Gerhard Freund

Impairment of shuttle box avoidance learning following prolonged alcohol consumption in rats

Abstract Prolonged consumption of alcohol (6 months in Experiment 1; 9 months in Experiment 2) concomitant with adequate nutrition was found to impair the acquisition of shuttle box avoidance in rats. Alcohol was administered in the form of a liquid diet as the only source of fluid and calories. Ethanol constituted 35 per cent of the total caloric value of the liquid diet. One control group received the identical liquid diet with isocaloric substitution of sucrose for ethanol, and another control group received lab Chow and water. Two weeks after alcohol was omitted from the diet, the alcohol-consuming rats were severely impaired in learning the avoidance task as compared to the sucrose-consuming and lab Chow control groups. The latter two control groups did not differ from one another.

Ethanol dependence in the rat: a parametric analysis.

Rats were maintained on liquid diets as their sole source of calories and fluid for 10, 15, 20, and 30 days. The diets consisted 35-40% of total calories in the form of ethanol. This procedure resulted in substantial ethanol intake leading to behavioral intoxication. Blood ethanol concentrations were found to be elevated throughout the day with a peak during the dark phase of the light cycle. The removal of ethanol resulted in evidence of physiological dependence, including behavioral manifestation of autonomic and somatic dysfunction and an increased susceptibility to audiogenic convulsions. Ten days of ethanol exposure was found to be sufficient for the reliable induction of ethanol dependence. Further increases in ethanol exposure resulted in increased hyperexcitability as measured by susceptibility to audiogenic convulsions. The severity of withdrawal behavior was found to be correlated with the blood ethanol concentration measured upon ethanol removal. A behavioral rating scale for the evaluation of alcohol withdrawal intensity in rats is described.

Hypothermia after acute ethanol and benzyl alcohol administration

Abstract The acute administration of ethanol like other CNS depressing drugs, lowers body temperatures in mice. Therefore many of the biological effects attributed to ethanol itself may be secondary to hypothermia. The degree of hypothermia was dose dependent and ranged from 1.5 C after 1.9 g/kg to 4.5°C after 5.7 g/kg body weight. This effect was independent of the route of administration (oral, intraperitoneal), the temperature of the administered solutions and the tonicity (0.9% sodium chloride). Hypothermia was prevented by elevating environmental temperatures. Benzyl alcohol which is widely used as preservative in parenteral solutions also has a behaviorally sedating and hypothermic effect.

Cholinergic receptor loss in brains of aging mice.

Abstract The number of synaptic cholinergic receptors in brains of mice decreases with aging after 18 months. Alterations in body weight, starvation, and circadian variations could not account for these changes. The decrease in receptors was not associated with significant changes in receptor affinity and brain protein and DNA and RNA content. The determination of postsynaptic cholinergic receptor density is a quantitative chemical correlate of aging of the rodent brain. Whether or not the declining receptor density is a cause of the age-related decline of learning behavior can be resolved by observing the effects of manipulations of receptor density on learning in animals.

Impairment of Shock Avoidance Learning after Long-Term Alcohol Ingestion in Mice

Chronic alcohol consumption impaired the learning of a two-way shuttle box avoidance task in mice 10 to 14 days after the discontinuation of ethanol in the diet. Control groups received laboratory chow ad libitum or were pair-fed with the alcohol-consuming mice by diets containing isocaloric amounts of sucrose. The performance of the two control groups was indistinguishable from each other, and only the ethanol-consuming mice performed poorly. It was therefore concluded that alcohol consumption per se and not a nutritional deficiency was responsible for the impairment of learning.

Benzodiazepine receptor loss in brains of mice after chronic alcohol consumption

Abstract Benzodiazepine receptors in crude mitochondrial fractions of whole brains of mice were decreased in density and affinity after the animals had consumed alcohol in liquid diets for 7 months and then solid laboratory food for 1 month. These mice were compared with control mice pair-fed with the same liquid diet containing isocaloric amounts of sucrose. The maximal binding (Bmax) of alcohol-treated mice was found to be decreased by 12% from 1580 to 1340 fmol/mg protein and the dissociation constant (KD) was increased from 1.4 to 2.0 nM. Acute intoxication lasting for 2 weeks had no effect. It is hypothesized that once brain damage in the form of decreased synaptic receptor numbers and affinity has been induced by chronic alcohol consumption, this change in receptors could in itself become a cause of self-perpetuating alcohol abuse. Specifically the loss of anxiolytic receptors caused by chronic alcohol consumption could enhance anxiety and the compensatory consumption of the sedative alcohol.

Impairment of Timing Behavior after Prolonged Alcohol Consumption in Rats

Prolonged alcohol consumption (5 months) concomitant with adequate nutrition was found to impair the acquisition and performance of timing behavior. Alcohol was administered in the form of a liquid diet containing 35 percent ethanol-derived calories as the only source of fluid and calories. One control group received the identical liquid diet with isocaloric substitution of sucrose for ethanol, and another control group received laboratory chow and water without restriction. Thirty days after ethanol was discontinued in the diet, the alcohol-consuming rats were severely impaired in acquisition and performance of timing behavior as compared to controls.

Sound-induced seizures during ethanol withdrawal in mice.

An ethanol withdrawal syndrome, consisting of tremors and convulsions, was induced in C57BL/6J mice by feeding them a liquid diet containing 27% of ethanol-derived calories at an environmental temperature of +12 to 13° C for 6 days. Control groups were pair-fed with liquid diets containing isocaloric amounts of sucrose or Laboratory Chow. Seven and 24 h after the beginning of withdrawal, all mice were exposed to bell ringing for 90 sec. This sound induced convulsions in nearly one-half of ethanol-consuming mice at 7 h and in a few mice at 25 h. Only one mouse of the control groups had a convulsion. These findings support the concept that the ethanol withdrawal syndrome is a partially latent state of hyperexcitability of the brain following depression by ethanol.

The effect of aging on acquisition and retention of shuttle box avoidance in mice

Abstract Shuttle box learning in mice declined with advancing age from 3 to 15 months. The retention of this task decreased progressively with increasing acquisition-retention time intervals from 3 to 12 months. This progressive impairment with time was demonstrable when the age at retention testing was constant (15 months) as well as when the age at acquisition was constant (3 months). Therefore, the progressive impairment of retention with advancing age could not be explained by impaired acquisition which occurs with advancing age. The rate of forgetting was similar between ages 3 and 9 months and 9 and 15 months. It was therefore concluded that under the conditions of the experiment retention decreases only proportionately with the acquisition-retention time interval and is not accelerated by the effects of aging per se .

Memory and postsynaptic cholinergic receptors in aging mice

Significant retention deficits were observed on passive avoidance tasks (step-down and step-through) in 15-, 20-, and 25-month-old male C57BL/6 mice compared with 4- and 8-month-old mice. In contrast, cholinergic muscarinic receptor binding ( [3H]quinuclidinyl benzilate) in cerebral cortex, striatum, hippocampus, and cerebellum in these same animals revealed no difference in this 4- to 25-month age range. In a separate comparison of 4- and 29-month-old female mice, [3H]QNB binding was significantly decreased in the older group in cerebral cortex, hippocampus, and striatum. Environmental enrichment, compared with an impoverished environment, significantly improved retention in mice on 24-hr step-down performance but affected QNB binding only minimally (6-7% decrease of QNB binding in cerebral cortex and hippocampus). Benzodiazepine ( [3H]flunitrazepam) receptor binding was significantly (12-15%) decreased in 29-month-old mice compared with 4-month-old mice in the cerebral cortex, hippocampus, cerebellum, and brain stem.