Association between sweet preference and paternal history of alcoholism in psychiatric and substance abuse patients.

BACKGROUND: The relationship between preference for stronger sweet solutions and propensity to excessive alcohol drinking is supported by both animal and human studies. This study was designed to test the hypothesis that sweet preference is associated with the genetic risk of alcoholism as measured by a paternal history of alcoholism. METHODS: Participants were 180 patients admitted to a residential treatment program for the treatment of alcoholism, drug dependence, or psychiatric conditions. In addition to a routine medical examination, patients completed the standard sweet preference test twice (on the 9th and 24th days after admission), and the family history of alcoholism was evaluated. RESULTS: Sweet preference was shown to be stable over time. It was strongly associated with a paternal history of alcoholism, with family history-positive patients approximately 5 times more likely to prefer stronger sweet solutions than family history-negative subjects. Such factors as dependence on alcohol, cocaine, opiates, cannabis, other drugs (including prescription drugs), and tobacco smoking, as well as demographics (gender and age), did not significantly interfere with association between sweet preference and paternal history of alcoholism. CONCLUSIONS: These findings provide some support for the hypothesis that preference for stronger sweet solutions is associated with a genetic predisposition to alcoholism as measured by a paternal history of alcoholism.

Sweet liking and family history of alcoholism in hospitalized alcoholic and non-alcoholic patients.

The present study was designed to test the hypothesis that preference for stronger sweet solutions may be associated with the genetic risk for alcoholism. Thirty-two male patients with alcohol dependence admitted for alcoholism in-patient treatment and 25 non-alcoholic control subjects were used in the study. Hedonic response to sweets was evaluated using the sweet preference test. Family history of alcoholism was evaluated using a Russian version of the Michigan Alcoholism Screening Test modified for the assessment of the alcohol-related behaviour of the subject's biological father. Similar to our previous findings, alcoholics were far more likely to prefer the highest offered sucrose concentration (0.83 M), compared to non-alcoholic controls. Such preference was determined by two factors: positive family history of alcoholism and alcoholic status. Statistically, these factors contributed to the likelihood of preferring sweet solutions independently. Therefore, the effects of these factors may enhance each other. These findings support the hypothesis that preference for a stronger sweet solution is associated with a paternal history of alcohol dependence and may reflect a genetic predisposition to alcoholism.

P rats develop physical dependence on alcohol via voluntary drinking: changes in seizure thresholds, anxiety, and patterns of alcohol drinking.

BACKGROUND: It has been proposed that the alcohol-preferring P rat meets many of the criteria for an animal model of alcoholism. However, the development of alcohol dependence has not been explored in rats that self-administer ethanol for less than 15-20 weeks. The present study investigated the development of physical dependence upon alcohol after 2-6 weeks of voluntary alcohol intake. Changes in bicuculline-induced seizure thresholds, microstructure of alcohol drinking, and anxiety-related behavior were used as indices of alcohol dependence. In addition, we evaluated the microstructure of alcohol drinking associated with the development of physical dependence upon alcohol. METHODS: Alcohol (10% ethanol solution) was measured in graduated drinking tubes with both alcohol and water available continuously. Microstructure of alcohol intake was monitored by a computerized drinkometer. Physical dependence upon alcohol was determined by measuring bicuculline-induced seizure thresholds after alcohol withdrawal. Anxiety-related behavior of P rats after alcohol withdrawal was determined by the social interaction and elevated plus maze tests. RESULTS: Initial alcohol intake in the alcohol-preferring P rat was relatively modest (3.9 +/- 0.4 g/kg/day). Four days of forced alcohol exposure (initiation) followed by 6 weeks of voluntary drinking resulted in an increase of alcohol intake to 5.5 +/- 0.2 g/kg/day. Ethanol self-administration for 6 weeks, but not for 2 or 4 weeks, produced a significant reduction (30%; p < 0.05) in bicuculline-induced seizure thresholds during alcohol withdrawal. Alterations in the microstructure of alcohol intake (i.e., 90% increase in the size of alcohol drinking bouts compared to the baseline [p < 0.001] with no change in bout frequency) were associated with the development of alcohol dependence. Termination of alcohol intake after 6 weeks of voluntary alcohol consumption resulted in increased anxiety according to both the social interaction and elevated plus maze tests. CONCLUSIONS: The results of this study indicate that 6 weeks of voluntary alcohol intake are sufficient for the development of physical dependence upon alcohol in the alcohol-preferring P rats as measured by susceptibility to bicuculline-induced seizures. This time is much shorter than the 15-20 weeks reported earlier. Development of physical dependence to alcohol was associated with an increase in daily alcohol intake (40% over the baseline), an increase in alcohol intake during each drinking bout (90% over the baseline), and elevated anxiety during alcohol withdrawal.

