Scheduled access to ethanol results in motor impairment and tolerance in female C57BL/6J mice.

We recently reported a method where water-restricted mice were given scheduled access to ethanol followed by access to water. C57BL/6J mice would repeatedly self-administer ethanol in amounts that produced high and stable blood ethanol concentrations (BEC) [Finn DA, Belknap JK, Cronise K, Yoneyama N, Murillo A, Crabbe JC. A procedure to produce high alcohol intake in mice. Psychopharmacol 2005;178:471-480]. The studies reported here demonstrate that behavioral signs of motor impairment result from these high alcohol intakes, and that there was some evidence of tolerance development across repeated sessions. Female C57BL/6J mice were allowed 30 min access to ethanol (5% v/v) followed by 2.5 h access to water either: every 3rd day for 12 days; every 2nd day for 28 days; or every 2nd day for 9 days. On intervening days, mice had 3 h access to water. A control group had daily access to water only. Mice consumed 2-2.5 g/kg ethanol in 30 min, resulting in BECs of 1.4-1.5 mg/ml. Motor impairment was assessed using the accelerating or fixed speed rotarod, balance beam or screen test. In all studies, mice were tested for motor impairment immediately after 30 min access to ethanol or water. In Experiment 1, ethanol-exposed mice had shorter latencies to fall from the fixed speed rotarod and more foot slips on the balance beam than the control group, indicating motor impairment. After drinking ethanol, mice also fell from a screen more quickly than during sober pretraining. In Experiment 2, mice tested (without prior training) for motor impairment and tolerance on the fixed speed rotarod at 6.5 and 10 RPM showed repeated motor impairment in the ethanol group, but did not develop tolerance. In Experiment 3, mice were first given rotarod training at 10 RPM. Following each fluid access period, performance was impaired in mice self-administering ethanol at 10, but not 15 RPM, when compared to control mice. There was no evidence of tolerance across days. However, on the last day, all mice were tested at both RPM following an i.p. injection of 2 g/kg ethanol. Ethanol-experienced mice were less impaired at both RPM than the ethanol-naïve mice, indicating tolerance development according to this between-groups index. These results suggest that C57BL/6J mice will repeatedly consume alcohol in amounts that produce motor impairment under these scheduled fluid access conditions, and that a modest degree of tolerance can be detected using appropriate tests.

Critical periods for the effects of alcohol exposure on learning in rats.

Critical periods for alcohol-induced deficits in spatial navigation and passive avoidance learning were investigated with a rat model of fetal alcohol syndrome. Rats were exposed to alcohol prenatally (Gestational Days 1-10 or 11-22) or postnatally (Postnatal Days 2-10) or throughout all 3 periods. Offspring were tested in either a spatial navigation or an avoidance task as juveniles or adults. As juveniles, the combined exposure group took longer to learn the spatial navigation task compared with all other groups. This effect was not seen in adults. Passive avoidance performance was not affected. These results suggest that long-term exposure to alcohol during development has adverse effects on spatial learning. The lack of differences in the short-term exposure groups implies that there may not be 1 critical period of alcohol exposure, but that the adverse effects of alcohol during development may be cumulative on some behaviors.

Critical periods for the effects of alcohol exposure on brain weight, body weight, activity and investigation.

Using an animal model of fetal alcohol syndrome - which equates peak blood alcohol concentrations across different developmental periods - critical periods for the effect of alcohol on brain weight, activity and investigative behavior were examined. The periods of alcohol exposure were from gestational day (GD) 1 through 10, GD 11 through 22, postnatal day (PD) 2 through 10, or all three periods combined. The critical period of alcohol exposure for an increase in activity in juveniles was GD 11 through 22. This pattern was not seen in the same animals in adulthood; instead, increases in both activity and investigation were seen in animals exposed from PD 2 through 10 and not seen in animals exposed during all three periods combined. Brain weight was reduced by alcohol exposure from GD 11 through 22, PD 2 through 10 and all three periods combined. The period from PD 2 through 10 was the only period when the brain weight to body weight ratio was reduced. In conclusion, exposure to alcohol during the periods in the latter half of gestation or early postnatal period seem to have the most deleterious effects on the brain, activity and investigation in the rat. In addition, the effects of alcohol exposure over both the prenatal and postnatal period cannot be easily predicted from the effects of shorter periods of exposure.

Effects of alcohol exposure during development on social behavior in rats.

