Alexey B. Kampov-Polevoy

To drink or not to drink : tests of anxiety and immobility in alcohol-preferring and alcohol-nonpreferring rat strains

Previous reports have provided mixed results about emotional states in rats that voluntarily drink substantial amounts of alcohol. The purpose of the present study was to compare several strains of alcohol-preferring rats (P, AA, FH) with several strains of alcohol-nonpreferring rats (NP, ANA, FRL), and the Maudsley strains on tests reflecting anxiety and immobility. At about 70 days of age the rats were placed in the elevated plus maze for a 5-min test; a forced swim test of 10 min was given 4 days later and this test was followed 4 days later by a modified forced swim test (the capsule), in which there were four false escape alleys. The FRL rats spent more time in the open arms of the elevated plus maze than any other strain, but there was no consistent relationship between elevated plus maze scores and alcohol intake. The alcohol-preferring P rats were the most active in the standard forced swim test and the alcohol-nonpreferring Maudsley Reactive rats were the least active, but there was no consistent relationship between immobility and alcohol intake overall. All rats were much more active in the capsule and there were no significant strain differences. However, the alcohol-preferring P and FH rats attempted to escape more than the other strains, resulting in an overall significant correlation between escape attempts and alcohol intake. These findings do not provide any support for the hypothesis that alcohol-preferring rats are drinking alcohol to reduce high anxiety states.

Pain sensitivity and saccharin intake in alcohol-preferring and -nonpreferring rat strains

The experiments were designed to study the association between consumption of palatable 0.1% (w/v) saccharin solution, voluntary drinking of 10% (v/v) ethanol solution, and pain sensitivity measured with the hot plate test. Rat lines that were genetically selected for high alcohol consumption (P and AA rats), alcohol-preferring Fawn Hooded (FH) rats and their F2[FH x FRL] hybrids, and the Maudsley Nonreactive strain (MNRA) had a high propensity to consume saccharin that resulted in a significant (almost twofold; p < 0.05) increase in their daily fluid intake when saccharin was available. These strains also had lower pain thresholds in the hot plate test than did their parallel strains [NP, ANA, Maudsley Reactive (MR)]. Most alcohol-nonpreferring strains [NP, ANA, and Flinders Resistant Line (FRL)] had preference ratios for saccharin about as high as those of the alcohol-preferring rats but, unlike the high alcohol drinkers, they did not increase their total fluid intake when saccharin was available. The mean saccharin intakes of the lines were strongly correlated with their alcohol drinking during the first 5 days, whereas their latencies on the hot plate were inversely related to their change in alcohol drinking with experience. The results are consistent with an endogenous opioid mechanism being involved in alcohol drinking.

To drink or not to drink: Open field behavior in alcohol-preferring and-nonpreferring rat strains

High open field activity has been associated with high alcohol intake in inbred mouse strains. The present study sought to determine if a similar relationship might exist in rats. Strains which voluntarily drink large amounts of alcohol (alcohol-preferring [P], alcohol-accepting [AA], Fawn-Hooded [FH]) or little or no alcohol (alcohol-nonpreferring [NP], alcohol-nonaccepting [ANA], Flinders Resistant Line [FRL]) were compared with the Maudsley strains of rats selectively bred for differences in open field defecation and activity. There were highly significant strain differences in open field activity, with the alcohol-preferring P rats exhibiting the highest activity and the alcohol-nonpreferring Maudsley Reactive rats exhibiting the lowest. However, the NP rats were almost as active as the P rats and the AA and ANA rats exhibited intermediate levels of activity which did not differ from each other. Thus, there was no consistent relationship between open field activity and high voluntary alcohol intake. Defecation was highest in the Maudsley Reactive rats, and there was a consistent negative relationship with alcohol intake (r = -0.455 across all strains). In a population of 57 FHxFRL F2 hybrids, there were no significant correlations between alcohol intake and open field activity (r = -0.01) or defecation (r = +0.12). We conclude, therefore, that there was no consistent relationship between voluntary alcohol intake and open field behavior across strains of rats.

