Effects of prenatal ethanol exposure on dopamine systems in C57BL/6J mice.

Young rats prenatally exposed to ethanol exhibit heightened responses to dopaminergie (DA) drugs, altered brain concentrations of dopamine, and its metabolite dihydroxyphenylacetic acid (DOPAC), and transient reductions in DA receptor binding. Adult mice exposed to ethanol prenatally also exhibit increased responses to DA drugs; however, brain concentrations of DA and DOPAC are unaltered. The effects of prenatal ethanol exposure on DA or DOPAC concentrations in young mice or on DA receptor binding in mice of any age are unknown. Therefore, to determine if the different effects of prenatal ethanol exposure on rats and mice are due to age at time of testing or species, we determined its effects on DA concentrations and turnover in young mice under conditions previously reported for adult offspring and on DA D1 and D2 receptor binding in both young and adult offspring. Consistent with our previous report for adult offspring, prenatal ethanol exposure did not alter DA concentrations or turnover. The treatment did, however, diminish periadolescent growth as previously reported and produced a transient increase in DA D1, but not DA D2 receptor binding. DA receptor binding was not altered in adult offspring. Although unrelated to prenatal ethanol exposure, the sexes differed on all of the DA measures. Combined with previous reports, the present study suggests that species rather than age is more likely to account for the different effects of prenatal ethanol exposure on DA systems, and that sex differences in DA systems should be further examined.

Prenatal ethanol effects and dopamine systems of adult C57 male mice.

Behavioral, pharmacological, and neurochemical studies indicate that prenatal ethanol exposure can alter dopamine (DA) systems of developing rats. In addition, some of the behavioral changes described for prenatal-ethanol-exposed rats and mice (e.g., reduced responding for food and other rewards) as well as their response to various psychoactive drugs (e.g., amphetamines, methylphenidate, haloperidol) suggest that the DA system changes might extend into adulthood. Neurochemical studies on the effects of prenatal ethanol on DA systems of adults have not been reported for either species. The present study provides a neurochemical assessment of prenatal ethanol effects on DA systems of fully mature mice. Compared to chow and sucrose controls, adult offspring of mice fed a diet containing 25% ethanol derived calories had preadolescent growth deficits as observed in previous studies which also showed long-term behavioral deficits. Prenatal ethanol exposure in the present study, however, did not alter the concentration of DA or dihydroxyphenylacetic acid (DOPAC) nor the progressive decline in the concentration of these compounds in either striatum or nucleus accumbens of mature mice at intervals after synthesis inhibition by alpha-methyl-DL-p-tyrosine. Thus, the present study provides no neurochemical confirmation of altered DA systems resulting from prenatal ethanol exposure under conditions previously observed to alter adult behavior.

Comparative effects of ethanol on motor activity and operant behavior.

Ethanol effects on two types of motor activity and on lever responding for food delivered on a fixed-ratio 20 (FR 20) reinforcement schedule were compared using C57BL/6 (C57) mice. Low doses of ethanol (1-2 g/kg) transiently elevated horizontal activity and high doses (2.5 and 3.0 g/kg) reduced this behavior throughout testing with a slight recovery toward the end of a 16-min test period. In contrast, similar ethanol doses produced a monotonic reduction in both vertical activity and lever responding for food under the FR 20 schedule. The ethanol-induced reduction in FR 20 lever responding was less prolonged than the reduction in vertical activity but was more prolonged than the reduction in horizontal activity. Because vertical activity and lever responding for food delivered on the FR 20 schedule were never elevated, were reduced at ethanol doses that either stimulated or depressed horizontal activity, and were unaffected by low ethanol doses that did not affect horizontal activity, it is unlikely that either are sensitive to the stimulatory effects of ethanol. Accountable mechanisms for the different effects of ethanol on the three behaviors are unknown; however, the present study eliminates ethanol dose, postinjection time, testing time, and food deprivation condition as possible reasons for the differences.

Effects of Ro 15-4513 and ethanol on operant behavior of male and female C57BL/6 mice.

Although the partial benzodiazepine receptor inverse agonist, Ro 15-4513, counteracts many ethanol effects, its effect on operant behavior or on ethanol-induced changes in this behavior, remains controversial. In this study, we examined the effects of Ro 15-4513, ethanol, and their interaction on behavior maintained by an FR 20 schedule of food reinforcement. Ro 15-4513 (1.0-4.0 mg/kg) and ethanol (1.5-3.0 g/kg) reduced lever-responding of both male and female mice. The disruptive effect of Ro 15-4513 was of short duration (approximately 10 min), and was greater in male than in female mice. Under equivalent dose and time parameters, ethanol disrupted behavior of both sexes to the same extent. In spite of the disruptive effects of both drugs when given alone, when given after ethanol and prior to testing, Ro 15-4513 attenuated the disruptive effects of ethanol in male mice. The present study extends previous reports by documenting: (1) that the disruptive effect of Ro 15-4513 on mice is of very short duration and occurs at lower doses than previously reported; (2) that, in spite of being disruptive itself, Ro 15-4513 can attenuate the disruptive effects of ethanol on schedule controlled behavior; and (3) that gender is an important consideration in determining the effects of this compound.

Gender differences in the effects of ethanol on C57BL/6 mice.

The influence of gender on the stimulatory and depressant effects of ethanol was examined in C57BL/6 (C57) mice. In Experiment 1, locomotor activity was assessed in young (2-month-old) male and female mice injected intraperitoneally (IP) with stimulatory (1.5 g/kg) or depressant (2.5 g/kg) doses of ethanol. Both the stimulatory and the depressive effects of ethanol were greater in young male than female C57 mice, and the gender difference was unrelated to blood ethanol concentration (BEC). In Experiment 2, older (9-month-old) male and female mice were given ethanol (2.5 g/kg) either by IP injection or gavage to determine if the gender differences in BEC and ethanol effects observed in the first experiment depended upon the route of ethanol administration. In this experiment, ethanol reduced locomotor activity more in males than females whether given by gavage or IP injection, and the males had higher BECs than females at the time of testing. Thus, the differences in the behavioral effects of ethanol appeared to be related to BEC. The greater depressive effect of ethanol on older male mice in this experiment is consistent with an earlier report of prolonged ethanol-hypnosis in older male C57 mice. Therefore, differences in BEC could account for the gender differences in the behavioral effects of ethanol on older but not young mice. The gender difference in BEC of mice obtained in the present and earlier reports is opposite to that reported for humans.(ABSTRACT TRUNCATED AT 250 WORDS)