hypothesis that NTX more effectively reduces alcohol drinking and seeking in a goal-directed than in a habit-associated operant model, and more effectively reduces alcohol versus sucrose self-administration, consistent with diminished alcohol reward. Rats were trained to self-administer 10% alcohol or 1.5% sucrose in a lever-press task and then underwent a within-subject assessment of NTX (0.1 to 1 mg/kg) effects on operant behavior. A fixed-ratio (FR5) reinforcement schedule was used to model goal-directed behavior, and a variable-interval (VI30) schedule was used to model habitual behavior. As predicted, NTX reduced fluid deliveries earned by the FR5-alcohol group significantly more than all other groups. However, NTX reduced lever presses during self-administration sessions in VI30-trained rats without reducing earned deliveries, due to the low contingency between rate of pressing and fluid deliveries under that schedule. Interestingly, when fluid delivery was withheld (extinction), NTX reduced reward-seeking in all rats. Finally, NTX blocked reinstatement of reward-seeking upon presentation of 0.2 ml alcohol or sucrose and associated cues in the FR5-trained but not VI30-trained rats. NTX reduced goal-directed alcohol drinking compared with other operant conditions. In addition, NTX blocked reinstatement of reward-seeking in rats trained on the goal-directed FR5 reinforcement schedule but not in rats trained on the habit-like VI30 reinforcement schedule. However, NTX also exerted nonspecific effects on reward-seeking that were revealed under low-effort contingency conditions or absence of reward. Together, these data support the hypothesis that NTX is less effective in conditioning models that are more habit-associated.

Underage alcohol drinking and medical services use in Hong Kong: a cross-sectional study

ObjectivesTo investigate the association of underage alcohol drinking with medical consultation and hospitalisation in Hong Kong.DesignCross-sectional study.SettingSecondary schools in Hong Kong.ParticipantsA total of 33 300 secondary 1 (US grade 7)...

A human laboratory pilot study with baclofen in alcoholic individuals

Preclinical and clinical studies show that the GABAB receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofen's biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10mg t.i.d. or an active placebo (cyproheptadine 2mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen's effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ≥7 repeats (DRD4L). Yet, baclofen's effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen's ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings.

Reduction of alcohol intake by the positive allosteric modulator of the GABAB receptor, rac-BHFF, in alcohol-preferring rats

Previous research has demonstrated that treatment with the positive allosteric modulator (PAM) of the GABAB receptor (GABAB PAM), rac-BHFF, suppressed lever-responding for alcohol and amount of self-administered alcohol in Sardinian alcohol-preferring (sP) rats. The present study was designed to extend the investigation on the anti-alcohol effects of rac-BHFF to alcohol drinking behavior. To this end, sP rats were exposed to the homecage, 2-bottle “alcohol (10%, v/v) vs water” choice regimen, with unlimited access for 24 h/day. rac-BHFF was administered once daily and for 7 consecutive days at the doses of 0, 50, 100, and 200 mg/kg (i.g.). Treatment with rac-BHFF resulted in an immediate, stable, and dose-related reduction in daily alcohol intake; the overall magnitude of reduction in alcohol intake averaged approximately 25%, 40%, and 65% in 50, 100, and 200 mg/kg rac-BHFF-treated rat groups, respectively. An increase in daily water intake fully compensated the reduction in alcohol intake, so that daily total fluid intake was unaffected by treatment with rac-BHFF. Daily food intake tended to be reduced only by the highest dose of rac-BHFF. These results complement closely with previous data indicating that (a) rac-BHFF suppressed operant, oral alcohol self-administration in sP rats and (b) the prototypic GABAB PAMs, CGP7930 and GS39783, reduced alcohol drinking in sP rats. However, while the reducing effect of CGP7930 and GS39783 on the daily alcohol intake tended to vanish after the first 2–3 days of treatment, the reducing effect of rac-BHFF on daily alcohol intake remained unchanged over the entire 7-day treatment period. These data strengthen the hypothesis that GABAB PAMs may represent a step forward in the search for GABAB receptor ligands with therapeutic potential for alcoholism.