Saccharin-induced increase in daily fluid intake as a predictor of voluntary alcohol intake in alcohol-preferring rats☆

This study examined the relationship between saccharin intake and ethanol consumption in alcohol preferring (P) rats and Fawn Hooded (FH) rats before and after exposure to forced ethanol (10%, v/v) solution. Both groups exhibited large increases (> 2X) in daily fluid intake (DFI) when saccharin (0.1%, w/v) was present and exhibited moderate levels of ethanol intake. Only the P rats significantly increased their ethanol consumption after exposure to ethanol as the sole drinking fluid. Correlational analyses revealed that the absolute intakes of saccharin and ethanol were not significantly correlated in either group, but the increase in DFI in the presence of saccharin was highly correlated with ethanol intake after forced ethanol exposure (r > +0.8; p < 0.05). Similarly, when correlations were conducted for these variables over both the P and FH groups, the correlation between increase in DFI in the presence of saccharin and alcohol intake was significantly higher than that between saccharin and alcohol intakes. Reexamination of previous data from 6 different rat strains also revealed a significant correlation between increase in DFI in the presence of saccharin and ethanol intake. These findings suggest that the dramatic increase in of DFI in the presence of saccharin may be an animal analog of the clinical phenomenon known as a loss of control.

Sweet liking phenotype, alcohol craving and response to naltrexone treatment in alcohol dependence.

AIMS To investigate the relationship between the sweet liking/sweet disliking phenotype (a putative probe of brain opioid function), craving for alcohol and response to treatment with naltrexone in individuals with alcohol dependence. METHODS Forty individuals with alcohol dependence were enrolled in a 12-week open-label study of 50 mg of naltrexone with four sessions of motivational enhancement therapy. Prior to treatment, individuals completed a sweet preference test and the Penn Alcohol Craving Scale. Subjects were categorized as sweet liking (SL), n = 15, or sweet disliking (SDL), n = 25, via a standard sweet tasting paradigm. The sweet tasting results were blinded to the subjects and to treatment staff. SL status, pretreatment craving and their interaction were examined as predictors of frequency of abstinent days and heavy drinking days during treatment with naltrexone. RESULTS SL and SDL subjects achieved similar reductions in percent heavy drinking days with treatment. During treatment, SDL subjects had 48% abstinent days compared to 30% for SL subjects (P = 0.034). Pretreatment craving did not predict % heavy drinking days or % abstinent days. An interaction effect was found between the SL/SDL phenotype and pretreatment craving such that SL subjects with high craving demonstrated higher rates of percent abstinent days whereas SDL subjects with high craving demonstrated lower rates of percent abstinent days, P < 0.001. CONCLUSIONS These findings indicate that the SL/SDL phenotype may predict variation in response to naltrexone and/or counseling treatment. Furthermore, the SL/SDL phenotype may interact with craving to provide a more robust prediction of outcome with naltrexone or counseling.

Sweet Liking and High Novelty Seeking: Independent Phenotypes Associated with Alcohol-related Problems

AIM We tested the hypothesis that high novelty seeking (NS; a trait that promotes experimentation) and hedonic response to sweet taste (a trait that may reflect processing of hedonic stimuli) act independently to increase the risk for having alcohol-related problems in young adults. METHODS The study was conducted in 158 healthy subjects (age 20-25 years) with no lifetime history of alcohol and/or drug abuse/dependence. NS was evaluated using the Tridimensional Personality Questionnaire. Pleasurable response to sweet taste was tested, using a sweet taste test to identify sweet likers (SL; those preferring the strongest offered sucrose solution) and sweet dislikers (SDL; those preferring weaker sucrose solutions). RESULTS NS score, but not SL/SDL status, was positively correlated with drinks per month (P = 0.0054) and drinks per drinking day (P = 0.021). When tested individually, both NS and SL/SDL status predict having alcohol-related problems (NS: odds ratio [OR] = 5.3, P = 0.0016 and SL/SDL: OR = 5.8, P = 0.0001) with an OR similar to positive family history of alcoholism status (OR = 5.7, P = 0.0007). The combination of SL status and high NS score (greater than gender-specific 70th percentile) greatly increased the estimated odds of having alcohol-related problems (OR 27.5, P < 0.0001). CONCLUSIONS These results support the hypothesis that high NS and SL phenotypes are independently associated with risk of alcohol-related problems. The combination of both phenotypes greatly increases the likelihood of alcohol-related problems. Although confirmation is necessary, this suggests that these phenotypes could contribute to improved methods to assess risk for alcohol-related problems and provide additional insight into processes underlying progression to alcohol-related problems.

