James L. York

A comparison of the discriminative stimulus effects of ethanol, barbital, and phenobarbital in rats.

Five different groups of rats were trained in a food-motivated, bar-pressing task to discriminate from the nondrug condition (physiologic saline, i.p.) the effects produced by i.p. injections of ethanol (330, 660, or 990 mg/kg), sodium barbital (80 mg/kg), or sodium phenobarbital (25 mg/kg). The establishment of highly effective discriminations required 20–40 training sessions for all drugs, with the exception that rats trained with 330 mg/kg of ethanol required 80–100 training sessions. After the drug-nondrug discriminations were well established, cross tests revealed that ethanol did not elicit drug-appropriate responding in the groups trained with sodium barbital or sodium in the groups trained with sodium barbital or sodium phenobarbital. However, both barbiturates elicited drug-approppriate responding to some extent in rats trained with ethanol as the discriminative stimulus. With barbital, the greatest generalization was observed in rats trained with the low dose of ethanol (330 mg/kg). The findings emphasize the need for the use of several training doses and for transfer tests in both directions when the stimulus effects of drugs are compared.

The ethanol stimulus in rats with differing ethanol preferences

Alcohol-accepting (AA) and alcohol-nonaccepting (ANA) rats (Alko, Finland) were tested for their ability to master a shock-motivated (0.6 mA scrambled AC current) T-maze discrimination in which IP injections of ethanol (1.0 g/kg, 10% w/v in saline, 20-min latency) and, on alternate days, equivolume saline were employed as a discriminative stimuli signalling the safety of right or left goal compartments. ANA rats reached the criterion level of performance (eight of ten correct first-trial responses) more quickly than did AA rats (12.3±2.3 versus 31.4±7.7 sessions, P<0.01) and also maintained a superior level of performance throughout the course of the experiment, suggesting that ethanol may have been a more salient cue for ANA rats than for AA rats. Injections of acetaldehyde (0.1–0.25 g/kg, 1.0–2.5% w/v in saline) produced ethanol-appropriate responding to a greater extent in ANA rats than in AA rats, indicating that the actions of acetaldehyde may contribute importantly to the stimulus condition produced by the injection of ethanol in ANA rats. Sodium pentobarbital (10.0 g/kg) was equally effective in mimicking the action of ethanol in both AA and ANA rats. AA and ANA rats did not differ significantly in the impairment of motor performance produced by a range of ethanol doses, suggesting that differences in stimuli related to motor impairment do not contribute to the differences observed in the cue value of ethanol for AA and ANA rats.

Clinical Significance of Alcohol Intake Parameters at Initiation of Drinking

A considerable effort is now being focused upon the identification in young adulthood of predictive variables that can be used to detect individuals at risk for developing future alcohol problems. One goal is that such individuals may be targeted for early intervention efforts aimed at preventing the development of serious alcohol-related problems. Another goal is to extend the understanding of the etiology of alcoholism by identifying physiological and behavioral mechanisms underlying the addictive process. Reviewed below are efforts focused upon the importance and predictive value of the response to early exposures to ethanol, including alcohol intake variables at onset of drinking.

Studies on the discriminative stimulus properties of ethanol in squirrel monkeys

Eight male squirrel monkeys were trained to use the pharmacological effects of ethanol [orally via gastric intubation 1600 mg/kg (IG), in normal saline] versus those produced by equivolume saline as discriminative stimuli in an operant conditioning (bar pressing) procedure in which the availability of banana-flavored food pellets was made contingent upon the drug condition of the animal (ethanol SD, saline SΔ for four monkeys; saline SD, ethanol SΔ for the other four monkeys). Test doses of 7.5 mg/kg pentobarbital IG and 80 mg/kg barbital IG closely mimicked the cue properties of ethanol, while doses of morphine sulfate (5.0–20 mg/kg IG) failed to elicit ethanol-appropriate responding. Other ethanolic beverages containing 1600 mg/kg ethanol in the same volume as the training dose, and found to mimic the cue properties of pure ethanol were bourbon, gin, beer, vodka, and red wine. The single test dose of cognac, scotch, and tequila clicited responding different from that of the training dose of ethanol. Thus, the pharmacological effects of ethanolic beverages containing the same dose of ethanol (1600 mg/kg) may be noticeably different to some subjects. Blood levels of ethanol produced by the different beverages may be an important variable. There was no differential effect of the beverages upon free-feeding behavior of the monkeys at the time of testing. Ethanol preference tests conducted at the end of the study (i.e., after nearly 2 years of drug discrimination training) indicated that the assignment of ethanol as the condition under which food pellets were available (SD condition) moderately increased the ethanol preference of those subjects as compared to monkeys for whom ethanol had served as the SΔ condition.

Residual Pressor Effects of Chronic Alcohol in Detoxified Alcoholics

Although research in population studies has indicated that recent alcohol intake is positively correlated with blood pressure, there is a need to study the relationship of blood pressure to measures of lifetime alcohol intake in alcoholics. To this end, we assessed systolic and diastolic pressures and lifetime alcohol intake through structured interviews with 253 normotensive recovering alcoholics. Blood pressures were first corrected with multiple linear regression for the influence of confounding or modifying variables and then were regressed against alcohol consumption measures. Systolic pressure was significantly correlated (positively) with only a few measures of recent alcohol intake, and the correlations were not high (r2 = .05 to .11, P < .05). Diastolic pressure was found to be highly and positively correlated with the duration of the drinking career, but more so in blacks than in whites. The total lifetime dose of alcohol was found to be positively correlated with diastolic but not systolic pressure, but only in black male alcoholics. The steeper slope of the regression of blood pressure versus lifetime total alcohol or duration of the drinking career in black alcoholics suggests greater cardiovascular susceptibility to alcohol toxicity as lifetime doses increase and as the drinking career lengthens.