Pharmacological Characterization of the 20% Alcohol Intermittent Access Model in Sardinian Alcohol‐Preferring Rats: A Model of Binge‐Like Drinking

Binge drinking is defined as a pattern of alcohol drinking that brings blood alcohol levels to 80mg/dl or above. In this study, we pharmacologically characterized the intermittent access to 20% ethanol (EtOH) model (Wise, Psychopharmacologia 1973;29:203) in Sardinian alcohol-preferring (sP) rats to determine to which of the compounds known to reduce drinking in specific animal models this binge-like drinking was sensitive to. Adult male sP rats were divided into 2 groups and allowed to drink either 20% v/v alcohol or water for 24hours on alternate days (Monday, Wednesday, and Friday) or 10% v/v alcohol and water for 24hours every day. After stabilization of their intake, both groups were administered 3 pharmacological agents with different mechanisms of action, naltrexone-an opioid receptor antagonist, SCH 39166-a dopamine D1 receptor antagonist, and R121919-a Corticotropin-Releasing Factor 1 (CRF1 ) receptor antagonist, and their effects on alcohol and water intake were determined. Intermittent 20% alcohol ("Wise") procedure in sP rats led to binge-like drinking. Alcohol drinking was suppressed by naltrexone and by SCH 39166, but not by R121919. Finally, naltrexone was more potent in reducing alcohol drinking in the intermittent 20% binge-drinking group than in the 10% continuous access drinking group. The Wise procedure in sP rats induces binge-like drinking, which appears opioid- and dopamine-receptor mediated; the CRF1 system, on the other hand, does not appear to be involved. In addition, our results suggest that naltrexone is particularly effective in reducing binge drinking. Such different pharmacological responses may apply to subtypes of alcoholic patients who differ in their motivation to drink, and may eventually contribute to treatment response.

기능성 소화불량증 환자의 영양소 섭취 및 식행동

As a disease that reduces quality of life, functional dyspepsia (FD) is associated with foods that may worsen its symptoms or cause it. The purpose of this study was to examine the nutritional status and dietary behaviors of FD patients. We investigated food intake, food intake frequency, and dietary habits of 45 FD subjects according to the Rome III Diagnosis Criteria. Average age and body mass index (BMI) were 47.7 years and <TEX>$22.6kg/m^2$</TEX> (males: <TEX>$23.4kg/m^2$</TEX>, females: <TEX>$22.1kg/m^2$</TEX>), respectively. Average energy intake was 77% of Korean Dietary Reference Intake (KDRI), and it was less than that of the Korea National Health and Nutrition Examination Surveys (KNHANES). Other nutrient intake levels were similar to the KNHANES. Energy intake proportion of carbohydrates : protein : fat was 56 : 18 : 26, and the ratio of fat intake was higher than that of the KNHANES. Beans, laver, tomato, and yogurt were consumed very frequently. In the results of meal regularity, dietary behaviors and composition of diet were relatively good. It is likely that the patient controlled their diet by eating cautiously and by reducing alcohol drinking and smoking. Our results indicate that FD patients' nutritional status by consumption of nutrients was at a level of normal healthy people and that dietary habits were better than normal adults. However, their fat intake levels were somewhat higher than normal people. Therefore, further research is required to identify the relationship between dietary intakes and FD.

A standardized kudzu extract (NPI-031) reduces alcohol consumption in nontreatment-seeking male heavy drinkers.

We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in nontreatment-seeking heavy drinkers to assess the safety and efficacy of 4weeks of kudzu extract in an outpatient setting. This randomized between-subject, double-blind, placebo-controlled study involved 2weeks of baseline, 4weeks of treatment, and 2weeks of follow-up. Seventeen men (21-33years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events. Medication adherence was excellent and there were no adverse events and changes in vital signs, blood chemistry, and renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34-57%, reduced the number of heavy drinking days, and significantly increased the percent of days abstinent and the number of consecutive days of abstinence. A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated, and resulted in a modest reduction in alcohol consumption in young nontreatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations.

The α1‐Adrenergic Receptor Antagonist, Doxazosin, Reduces Alcohol Drinking in Alcohol‐Preferring (P) Rats