Suppression of ethanol intake in alcohol-preferring rats by prior voluntary saccharin consumption

In a situation offering a free choice between 0.1% saccharin solution and tap water, Fawn Hooded (FH) rats consumed 363.0 +/- 33.5 ml/kg/day of saccharin solution. Subsequently those animals drank 3.0 +/- 0.4 g/kg of ethanol in a free choice between water and 10% ethanol solution. Control FH rats that did not have access to saccharin consumed 5.0 +/- 0.5 between groups was significant: p = 0.006). When control rats were exposed to the choice between 10% ethanol solution and 0.1% saccharin solution for 4 days they consumed 383.7 +/- 27.5 ml/kg/day of saccharin solution and their ethanol intake dropped to 1.2 +/- 0.3 g/kg/day. When these rats were returned back to alcohol/water choice and exposure to saccharin was discontinued, their alcohol intake was still reduced (3.7 +/- 0.3 g/kg/day for at least 10 consecutive days). Exposure of alcohol-experienced alcohol-preferring P rats with high (6.8 +/- 0.5 g/kg/day) and stable alcohol intake to saccharin/water choice for 4 days also resulted in a significant attenuation of their ethanol intake for at least 6 days following saccharin cessation. Thus, voluntary consumption of saccharin can suppress subsequent alcohol intake in both alcohol-naive and alcohol-experienced rats.

Sweet-liking is associated with transformation of heavy drinking into alcohol-related problems in young adults with high novelty seeking.

BACKGROUND We tested the hypothesis that high novelty seeking (NS) (a trait that promotes experimentation) and sweet-liking (SL) (a phenotype that may reflect processing of hedonic stimuli) act independently and synergistically to increase the risk of having alcohol-related problems in young adults. METHODS A sample of 163 young adults, ages 18 to 26, was recruited and balanced for gender and evidence for presence of alcohol problems to yield 150 evaluable participants. NS was evaluated using the Tridimensional Personality Questionnaire. Pleasurable response to sweet taste was tested to identify sweet-likers and sweet-dislikers. Alcohol use and problems were assessed by the Alcohol Use Disorders Identification Test and the Rutgers Alcohol Problem Index. RESULTS NS, but not SL, was positively and significantly associated with alcohol consumption and alcohol problems; however, the effect of NS on alcohol problems was significantly enhanced in the presence of the SL phenotype, thus showing a strong synergistic interaction. The combination of SL and high NS was associated with increased odds of having alcohol problems -20.64 (95% CI: -89.98, 4.74) compared to those with low NS and sweet-disliking. Other combinations did not produce such odds ratios. SL and low NS showed OR = 1.88 (95% CI 0.44, 7.99), and sweet-dislikers and high novelty seekers had OR = 4.07 (95%, CI 1.01, 16.46). CONCLUSIONS These results support and extend our hypothesis that as clinically distinct phenotypes, high NS and the SL phenotype are associated with risk of alcohol-related problems. High NS is associated with the use of alcohol, and the presence of the SL phenotype appears to bias an individual to alcohol problems once alcohol use is initiated. Understanding the biology and phenomenology of these phenotypes will allow a more complete picture of the processes that lead to alcohol problems.

Association of the Sweet-Liking Phenotype and Craving for Alcohol With the Response to Naltrexone Treatment in Alcohol Dependence: A Randomized Clinical Trial.