In addition to the cognitive deficits associated with fetal alcohol syndrome (FAS), clinical and animal studies indicate that alcohol exposure might also have detrimental effects on social behavior. In a rat model of FAS, experimental rats were given alcohol from gestational day (GD) 1 to 22 and from postnatal day (PD) 2 to 10, a period roughly equivalent to all three trimesters in humans. Control groups consisted of rats exposed to the administration procedures but not to alcohol and nontreated rats. At 30 days of age, rats were tested for social behavior in an alley maze that contained its cagemate in the goal box. After varying periods of isolation, the animals' latencies to reach the goal box and their social behaviors once inside the goal box were recorded. Alcohol-exposed animals ran faster than control rats to the occupied goal box regardless of the amount of isolation. The alcohol-exposed animals also exhibited aberrant social interactions with their cagemate once inside the goal box compared to one or both of the control groups. Specifically, the alcohol-exposed animals showed greater amounts of anogenital sniffing, chasing, hopping and darting, and retrieving and lesser amounts of pinning and biting compared to one or both of the control groups. The alcohol-induced change in anogenital sniffing varied over increasing amounts of isolation compared to both control groups, but the alterations in the other behaviors did not. It is argued that the altered social behavior of alcohol-exposed animals is not the result of changes in the animals' motivational state or social learning and may be the result of an increased responsiveness to social stimuli.

Maternal urinary tract infection alters water maze performance in the offspring.

The effects of maternal urinary tract infection (UTI) or endotoxin exposure on fetal outcome in rats were investigated. Prior to conception, dams of the UTI group were water-deprived and anesthetized. The urinary tract was then catheterized and injected with 0.2 of 1 x 10(9) Escherichia coli. The endotoxin group was injected with 0.03 mg/kg lipopolysaccharide on the fourth day of gestation and then every third day thereafter. The control groups were treated in the same manner, with the exception that the infection control was not catheterized or injected with E. coli, and the endotoxin control was not exposed to lipopolysaccharide. A nontreated control group was weighed daily. Beginning on postnatal day (PD) 19, offspring were tested daily in a water maze spatial navigation task. The retention latencies (Sessions 7--10) revealed deficits in the infection and endotoxin groups. In the rat model, these findings suggest that exposure during gestation to a maternal immune challenge may result in adverse fetal outcome.

Extended visual fixation in the early preschool years: look duration, heart rate changes, and attentional inertia.

Visual fixation in infants from 6 months to 2 years of age was examined for its fit to the theory of "attentional inertia." A children's movie ("Sesame Street" movie, "Follow that Bird") or an extended audiovisual stimulus (computer-generated patterns) was presented to 40 children for a minimum of 20 min while fixation was videotaped and heart rate (HR) was recorded. Consistent with attentional inertia theory, fixations toward the stimuli had a lognormal distribution, HR decreased over the course of a look, and HR returned to prestimulus levels immediately before look offset. Older children (18 months, 24 months) showed a distinction in the parameters describing the lognormal distribution for the "Sesame Street" movie and the audiovisual patterns, whereas younger children (6 months, 12 months) responded similarly to the two stimulus types. Fixation patterns of children in this age range suggest attention increases over the course of a look, and parameters consistent with attentional inertia theory differentially develop in this age range.

Anxiety-like behavior in mice in two apparatuses during withdrawal from chronic ethanol vapor inhalation.

BACKGROUND: Anxiety during ethanol withdrawal may be a factor in relapse to alcohol abuse and dependence. Animal models of ethanol withdrawal have typically used forced consumption of an ethanol-containing liquid diet to induce dependence. Ethanol vapor inhalation offers an advantage over liquid diet consumption in that the onset of withdrawal can be temporally controlled more precisely, allowing studies of the development of withdrawal symptoms. METHODS: The purpose of the current study was to induce ethanol dependence in mice using an inhalation procedure and to assess withdrawal anxiety symptoms behaviorally in the elevated zero maze and in the light/dark box. Male and female mice were exposed to 3 days of ethanol vapors. Anxiety-like behavior was measured on the elevated zero maze and light/dark box at multiple time points during withdrawal. RESULTS: Mice experiencing ethanol withdrawal demonstrated increased anxiety-like behaviors relative to control animals in both apparatuses. However, this finding was specific to the procedure used with the elevated zero maze and was strongly influenced by sex in the light/dark box. CONCLUSIONS: Ethanol vapor inhalation appears to be a valid tool for the study of withdrawal-induced anxiety.