Evidence supports a role for the noradrenergic system in alcohol drinking in animals and humans. Our previous studies demonstrated the efficacy of prazosin, an α1-adrenergic antagonist, in decreasing alcohol drinking in rat models of alcohol dependence. Prazosin has also been shown to decrease alcohol drinking in treatment-seeking alcohol-dependent men. Clinically, the use of prazosin is limited by the requirement for multiple daily administrations, whereas doxazosin, a structurally similar α1-adrenergic antagonist, requires only once-daily dosing. In this study, we tested the hypothesis that doxazosin, like prazosin, would decrease alcohol drinking in rats selectively bred for alcohol preference (P line). Adult male P rats were given 2h/d scheduled access to a 2-bottle choice (15% v/v alcohol vs. water) session 5d/wk (M-F), with food and water available ad libitum 24h/d. Rats were injected with doxazosin (0 to 10mg/kg, IP) 40minutes prior to initiation of the alcohol access session in 3 trials (of 3, 5, and 5 consecutive days) each separated by 5 to 8weeks. The third trial included 1day without alcohol access (for locomotor testing), and 1day of a single hour of alcohol access (for plasma alcohol determination). Doxazosin significantly reduced alcohol intake in all 3 trials. The 5mg/kg dose consistently reduced alcohol intake, increased water drinking, did not affect locomotor activity, and resulted in lower plasma alcohol concentrations, suggesting that the doxazosin-induced reduction in alcohol drinking was not dependent on a motor impairment or an alteration in alcohol clearance. Doxazosin decreases voluntary alcohol consumption by male alcohol-preferring (P) rats, supporting a role for the noradrenergic system in alcohol drinking in P rats and suggesting that doxazosin could potentially be an effective once-daily pharmacotherapeutic agent for the treatment of alcohol use disorders.

Anti-Alcohol and Anxiolytic Properties of a New Chemical Entity, GET73.

N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats.

Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats

BackgroundA dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking. MethodsWe compared intermittent and continuous access to 20% (v/v) alcohol in a two-bottle free choice drinking paradigm. Following a total of twenty 24-hour exposures for every experimental group, we assessed signs of alcohol withdrawal, including anxiety-like behavior and sensitivity to stress. The selective CRH1 receptor (CRH1R) antagonist antalarmin (0, 10, 20mg/kg, i.p.) was tested on alcohol consumption. ResultsIntermittent access to 20% alcohol led non-selected Wistar rats to escalate their voluntary intake to a high and stable level, whereas continuously exposed animals maintained a lower consumption. These groups did not differ in physical withdrawal signs. In addition, no differences were found when anxiogenic-like behavior was studied, neither under basal conditions or following restraint stress. Nevertheless, sensitivity to the treatment with the CRH1R antalarmin was observed since a reduction of 20% alcohol intake was found in both groups of animals regardless of the regimen of alcohol exposure. In addition, antalarmin was effective when injected to animals exposed to intermittent 10% (v/v) alcohol whereas it failed to suppress 10% continuous alcohol intake. ConclusionsPharmacological blockade of CRH1R reduced alcohol drinking when sustained high levels of intake were achieved suggesting that the CRH system plays a key role when high doses of ethanol are consumed by non-dependent subjects. This supports the notion that CRH system not only maintains the dependent state but also engages the transition to dependence.

Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats

Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1–10 mg/kg, subcutaneously [s.c.]; n = 8/dose), LY255582 (LY; 0.03–1 mg/kg, s.c.; n = 8/dose), or vehicle were injected 30 min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors.

Pregabalin reduces alcohol drinking and relapse to alcohol seeking in the rat

Pregabalin (Lyrica™) is a structural analogue of γ-aminobutyric acid (GABA) approved by FDA for partial epilepsy, neuropathic pain and recently generalized anxiety disorder. While the exact cellular mechanism of action of pregabalin is still unclear, evidence from several studies suggests that it reduces excitatory neurotransmitter release and postsynaptic excitability. Based on these mechanisms we sought interesting to evaluate the effect of pregabalin on alcohol-abuse-related behaviours. For this purpose, using genetically selected alcohol-preferring Marchigian Sardinian (msP) rats, we evaluated the effect of pregabalin on alcohol drinking and relapse to alcohol seeking elicited by environmental conditioning factors or stress. Our results showed that treatment with pregabalin (0, 10, 30 and 60 mg/kg) given orally selectively reduced home cage alcohol drinking in msP rat. This effect was confirmed in self-administration experiments where pregabalin (0, 10 and 30 mg/kg) significantly reduced operant responding for alcohol but not for food. Using alcohol reinstatement models we also found that pregabalin (0, 10 and 30 mg/kg) abolished seeking behaviour elicited by the pharmacological stressor yohimbine as well as cues predictive of alcohol availability. Results demonstrate that pregabalin may have potential in the treatment of alcohol addiction.