Suppression of alcohol intake by chronic naloxone treatment in P rats: tolerance development and elevation of opiate receptor binding.

BACKGROUND: This study was planned to determine the feasibility of using a slow release naloxone preparation to treat alcoholism, because compliance with medication is a significant problem in alcoholics. METHODS: Experiments were performed in alcohol-preferring P rats maintained either on continuous access or on limited access (1 hr/day) to alcohol with water and food provided ad libitum. Naloxone (Nx) was administered either by twice daily subcutaneous injections or by slow release (1.1 mg/kg/hr) osmotic minipump. In limited access experiments, Nx was injected immediately before access to alcohol. RESULTS: An initial experiment estimated the dose-effect curve for Nx subcutaneous suppression on alcohol intake. Nx (2.5-20 mg/kg) had a stronger effect during the first 2 hr after injection (ED50 = 2.1 mg/kg); however, the effect was more modest on 24-hr consumption. Similar results were found with chronic Nx treatment. Low doses of Nx (0.5 and 2.0 mg/kg) injected immediately before limited access to alcohol produced almost complete suppression of alcohol intake for at least 14 consecutive days. However, 14 days of treatment with 26 mg/kg/day by minipump or injection produced an initial 50% suppression of 24-hr alcohol intake with the gradual development of tolerance. An acute challenge with Nx immediately after the pumps were scheduled to be empty provided additional evidence of tolerance development in chronically Nx-treated rats. Brain micro-opiate receptors, estimated autoradiographically by using the ligand [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin, showed that rats chronically exposed to Nx and showing tolerance to Nx suppression of drinking exhibited 17% to 250% increases in [3H][D-Ala2,N-Me-Phe4, Gly-ol5][tyrosyl-3,5-3H]-enkephalin binding. CONCLUSIONS: High doses of Nx are required to suppress continuous access alcohol consumption in P rats, and tolerance develops to the ethanol consumption-suppressing effect of Nx that may be related to increases in micro-opiate receptors.

Association between preference for sweets and excessive alcohol intake: a review of animal and human studies.

This report reviews a series of studies demonstrating a relationship between the consumption of sweets and alcohol consumption. There is consistent evidence linking the consumption of sweets to alcohol intake in both animals and humans, and there are indications that this relationship may be at least partially genetic in nature. Alcohol-preferring rats have a tendency to consume sucrose and saccharin solutions far beyond the limits of their normal fluid intake and this has been proposed to be a model of the clinical phenomenon known as loss of control. Furthermore, rats and mice, genetically bred to prefer alcohol, tend to choose more concentrated sweet solutions, compared to animals which do not prefer alcohol. Similar tendencies to prefer ultra-sweet solutions have been noted in studies of alcoholic subjects, with most alcoholics preferring sweeter sucrose solutions than do controls. Evidence also exists that those alcoholics who prefer sweeter solutions may represent a familial form of alcoholism. Finally, consumption of sweets and/or sweet solutions may significantly suppress alcohol intake in both animals and in alcoholics. Carbohydrate structure and sweet taste may contribute to this effect through different physiological mechanisms involving serotonergic, opioid, and dopaminergic functions. The possibility that there is concordance between sweet liking and alcohol consumption and/or alcoholism has theoretical, biological, and diagnostic/practical implications.

