The Long-Term Behavioral Effects of Prenatal Alcohol Exposure in Rats

Prenatal exposure to alcohol can cause a variety of behavioral disturbances later in life. Many of the reports in animals of the behavioral teratogenic effects of alcohol have focused on assessing younger animals. The purpose of this paper is to review some of the longer lasting behavioral consequences of gestational alcohol exposure in animals. It is not meant as a comprehensive review, but rather focuses on selected studies. It is concluded that prenatal alcohol exposure does have long lasting effects, although some of these might only occur under challenging or stressful circumstances. It is hypothesized that as the animal matures compensatory mechanisms or strategies develop to compensate for these dysfunctions. Thus, behavioral problems may only be detected when these compensatory systems break down, either as a result of stress, because of complex testing procedures, or old age.     

Subjective Response to Alcohol: A Critical Review of the Literature

Background: Subjective response to alcohol (SR), which reflects individual differences in sensitivity to the pharmacological effects of alcohol, may be an important endophenotype in understanding genetic influences on drinking behavior and alcohol use disorders (AUDs). SR predicts alcohol use and problems and has been found to differ by a range of established risk factors for the development of AUDs (e.g., family history of alcoholism). The exact pattern of SR associated with increased risk for alcohol problems, however, remains unclear. The Low Level of Response Model (LLR) suggests that high‐risk individuals experience decreased sensitivity to the full range of alcohol effects, while the Differentiator Model (DM) asserts that high risks status is associated with increased sensitivity to alcohol's positive effects but decreased sensitivity to negative effects. Aims: The current paper (1) reviews two prominent models of subjective response, (2) reviews extant laboratory‐based research on subjective response, (3) highlights remaining gaps in our understanding and assessment of subjective response, and (4) encourages collaborative efforts to address these methodological and conceptual concerns. Methods: This paper reviews studies which employed placebo‐controlled and non‐placebo‐controlled alcohol challenge paradigms to assess a range of alcohol effects including impairment, stimulation, and sedation. Results: The research literature provides at least partial support for both the LLR and DM models. High‐risk individuals have been shown to have a reduced response to alcohol with respect to sedative or impairing effects, particularly on the descending limb of the blood alcohol curve (BAC). There is also evidence that ascending limb stimulant effects are more pronounced or operate differently for high‐risk individuals. Discussion: Despite commendable advances in SR research, important questions remain unanswered. Inconsistent results across studies may be attributable to a combination of an inadequate understanding of the underlying construct and methodological differences across studies (e.g., number and timing of assessments across the BAC, inclusion of a placebo condition). With respect to the underlying construct, existing measures fail to adequately distinguish between cognitive/behavioral impairment and sedation, aspects of which may be perceived positively (e.g., anxiolysis) due to their ability to act as negative reinforcers. Conclusions: Addressing the concerns raised by the current review will be integral to making meaningful scientific progress in the field of subjective response.     

Effects of Assessment Frequency on Subjective Intoxication Ratings After Alcohol Consumption

BACKGROUND: It is common for subjective intoxication measures to be administered frequently throughout an experimental session. It is unclear, however, whether repeated assessments affect the experience of intoxication. This study examined the effect of assessing subjective intoxication levels during alcohol consumption on subsequent perceptions of intoxication after drinking. METHODS: Forty-two participants consumed a moderate dose of alcohol (men, 82 g/kg; women, 0.74 g/kg) during a 30-min period. Participants either reported or did not report subjective intoxication levels at 10-min intervals during the drinking period. After the drink, all participants rated their level of subjective intoxication on several occasions. RESULTS: Individuals who reported their intoxication during the drinking period reported higher levels after consumption than did those who did not rate their intoxication during drinking. CONCLUSIONS: These data suggest the potential for reactivity effects when conducting repeated assessments of perceived subjective intoxication.     

Expanding the Utility of the Biphasic Alcohol Effects Scale (BAES) and Initial Psychometric Support for the Brief-BAES (B-BAES)

Background:  The utility of one of the most widely used subjective alcohol assessment tools, the Biphasic Alcohol Effects Scale (BAES) has been somewhat limited based on lack of psychometric studies in large and diverse samples, a range of alcohol doses, the length of the measure, and the original instructional set which precluded baseline measurement and disclosed to subjects that they received alcohol.
Methods:  The current study investigated the factor structure of the BAES with a modified instructional set at pre-drink baseline and after consumption of various doses of alcohol, in a sample of 190 men and women, heavy and light social drinkers. This study tested the psychometric properties of a brief version of the BAES (Brief-BAES or B-BAES).
Results:  Results demonstrated robust support of the stimulant and sedative constructs across all conditions, and demonstrated strong psychometric support for the 6-item B-BAES.
Discussion:  This is the first comprehensive study to expand the utility of the BAES by instructional set, baseline measurement, at various alcohol doses, and by drinking history and sex. In addition, the introduction of the B-BAES may further increase the utility of this scale, particularly in paradigms with repeated measurement or time constraints.     