An Intervention to Reduce Alcohol Consumption in Undergraduate Students Using Implementation Intentions and Mental Simulations: A Cross-National Study

Excessive alcohol consumption has been linked to deleterious health consequences among undergraduate students. There is a need to develop theory-based and cost-effective brief interventions to attenuate alcohol consumption in this population. The present study tested the effectiveness of an integrated theory-based intervention in reducing undergraduates' alcohol consumption in excess of guideline limits in national samples from Estonia, Finland, and the UK. A 2 (volitional: implementation intention vs. no implementation intention) × 2 (motivation: mental simulation vs. no mental simulation) × 3 (nationality: Estonia vs. Finland vs. UK) randomized-controlled design was adopted. Participants completed baseline psychological measures and self-reported number of alcohol units consumed and binge-drinking frequency followed by the intervention manipulation. One month later, participants completed follow-up measures of the psychological variables and alcohol consumption. Results revealed main effects for implementation intention and nationality on units of alcohol consumed at follow-up and an implementation intention × nationality interaction. Alcohol consumption was significantly reduced in the implementation intention condition for the Estonian and UK samples. There was a significant main effect for nationality and an implementation intention × nationality interaction on binge-drinking frequency. Follow-up tests revealed significant reductions in binge-drinking occasions in the implementation intention group for the UK sample only. Results support the implementation intention component of the intervention in reducing alcohol drinking in excess of guideline limits among Estonian and UK undergraduates. There was no support for the motivational intervention or the interaction between the strategies. Results are discussed with respect to intervention design based on motivational and volitional approaches.

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Merger Fever: Can Two Separate Mechanisms Work Together to Explain Why We Drink?

Recent advances on the relationship between alcohol consumption and cardiovascular mortality

Several epidemiological data both on apparently healthy people and on patients with a history of cardiovascular events, indicate a consistent risk reduction in cardiovascular events or all-cause mortality among moderate alcohol drinkers, but, on the other hand, the harm of excess and irregular drinking. If cardiovascular patients are heavy alcohol drinkers, they must be strongly advised to abstain or at least substantially reduce alcohol drinking in the range of the "protective windows" showed in recent meta-analyses; if not contraindicated, regular alcohol consumers should not exceed one drink/day for women or up to two drinks/day for men as a component of a balanced cardio-protective dietary pattern with appropriate energy intake levels. At present, we believe that a cardiovascular patient who is teetotaler should neither be recommended, nor "prescribed" to start drinking for health gain. This patient, however, must be properly informed of the potential health benefits of a regular habit of drinking alcohol in moderation.

Activation of Nuclear PPARγ Receptors by the Antidiabetic Agent Pioglitazone Suppresses Alcohol Drinking and Relapse to Alcohol Seeking

Pioglitazone and rosiglitazone belong to the class of thiazolidinediones (TZDs). They were first developed as antioxidants and then approved for the clinical treatment of insulin resistance and Type 2 diabetes. TZDs bind with high affinity and activate peroxisome proliferator-activated receptor-gamma (PPARγ) receptors, which in the brain are expressed both in neurons and in glia. We evaluated the effect of PPARγ activation by TZDs on alcohol drinking, relapse-like behavior, and withdrawal in the rat. We also tested the effect of TZDs on alcohol and saccharin self-administration. We showed that activation of PPARγ receptors by pioglitazone (0, 10, and 30 mg/kg) and rosiglitazone (0, 10 and 30 mg/kg) given orally selectively reduced alcohol drinking. The effect was blocked by pretreatment with the selective PPARγ antagonist GW9662 (5 μg/rat) given into the lateral cerebroventricle, suggesting that this TZD's effect is mediated by PPARγ receptors in the central nervous system. Pioglitazone abolished reinstatement of alcohol seeking, a relapse-like behavior, induced by yohimbine, a pharmacologic stressor, but did not affect cue-induced relapse. In the self-administration experiments, pioglitazone reduced lever pressing for alcohol but not for saccharin. Finally, pioglitazone prevented the expression of somatic signs of alcohol withdrawal. These findings provide new information about the role of brain PPARγ receptors and identify pioglitazone as candidate treatments for alcoholism and possibly other addictions.