Preference for higher sugar concentrations and Tridimensional Personality Questionnaire scores in alcoholic and nonalcoholic men.

Animal studies have shown a positive association between the consumption of high concentrations of sweet solutions and subsequent alcohol intake. In a previous clinical study, it was shown that a preference for a high (0.83 M) concentration of sucrose (sweet liking) is characteristic of alcoholics, compared with controls. The present study was designed to determine whether personality variables, reported to be associated with subtypes of alcoholism, differentiate sweet liking alcoholics from sweet liking controls. Fifty-two male controls and 26 alcoholic patients were tested for sweet preference and administered the Tridimensional Personality Questionnaire. Sweet liking alcoholics scored significantly higher on the Tridimensional Personality Questionnaire Novelty Seeking and Harm Avoidance scales and related subscales when compared with sweet liking controls. Further analysis showed that preferred sucrose concentration, Harm Avoidance score, and Novelty Seeking predicted alcoholic versus nonalcoholic group status at 65% sensitivity and 94% specificity, with a correct classification in 85% subjects. We hypothesize that sweet liking may identify a specific alcoholism subtype also characterized by high novelty seeking and high harm avoidance. These findings may have theoretical biological significance and practical clinical implications.

Ultrasonic vocalization behavior differs between lines of ethanol-preferring and nonpreferring rats.

To further understand the relationship between emotional state and alcohol intake in rats, the tendency to emit ultrasonic vocalizations in response to an aversive, but nonpainful, air puff stimulus was tested in several rat lines. Included in this group were Maudsley Reactive (MR) and Non-Reactive (MNR) rats, and several lines of rats with either high ethanol preference or a low ethanol preference: Preferring, (P), Alko-Alcohol (AA), and Fawn-Hooded (FH) animals; and Non-Preferring (NP), Alko-Non-Alcohol (ANA), and Flinders Resistant Line (FRL). MR rats emitted fewer ultrasonic vocalizations (USVs) and showed less preference for ethanol than did MNR animals. An overall analysis that included the P, NP, FH, FRL, AA, and ANA groups demonstrated a significant negative correlation between the total number of USVs emitted and ethanol consumption. NP, FRL, and especially ANA rats (low ethanol-preferring) emitted the most USVs--to an extent similar to that typically found for normal rats. The duration of vocalizing was higher only in the NP and the FRL rats the relative to their P and FH comparison groups, respectively. In the ethanol-preferring and nonpreferring lines, the numbers of USVs emitted correlated positively with the duration of vocalizing, but not with the latency to vocalize, which in turn did not correlate strongly with ethanol intake. The latency to vocalize did not correlate significantly with ethanol intake across all drinking lines or MR or MNR rats, but was found to be higher in FH and AA rats relative to their nondrinking comparison groups. These associations suggest that the relationship between emotional state and ethanol drinking is complex and cannot be attributed to a simple elevated state of anxiety or emotionality. Further examination of the central nervous system mechanisms mediating the difference in USVs between paired lines of ethanol-preferring and nonpreferring rats may identify neurochemical factors that predict ethanol preference.

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.

Behavioral similarities and differences among alcohol-preferring and -nonpreferring rats: confirmation by factor analysis and extension to additional groups.

