Search

A consummatory conflict procedure that involves an abrupt reduction in magnitude of an expected reward (negative contrast) has been shown to be particularly sensitive to the effects of anxiolytic agents. As previously reported with chlordiazepoxide, another benzodiazepine (BDZ), midazolam released suppressed consummatory performance in a dose-dependent manner. This effect was not due to a general appetite stimulatory effect of the drug. The effects of three 5-HT antagonists on negative contrast were examined to evaluate the role serotonin may play in the anxiolytic action of BDZ. Methysergide was found to be ineffective, cinanserin tended to reduce contrast at two intermediate doses, and cyproheptadine eliminated the contrast effect in a similar fashion as midazolam. The effectiveness of cyproheptadine may not be attributed to its anticholinergic or antihistaminergic actions since scopolamine and pyrilamine did not produce similar effects. The results are discussed in terms of the role serotonin may play in the anti-conflict action of BDZ, as well as possible interactional effects of GABA.

This study investigated whether female offspring of alcohol-treated mothers are, themselves, more or less susceptible than control offspring to the deleterious effects of alcohol on the outcome of their own pregnancy. One group of pregnant C57BL mice was fed a liquid diet containing 25% ethanol-derived calories (EDC) and another group was pair-fed an isocaloric (0% EDC) control diet. A third group was fed lab chow ad libitum (LC). The female offspring resulting from those matings were subsequently mated upon reaching 90 days of age. These pregnant mice were then separated into three prenatal treatments (25% EDC, 0% EDC, and LC). On gestation-day 19, second generation fetuses were removed by cesarean section, weighed, and sexed. Results indicated that number of implants, live births, and percent prenatal mortality did not differ between groups. However, fetal weight was lower in groups prenatally exposed to ethanol than in controls, regardless of the prenatal history of the mothers, themselves. More importantly, the data suggest that offspring of alcohol-treated mothers who do not consume alcohol themselves during their own pregnancy may still have a tendency to have offspring of lower birth weight. On the other hand, if mothers prenatally exposed to alcohol do consume alcohol during their own pregnancy, the impact of fetal weight suppression is even greater than expected for in utero alcohol exposure alone. These effects may be due to the fact that mothers who were prenatally exposed to alcohol weighed less than controls at the time of becoming pregnant. As such, these data imply an increased risk for low birth weight offspring in children of alcoholic mothers who drink during their own pregnancy.

Basic scientists and clinicians alike are in agreement that children of alcoholic mothers are at risk for a variety of birth defects. These defects have been labeled fetal alcohol syndrome or, in a milder form, fetal alcohol effects. Prevention or therapeutic intervention of this disorder requires an understanding of the mechanism of action of alcohol on the developing fetus. This paper addresses the possible role of prostaglandins as biochemical mediators of the teratogenic actions of alcohol.

RO15-4513, an imidazobenzodiazepine that has been reported to antagonize several behavioral and biochemical actions of ethanol, was given to C3H mice at various times during withdrawal from chronic (72 hours) continous exposure to ethanol vapor. When administered immediately following chronic ethanol exposure, RO15-4513 (6 or 12 mg/kg) did not influence the withdrawal response. However, when given at subsequent times (3, 5, and 8 hours postethanol withdrawal), RO15-4513 significantly increased the severity of the withdrawal response in ethanol-exposed mice. Moreover, this exacerbation was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1188. Thus, these data indicate that the benzodiazepine inverse agonist, RO15-4513, is capable of exacerbating, but not precipitating, ethanol withdrawal.

Glycemic conditioning was investigated in four experiments in which insulin was administered to animals in particular stimulus contexts. Both hyperglycemic and hypoglycemic conditioned responses were obtained, with the directionality of the CR dependent upon which environmental complex was used as the CS. These bidirectional glycemic CRs were obtained in both within-Subject and between-Subject conditioning procedures. Additional experiments indicated that the hyperglycemic CR was probably not related to illumination differences between the two conditioning contexts, nor to a differential opportunity for activity in the two conditioning contexts. Several possible reasons for the occurrence of bidirectional glycemic CRs were considered.

The influence of pre-pregnancy alcohol consumption on alcohol self-selection during pregnancy and lactation was examined in C57BL mice. One group of animals was given a two-bottle choice between water and a 10% w/v ethanol solution for three weeks prior to breeding, throughout pregnancy, and during lactation, while a second group was given the alcohol-water choice beginning on the first day of pregnancy. Relative alcohol intake (g ethanol/kg body weight) as well as alcohol “preference” decreased below pre-pregnancy levels during both pregnancy and lactation. That is, voluntary alcohol consumption was attenuated in pregnant and lactating mice, regardless of strain-typical pre-pregnancy high consumption. However, mice given a choice between alcohol and water prior to pregnancy did not decrease their alcohol consumption during pregnancy as much as mice not given the pre-pregnancy alcohol choice. There was no correlation between pre-pregnancy alcohol consumption and subsequent intake. The mechanism underlying decreased voluntary alcohol consumption during pregnancy remains to be elucidated, but it is clear that prior experience with alcohol influences the phenomenon.