A theory‐based intervention to reduce alcohol drinking in excess of guideline limits among undergraduate students

Undergraduate students frequently exceed guideline limits for alcohol intake in a single session and are highly susceptible to associated health, social, and economic problems. Psychological theory suggests that interventions aimed at reducing alcohol consumption should target both motivational and volitional phases of action to be effective. This study reports an integrated theory-based intervention aimed at reducing undergraduates' alcohol consumption in excess of guideline limits. The study adopted a 2 (motivation: mental simulation vs. no mental simulation) × 2 (volitional: implementation intention vs. no implementation intention) randomized controlled design presented in an online format. Undergraduate students (N= 238; females, n= 133, M age = 20.11, SD= 2.09; males, n= 105, M age = 20.38, SD= 1.35) completed baseline psychological measures and self-reported alcohol consumption as units consumed and heavy episodic drinking occasions followed by the intervention manipulation (if any). One month later participants completed follow-up measures of the psychological variables and alcohol consumption. Significant reductions in alcohol consumption were observed at follow-up. Participants receiving a mental simulation intervention reported significantly fewer units of alcohol consumed and heavy episodic drinking occasions. Among participants with high baseline alcohol consumption, participants in the combined mental simulation and implementation intention intervention group consumed significantly fewer units than other groups. Results support the use of these theory-based strategies to reduce alcohol drinking in excess of guideline limits among undergraduates. There was preliminary support for the interaction between the two strategies among heavier drinkers. Targeting both motivational and implemental phases of action poses a high probability for success in changing alcohol-related behaviour in this population.

Motivation for Alcohol Becomes Resistant to Quinine Adulteration After 3 to 4 Months of Intermittent Alcohol Self‐Administration

Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (>8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration. Outbred Wistar rats underwent 3 to 4 months or approximately 1.5 months of intermittent, home-cage, two-bottle access (IAA) to 20% alcohol (v/v) or water. Then, after brief operant training, the effect of the bitter-tasting quinine (0.1 g/l) on the motivation to seek alcohol was quantified via progressive ratio (PR). Motivation for quinine-adulterated 2% sucrose under PR was assayed in a separate cohort of 3 to 4 months IAA rats. The effects of quinine on home-cage alcohol consumption in IAA rats and rats with continuous access to alcohol were also examined. Finally, a dose-response for quinine taste preference in IAA and continuous-access animals was determined. Motivation for alcohol after 3 to 4 months IAA, measured using an operant PR procedure, was not altered by adulteration of alcohol with 0.1 g/l quinine. In contrast, after 3 to 4 months of IAA, motivation for sucrose under PR was significantly reduced by adulteration of sucrose with 0.1 g/l quinine. In addition, motivation for alcohol after only approximately 1.5 months IAA was significantly reduced by adulteration of alcohol with 0.1 g/l quinine. Furthermore, home-cage alcohol intake by IAA rats was insensitive to quinine at concentrations (0.01, 0.03 g/l) that significantly reduced alcohol drinking in animals with continuous access to alcohol. Finally, no changes in quinine taste preference after 3 to 4 months IAA or continuous access to alcohol were observed. We have developed a novel and technically simple hybrid operant/IAA model in which quinine-resistant motivation for alcohol is evident after an experimentally tractable period of time (3 to 4 months vs. 8 months). Quinine dramatically reduced sucrose and water intake by IAA rats, indicating that continued responding for alcohol in IAA rats despite adulteration with the normally aversive quinine might reflect maladaptive or compulsive motivation for alcohol. This model could facilitate identification of novel therapeutic interventions for pathological alcohol seeking in humans.

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.

Therapeutic drug monitoring of naltrexone in alcohol dependent patients

Rationale: The µ-opiate receptor antagonist naltrexone is a new option for the treatment of alcohol dependence. It has been shown to reduce craving for alcohol and alcohol intake. Objective: The aim of this study was to relate plasma concentrations of naltrexone and its major active metabolite 6β-naltrexol in patients during treatment with naltrexone with clinical effects. Methods: A high performance liquid chromatographic method with column switching and spectrophotometric detection was established and validated and used for determination of naltrexone and 6β-naltrexol in plasma samples collected under steady state conditions. Results: Plasma concentrations exhibited high interindividual variabilities. The sum of concentrations naltrexone plus 6β-naltrexol correlated significantly with the reduction of alcohol intake. Receiver operating characteristics (ROC) analyses revealed significantly (p=0.043) higher rates of reduced alcohol drinking when plasma concentrations of naltrexone and 6β-naltrexol were above 16ng/ml. Conclusions: These data give evidence that monitoring of drug concentrations may be a useful option to improve the outcome of naltrexone treatment aiming to reduce alcohol consumption.