Anticipated Stimulant and Sedative Effects of Alcohol Vary with Dosage and Limb of the Blood Alcohol Curve

Anticipations of alcohol's effects reportedly covary with the amount consumed. Alcohol's stimulant and sedative properties also may contribute to alcohol consumption. Anticipations of stimulant and sedative effects have not been investigated extensively. The present study examined the stimulant and sedative effects subjects anticipated experiencing if they were on the ascending or descending limb of the blood alcohol curve after consuming two or four standard drinks. One hundred sixty-six undergraduates reported anticipating greater stimulant effects than sedative effects on the ascending limb of the blood alcohol curve, and greater sedative effects than stimulant effects on the descending limb. Subjects also reported anticipating larger effects with larger doses. Men tended to anticipate smaller effects than women. These results support the notion that specific anticipated effects vary with dosage and the limb of blood alcohol curve, suggesting that the study of anticipated effects of alcohol should employ these variables.     

Influence of Dissolved Oxygen Concentration on the Pharmacokinetics of Alcohol in Humans

Background: Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). Methods: Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC ≤0.015%, 10 min at BAC ≤0.010%, and 5 min at BAC ≤0.006%. Results: The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p < 0.05). In analyzing pharmacokinetic parameters, AUC_inf and K_el of the high oxygen groups were lower than in the normal oxygen group, while C_max and T_max were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC_inf and t_1/2 was expected to be reduced in the high oxygen group compared to the normal oxygen group. Conclusions: In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol‐related side effects and accidents.     

Effects of aripiprazole on subjective and physiological responses to alcohol

Background:  Aripiprazole is an atypical antipsychotic with partial agonist activity at D₂ receptors, which could reduce the reinforcing effects of alcohol. The present study examined whether aripiprazole modifies the behavioral and physiological effects of a moderate dose of alcohol in a group of social drinkers.
Methods:  Eighteen healthy subjects (9 men; mean age = 27.6 years) completed a double-blind, within-subject study with 3 experimental sessions in a randomized sequence, during which they received no medication, aripiprazole 2.5 mg, or aripiprazole 10 mg on the day prior to the laboratory session. During the session, subjects consumed alcohol that was served as three standardized drinks (i.e., a total of 0.8 g/kg for men and 0.7 g/kg for women). Breath alcohol concentration (BrAC), heart rate, blood pressure, static ataxia, and subjective effects were measured regularly throughout the laboratory sessions.
Results:  Alcohol consumption produced physiological and subjective responses that were consistent with the literature on its effects. Pre-treatment with aripiprazole was generally well tolerated, with tiredness being the most commonly reported adverse event. The medication was associated with modest physiological effects. It also significantly and dose-dependently increased the sedative effects of alcohol and, to a lesser degree, decreased the euphoric effects of alcohol.
Conclusions:  These findings require replication in a larger subject sample that includes heavy drinkers and in a study that employs a placebo session. Based on its capacity to increase the sedative effects and decrease the euphoric effects of alcohol, aripiprazole could be of value in the treatment of heavy drinking.     

Fetal Alcohol Effects: Mechanisms and Treatment

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Edward P. Riley. The presentations were (1) Does alcohol withdrawal contribute to fetal alcohol effects? by Jennifer D. Thomas and Edward P. Riley; (2) Brain damage and neuroplasticity in an animal model of binge alcohol exposure during the third trimester equivalent, by Charles R. Goodlett, Anna Y. Klintsova, and William T. Greenough; (3) Ganglioside GM1 reduces fetal alcohol effects, by Basalingappa L. Hungund; and (4) Fetal alcohol exposure alters the wiring of serotonin system at mid-gestation, by F. Zhou, Y. Sari, Charles Goodlett, T. Powrozek, and Ting-Kai Li.     