Importance Identification of moderators of the response to naltrexone hydrochloride treatment for alcohol dependence could improve clinical care for patients with alcohol use disorders. Objective To investigate the preliminary finding that the sweet-liking (SL) phenotype interacts with a high level of craving for alcohol and is associated with an improved response to naltrexone in alcohol dependence. Design, Setting, and Participants This 12-week double-blind, randomized, placebo-controlled clinical trial was conducted from February 1, 2010, to April 30, 2012, in an academic outpatient medical center. Eighty actively drinking patients were randomized by the SL (n = 22) or the sweet-disliking (SDL) (n = 58) phenotype and by pretreatment high (n = 40) or low (n = 40) craving for alcohol, with high craving defined as greater than the median. Patients and staff were blinded to categorization. Patients were excluded for unstable medical or psychiatric illness, including dependence on drugs other than nicotine. Four patients (2 in the placebo arm and 2 in the naltrexone arm) stopped medication therapy because of adverse effects. Data were analyzed from January 15, 2013, to May 15, 2016, based on intention to treat. Interventions Oral naltrexone hydrochloride, 50 mg/d, or daily placebo with weekly to biweekly brief counseling. Main Outcomes and Measures The a priori hypothesis tested SL/SDL phenotype, pretreatment craving, and their interaction as moderators of frequency of abstinent and heavy drinking days during treatment, assessed with the timeline follow-back method. Results Eighty patients were randomized (57 men [71%]; 23 women [29%]; mean [SD] age, 47.0 [8.6] years). A nonsignificant effect of naltrexone on heavy drinking was noted (4.8 fewer heavy drinking days; Cohen d = 0.45; 95% CI, -0.01 to 0.90; F1,67 = 3.52; P = .07). The SL phenotype moderated the effect of naltrexone on heavy drinking (6.1 fewer heavy drinking days; Cohen d = 0.58; 95% CI, 0.12-1.03; F1,67 = 5.65; P = .02) and abstinence (10.0 more abstinent days; Cohen d = 0.57; 95% CI, 0.11-1.02; F1,67 = 5.36; P = .02), and high craving moderated heavy drinking (7.1 fewer heavy drinking days; Cohen d = 0.66; 95% CI, 0.20-1.11; F1,67 = 7.37; P = .008). The combination of the SL phenotype and high craving was associated with a strong response to naltrexone, with 17.1 fewer heavy drinking days (Cohen d = 1.07; 95% CI, 0.58-1.54; F1,67 = 19.33; P < .001) and 28.8 more abstinent days (Cohen d = 0.72; 95% CI, 0.25-1.17; F1,67 = 8.73; P = .004) compared with placebo. Conclusions and Relevance The SL phenotype and a high craving for alcohol independently and particularly in combination are associated with a positive response to naltrexone. The SL/SDL phenotype and a high craving for alcohol merit further investigation as factors to identify patients with alcohol dependence who are responsive to naltrexone. Trial Registration clinicaltrials.gov Identifier: NCT01296646.

Fluoxetine Reduces Saccharin-Induced Elevation of Fluid Intake in Alcohol-Preferring Fawn-Hooded Rats

Previous work has established that saccharin and alcohol intakes are highly correlated in a variety of rat strains. In addition, it has been shown that alcohol-preferring rats consume saccharin beyond the limit of their normal daily fluid intake (DFI). It has been hypothesized that alcohol-preferring rats have impaired control over consumption of reinforcing substances, which may be related to a deficiency of brain serotonin. In the present study, we examined the effect of the serotonin reuptake inhibitor fluoxetine (2.5, 5.0, 10.0 mg/kg, IP, twice a day) on saccharin intake in alcohol-preferring Fawn-Hooded (FH) rats. It was confirmed that alcohol preferring FH rats almost triple their DFI when saccharin/water choice was introduced. Treatment with fluoxetine resulted in a dose-dependent decrease in saccharin intake to, but not below, the normal level of their DFI. No significant effects of fluoxetine on water intake were observed. Despite a significant (up to 69%) decrease in saccharin intake, only a minimal reduction (< 4%) in saccharin preference occurred. We conclude that fluoxetine reduces the exessive elevation of fluid intake observed at the presence of the palatable saccharin solution in Fawn-Hooded rats. These findings may provide more evidence for the involvement of the serotonergic system in the brain in exessive drinking of rewarding substances.