Thirteen behavioral variables from six tasks were measured in alcohol-preferring (AA, FH, and P) and -nonpreferring (ANA, FRL, and NP) rat lines/strains and subjected to Factor Analysis. Four Independent factors accounted for > 90% of the variance. Defecation in the open field and ultrasonic vocalizations after an air puff were negatively correlated with alcohol intake and preference, whereas the increase in daily fluid intake in the presence of saccharin was positively correlated. Other factors could be labeled Activity, Emotionality, and immobility Factors, and each was independent of the Alcohol Factor. When an additional alcohol-preferring rat line (HAD) and two additional nonpreferring groups (LAD and ACI) were tested, they were found to differ on most behaviors that were associated with alcohol intake and preference in the Factor Analysis; vocalizations and saccharin-induced increase in fluid intake, but not defection. A new Factor Analysis was then performed incorporating these three new groups and including five new behavioral measures. The following measures had high loadings on the Alcohol Factor: alcohol intake under choice conditions; alcohol preference; forced alcohol intake; alcohol acceptance (forced alcohol intake/basal water intake x 100); ultrasonic vocalization; saccharin intake; saccharin-induced increase in daily fluid intake; defecation in the open field test; and immobility in a modified forced swim test. These findings indicate that there are indeed certain behavioral characteristics that are common among alcohol-preferring rat lines/strains, but there are also substantial group differences on other behavioral measures. For those behavioral measures reflecting emotionality (defecation and ultrasonic vocalization) that loaded highly on the Alcohol Factor, the alcohol-preferring rats had lower scores.

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.

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.

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.

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.

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.

Reduction in the level of immobilization in forced swim test and ethanol intake in rats by oxygen therapy.

Experiments replicated the previous finding that rats with high immobilization time in the forced swim test (passive rats) consumed more 15% ethanol solution in a free choice situation with tap water than rats with active behavior (active rats). Exposure of passive rats to oxygen under normal and elevated (2 ata) pressure resulted in the decrease in immobilization scores in the forced swim test as well as reduction in alcohol consumption and preference.

Saccharin intake predicts ethanol intake in genetically heterogeneous rats as well as different rat strains.

Saccharin and ethanol intakes were measured in seven strains of rats known to differ in their preferences for ethanol: The Fawn-Hooded (FH), alcohol-preferring (P) and Maudsley Reactive rats have been reported to drink ethanol voluntarily, whereas the alcohol-nonpreferring, Maudsley Nonreactive and Flinders Line (FSL and FRL) rats do not. Saccharin and ethanol intakes were highly correlated (r = +0.61) over all strains, with the FH rats drinking the most of both solutions. Correlation coefficients between pairs of drinking versus nondrinking rat strains were even higher. In a second experiment, genetically heterogeneous F2 progeny from cross-breeding the ethanol-preferring FH rats with the ethanol-nonpreferring Flinders Resistant Line (FRL) rats were studied. The results indicated a high positive correlation between saccharin and ethanol intakes (+0.65). These findings suggest that the association between saccharin and ethanol intakes previously reported in rat strains with different preferences for ethanol may have a similar genetic basis.

Initial acceptance of ethanol: gustatory factors and patterns of alcohol drinking.

Individual differences related to taste, determined by prior two-bottle tests of quinine and saccharin selection against water, were found to be related to the initial selection of 15% ethanol solution during the first week of access by 60 randomly bred male rats. The 36 rats that drank the least alcohol during the first week (mean +/- SE: 0.49 +/- 0.06 g/kg/day), however, greatly increased their intake during the second and third weeks, to the level of the 24 initially high alcohol drinkers (4.07 +/- 0.39 g/kg/day during 1st week), and the influence of gustatory factors was no longer apparent. Subsequently, the initially low rats drank less alcohol when saccharin was the alternative fluid. The results can be interpreted as showing that initially low rats, that only drank rather large amounts of alcohol after prolonged exposure, resemble Cloninger's Type 1 alcoholics not only in this temporal pattern but also in being high in novelty seeking, and low in harm avoidance and reward dependence, and that the initially high rats that spontaneously drank rather large amounts even in the first week show the opposite characteristics and resemble Type 2 alcoholics. Although these rats are not themselves models for alcoholism, the results nevertheless suggest it might be possible to develop two separate animal models for the two types of alcoholism.