A survey of muscle function in detoxified alcoholics.

Selected characteristics of arm and leg muscle contraction were examined in a racially mixed group of male detoxified alcoholics (N = 45, ages 20-49) and age-matched controls (N = 75). Lifetime drinking histories estimated the mean lifetime consumption of ethanol to be 8.96, 12.1 and 20.4 kg ethanol/kg body weight for alcoholic subjects aged 20-29, 30-39 and 40-49, respectively. The severity of the alcohol dependence syndrome (ADS scale) was marked in alcoholics, but was not age-dependent. Alcoholics did not differ significantly from controls on health status or physical activity scales. The performance of alcoholic subjects was impaired on all muscle function measures, with relatively more impairment found in older alcoholics. Maximal knee extension force generated at 3 muscle lengths (hip, angle, 45 degrees, 90 degrees, 180 degrees) was impaired only in alcoholics 30-49 years of age. Forearm (handgrip) muscle strength was impaired in all age groups of alcoholics. Maximal muscle (biceps) contraction speed at 3 levels of resistance was impaired only in alcoholics in their fifth decade of life. The greatest deficit in alcoholics (all age groups) was observed in the anaerobic power (bicycle ergometer) test. Thus, the magnitude of dysfunction and the extent of age-relatedness was found to be a function of the muscle test employed.

Assessment of tolerance to barbital by means of drug discrimination procedures.

This study was designed to determine the relative development of tolerance to the discriminative-stimulus and hypnotic properties of barbital. By selectively reinforcing lever presses only in the presence of one of the drug states, rats were trained in a Skinner Box to discriminate the effect of sodium barbital (80 mg/kg) injection from that of saline injection. After the rats were well trained, the administration of daily hypnotic doses of barbital (240 mg/kg) for 8 days produced marked tolerance to the hypnotic effect of the barbiturate in all animals. The ability of the 80 mg/kg dose to serve as a discriminative stimulus was not impaired in animals which had been trained with the drug as the condition during which bar presses had been reinforced (SD condition). Animals for which bar presses had gone unrewarded under barbital (Sδ condition) displayed a tendency to develop tolerance to the stimulus properties of barbital. These findings are interpreted in the light of dose-effect studies, and it is suggested that the acquired polarity of the drug condition determined by its assignment as SD or Sδ may influence the discriminability of the drug in future exposures.

Application of Bioelectric Impedance Methodology and Prediction Equations to Determine the Volume of Distribution for Ethanol

In large-scale epidemiologic studies of drinking behavior there is a need for simple and reliable estimates of the body water compartment of subjects. This, in turn, provides an estimate of the volume of distribution of ingested ethanol and a better estimate of tissue exposure levels than the use of total body weight as the volume of distribution for alcohol. The volume of distribution for ethanol (total body water, TBW) was estimated in a racially mixed group of 276 alcoholics and 166 nonalcoholics (aged 20-59 years) by means of bioelectric impedance methodology (BIA) and by means of prediction equations based upon age, body weight, and height. Estimations of mean TBW from BIA were found to be only slightly higher (1-4%) than those provided by the prediction equations. TBW values generated from both prediction equations were also highly correlated with TBW values obtained by impedance methodology, with the highest correlations observed in females (particularly black) and in alcoholics (particularly female).

Age effects on chronic tolerance to ethanol hypnosis and hypothermia

Male Fischer 344 rats of three different ages (young, 4 months; middle, 13 months; and old, 25 months) were tested for their hypnotic and hypothermic response to a 3.5 g/kg dose of ethanol on day 1 and after an 8-day exposure to 4.0 g/kg of ethanol administered via intragastric intubation. All three age groups displayed, to a similar extent, an increased rate of blood ethanol disappearance (metabolic tolerance) on day 10 and day 16, as compared to day 1. Both young and middle-age rats demonstrated tolerance to ethanol hypothermia, but older rats did not. The same test dose of ethanol (3.5 g/kg, IP) administered on day 16, after a 5-day interval with no ethanol, produced a hypnosis response similar to that observed on day 1 (no tolerance), but the response to ethanol hypothermia was still significantly reduced over the day 1 and day 10 value in young and middle-age rats, suggesting a persistence and intensification of tolerance to hypothermia over the 5-day rest interval. However, tolerance to ethanol hypothermia was not observed in old rats. Thus, the effects of age on the development of chronic functional tolerance were complex and depended upon the test measure used.

Muscle fiber composition and length-tension relationships in rats chronically exposed to alcohol

Adult Fischer 344 rats were fed an alcohol diet (7-9 g/kg/day) for 12 weeks and were compared to pair-fed controls with regard to the contraction and fiber characteristics of the gastrocnemius and plantaris muscles of the leg. Muscles were isolated in situ with blood and nerve supplies intact. The muscles were stretched by 1 mm increments and were stimulated at each muscle length with a voltage (1 msec pulse) that had been observed to produce maximal twitch force at the initial muscle length. Maximal twitch tension was found to be only 10% less in alcohol than pair-fed rats and the increase in force resulting from stretching was approximately 15% less in alcohol than pair-fed rats. No significant changes in sciatic nerve conduction velocities were produced by alcohol exposure. Moreover, no significant differences in muscle weight or the number and size of Type I, Type IIa or Type IIb muscle fibers were observed. Although the 12 weeks of alcohol exposure affected muscle physiology and histology in the direction of increased impairment, the differences were not large enough to be statistically significant.