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose has been shown to be reduced by chlordiazepoxide (CDP) and ethanol (ETOH). In a previous experiment, doses of 0.75 and 1.0 g/kg ETOH substantially reduced contrast while doses of 0.25 and 0.5 g/kg ETOH were much less effective. In this study, doses of 6 and 8 mg/kg CDP were shown to attenuate the negative contrast effect while smaller doses (2 and 4 mg/kg) influenced contrast to a lesser degree. Evidence for an additive effect of CDP and ETOH on contrast reduction was obtained when 4 mg/kg CDP and 0.5 g/kg ETOH were administered together.

A new potentially useful measure for assessing physical dependence in mice chronically exposed to ethanol is described. C3H/He mice continuously exposed to ethanol vapor for four (Experiment 1) or three (Experiment 2) days spent more time engaged in stereotypic climbing behavior than controls. This stereotypic climbing behavior correlated well, both temporally as well as in intensity, with other previously described signs of ethanol withdrawal. All measures of withdrawal behavior (including climbing) peaked at eight hours after withdrawal and returned to control levels by 30–33 hours. The utility of this behavioral assay for assessing physical dependence on ethanol is further discussed with reference to possible underlying neurochemical events.

Negative contrast that occurs when rats are shifted from 32% to 4% sucrose was reduced by IP injections of ethanol (1.0 g/kg) on postshift day 2, but not on postshift day 1. Smaller doses (0.25 and 0.5 g/kg) were ineffective, while larger doses (1.5 and 2 g/kg) produced sedation. A dose of 0.75 g/kg had effects similar to the 1.0 g/kg dose when administered on post-shift day 2. These results parallel those obtained with chlordiazepoxide and differ somewhat from amobarbital treatment.

Embryonic tissue of rodents and other species has been reported to produce prostaglandins (PG) of the E series during gestation. We attempted to establish the presence of PGE in C57BL/6J mouse embryos and peri-embryonic tissue as an initial step in examining the role of maternal ethanol treatment on PG production. Gestation day 10 embryos were found not to produce or degrade PGE. However, a tissue complex which included embryonic tissue, peri-embryonic membranes, placenta and uterus was capable of producing PGE from both endogenous and exogenous arachidonic acid. Furthermore, in vivo and in vitro aspirin was able to suppress PGE production from this tissue. It is concluded that gestation day 10 C57BL/6J mouse embryonic tissue, unlike that of rat, is not capable of measurable PGE production. However, uterine and peri-embryonic tissues, needed to support pregnancy, are capable of significant PGE production.

Two experiments were conducted to investigate the influence of ovariectomy (OVX) on alcohol sensitivity in mice. In the first experiment, OVX, sham-operated, and nonsurgical control C57BL mice were examined for brain alcohol levels associated with alcohol-induced motor incoordination, alcohol-induced loss of righting reflex, and voluntary alcohol consumption. The second experiment employed four strains of mice (C57BL, C3H, DBA, and Swiss Webster) to evaluate the influence of OVX on alcohol-induced spontaneous activity. Taken together, the results indicated that surgical removal of the ovaries in mice does not influence alcohol-induced motor incoordination, loss of righting reflex, or spontaneous activity. Voluntary alcohol consumption, however, was affected by ovariectomy, since mice in the OVX group consumed less alcohol relative to body weight (g/kg) than controls.

The purpose of this study was to examine the effects of two partial benzodiazepine inverse agonists, RO15-4513 and FG-7142, alone and in combination with ethanol on locomotor activity in C57BL/6 mice. When administered alone, 1.5 g/kg ethanol did not significantly influence activity, confirming previous reports indicating this mouse strain is relatively insensitive to the excitatory properties of ethanol. RO15-4513 treatment also did not significantly influence locomotor activity when administered alone. However, coadministration of RO15-4513 (1.5–6 mg/kg) and ethanol markedly increased locomotor activity. Moreover, the unmasking of ethanol's stimulant action by RO15-4513 (6 mg/kg) was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1788. In contrast, FG-7142 (10–20 mg/kg) increased activity to the same extent in both saline and ethanol-injected mice. This effect was blocked by RO15-1788 pretreatment as well. Neither RO15-4513, FG-7142, nor RO15-1788 significantly influenced blood ethanol concentrations. It is suggested that RO15-4513 unmasked the stimulant effects of ethanol by virtue of its ability to antagonize the depressant properties of ethanol in C57BL/6 mice.