Effects of stress and alcohol on subjective state in humans

BACKGROUND: There is increasing evidence that stress and hypothalamic-pituitary-adrenal axis activation interact with drugs of abuse and influence drug-taking behaviors. Both studies with laboratory animals and survey data with alcohol users suggest that acute or chronic stressful events increase alcohol intake. One mechanism for the increase in alcohol intake may be that stress alters the subjective effects produced by the drug in ways that enhance the reinforcing properties of alcohol. Therefore, in this study we determined whether an acute social stressor alters subjective responses to ethanol in humans. The stressor was a modified version of the Trier Social Stress Test, an arithmetic task that increases cortisol levels. METHODS: Twenty male volunteers participated in two laboratory sessions, in which they performed the Trier Social Stress Test on one session and no task on the other session, immediately before consuming a beverage that contained ethanol (0.8 g/kg in juice) or placebo (juice alone). Eleven subjects received ethanol on both sessions, and nine subjects received placebo on both sessions. Primary dependent measures were self-report questionnaires of mood states. Salivary levels of cortisol were obtained to confirm the effectiveness of the stress procedure. RESULTS: Stress alone produced stimulant-like subjective effects. In the group who received ethanol, stress increased sedative-like effects and decreased stimulant-like effects. CONCLUSIONS: At this relatively high dose of ethanol, stress increased sedative effects of alcohol and did not increase desire for more alcohol. It is possible that in some individuals, the increased sedative effects after stress may increase the likelihood of consuming more alcohol. The effects of stress on consumption at this, or lower, doses of alcohol remain to be determined.     

Alcohol affects executive cognitive functioning differentially on the ascending versus descending limb of the blood alcohol concentration curve

BACKGROUND: Executive cognitive functioning (ECF), a construct that includes cognitive abilities such as planning, abstract reasoning, and the capacity to govern self-directed behavior, has been recently researched as an antecedent to many forms of psychopathology and has been implicated in alcohol-related aggression. This study was designed to examine whether differential ECF impairments can be noted on the ascending versus the descending limbs of the blood alcohol concentration curve. METHODS: Forty-one male university students participated in this study. Twenty-one subjects were given 1.32 ml of 95% alcohol per kilogram of body weight, mixed with orange juice, and the remaining 20 were given a placebo. Participants were randomly assigned to either an ascending or descending blood alcohol group and were tested on six tests of ECF on their assigned limb. Subjective mood data were also collected. RESULTS: Intoxicated participants on both limbs demonstrated ECF impairment; the descending-limb group showed greater impairment than their ascending-limb counterparts. Intoxicated subjects were significantly more anxious at baseline than placebo subjects. The introduction of this covariate nullified any significant differences in subjective mood found on either limb of the blood alcohol concentration curve, but ECF impairments remained robust. CONCLUSIONS: Our results support the conclusion that alcohol negatively affects cognitive performance and has a differential effect on the descending versus the ascending limb of the blood alcohol concentration curve. The latter finding may have important ramifications relating to the detrimental consequences of alcohol intoxication.     

SIAM-Like Phenomenon Caused by Low Doses of Alcohol

Background: Swift increase in alcohol metabolism (SIAM) is usually evoked by a large dose of ethanol, which is often demonstrated by an abrupt increase in oxygen uptake. SIAM was induced by low doses of ethanol and evaluated by pharmacokinetic analyses of ethanol and its metabolites. Methods: Rabbits were initially administered 1.0 g/kg of ethanol solution and the same dose was given to the bolus group 6 hours after the first injection. The infusion group was administered 0.25 g/kg/h of ethanol 2 hours after the first injection. Blood concentrations of ethanol, acetaldehyde, and acetate were then determined and comparisons were made using pharmacokinetic parameters. Results: A significantly higher ethanol elimination rate was observed after re-administration of ethanol to the bolus group. Other pharmacokinetic parameters were unaffected. The concentration at steady state (Css) for the infusion group was stable. A significantly higher level of mean residence time (MRT) in blood acetaldehyde was observed for the bolus group, whereas no MRT changes were observed for the infusion group. A significantly higher level of blood acetate Css was observed after re-administration of ethanol to the bolus group, following the changes in area under concentration and MRT. No Css changes were observed for the infusion group. The Css of acetate at stage 2 was significantly higher for the bolus group, compared to the infusion group. Conclusion: Low doses of ethanol enhanced alcohol metabolism in rabbits, according to a pharmacokinetic analysis of circulating ethanol concentrations. Simultaneous analyses of its metabolites followed the kinetic of ethanol.     

Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers

BACKGROUND: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. METHODS: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. RESULTS: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. CONCLUSIONS: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.