An analysis of some effects of ethanol on performance in a passive avoidance task

In a one-trial step-through passive avoidance task, pretraining administration of ethanol was shown to decrease the latencies to step through at both training (day 1) and testing (day 2) for both rats and mice. A detailed analysis of these effects showed that they differed from those reported previously by others. The mechanisms underlying these effects of ethanol were also examined. The decreased day 1 latency to step through seen in rats may have been caused by an ethanol-induced hypermotility. However, ethanol did not increase the locomotor activity of mice, although it also reduced the day 1 latency to step through of this species. In addition, it was found that the ethanol-induced impairment of passive avoidance responding (i.e. the decreased day 2 latency to step through) was not state-dependent and that it was unlikely that it could be explained by a drug-induced impairment of task acquisition, long-term memory formation or memory recall. It also seemed unlikely that the impairment could be explained by an ethanol-induced decrease in shock sensitivity. Other mechanisms which may be involved are discussed.     

Task-dependent ethanol effects on escape in rats bred for ethanol sensitivity

Lines of rats selectively bred for differences in degree of locomotor depression by ethanol were tested for ethanol-induced impairment of jumping to a descending platform to escape 0.3 mA shock. The MA (“most affected”) line showed greater decreases in height jumped than the LA (“least affected”) line at IP doses of 1.25, 1.75, and 2.25, but not a 00.75 g ethanol/kg. MA rats also showed greater increases in latency to first jump (at 1.75 and 2.25 g/kg) which largely accounted for the line difference in decrease in height jumped. Males showed greater impairment than females on both measures. While extending the greater ethanol sensitivity of MA than LA rats to impairment of an escape response, the results contrast with previous studies of water escape where the LA line showed greater impairment than the MA line.     

Behavioral effects of ethanol inhalation in rats

Behavioral effects of ethanol inhalation were studied on two fixed-ratio (FR) liquid-reinforced schedules and a continuous reinforcement (CRF) schedule intracranial self-stimulation (SS) in rats using the inhalational behavioral chamber designed in our laboratory. In the FR-24 schedule ethanol caused a decrease of reinforcement rate at 161 ppm and higher concentrations. In the FR-50 schedule decreases of the rate were observed at 102 ppm and 203 ppm. In the SS behavior ethanol produced a decrease in the rate of reinforcement at 603 ppm and higher concentrations. In rats of this schedule, blood ethanol concentrations were measured to be 393 micrograms/ml and 545 micrograms/ml after exposure to 600 ppm and 1200 ppm of ethanol respectively. Acute tolerance to ethanol was observed in these experiments, particularly in the FR-24 schedule. Thus ethanol inhalation could produce adequate blood concentrations so as to produce behavioral effects.     

Intra-hippocampal KN-62 hinders the memory of habituation acquired alone, but not simultaneously with a water-finding task

Rats were implanted bilaterally with cannulae in the CA1 region of the dorsal hippocampus. After recovery from surgery, they were submitted to a water-finding task, which required detecting a water tube in an open field, and then remembering its location under conditions of thirst. This task was acquired simultaneously with habituation to the open field. Training and test sessions lasted 2 min, in addition to the time spent at the water tube. The training-test interval was 24 h, during which the animals were deprived of water. Immediate post-training intra-hippocampal administration of the calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-62 (3.6 ng/side) attenuated memory of the water-finding task, but not that of the habituation acquired concomitantly. However, when the habituation was carried out alone in the absence of the water-finding task, its retention was inhibited by KN-62. Thus, depending on circumstances, habituation can be memorized with or without hippocampal CaMKII activity. In the post-training period, CA1 neurones appear to 'choose' which task will be processed by a metabolic pathway that includes CaMKII.     

Mental rehearsal of a task before or after ethanol: tolerance facilitating effects

Two groups of six male social drinkers learned a psychomotor skill task and then drank the same dose of ethanol (0.62 g/kg) on each of five sessions. Sessions 1 and 5 provided pre-treatment and post-treatment measures of task performance under ethanol. During treatment sessions 2, 3 and 4, one group (MRBD) mentally rehearsed the task before drinking and the other group (MRAD) mentally rehearsed the task after drinking. On the post-treatment session, the MRAD group was significantly less impaired (i.e. more tolerant) than the MRBD group. Thus, mental rehearsal of a task under ethanol facilitates the development of tolerance to the behavioral effects of the drug.     

Differential effects of ethanol on plasma catecholamine levels in rats

Acute ethanol administration (1-4 g/kg, i.p.) had no effect on plasma catecholamine levels in nonstressed animals except at the highest dose where levels of both catecholamines increased. In animals stressed for 30 min, the higher doses had a biphasic effect on plasma catecholamines; at earlier times during stress a reduction in stress-induced increases in both catecholamines was seen, whereas later during stress or after release from stress an increase was noted. Semi-chronic ethanol administration (0.5 and 2 g/kg/day, i.p.) had no significant effect on plasma catecholamine levels in nonstressed rats. In stressed rats, ethanol reduced stress-induced catecholamine increases but these reductions were less than those seen after acute administration. Although ethanol reduced the gross behavioral stress response, no correlation between gross behavioral and biochemical responses was detected. These data show that ethanol can indeed reduce the behavioral and biochemical stress responses in rats but that effects seen depend on the state (nonstressed vs stressed) of the animal, the dose of ethanol (low vs high) used, the length of ethanol administration (acute vs semi-chronic), and the time of measurement of the catecholamine level after ethanol administration.     

Discriminative stimulus effects of ethanol in rats using a three-choice ethanol-midazolam-water discrimination

Three-choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other. This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma-aminobutyric acid type A (GABAA) receptor complex. As an extension to these studies, male Long-Evans rats were trained to discriminate midazolam (3.0 mg/kg, i.p.) from ethanol (1.0 g/kg, i.g.) from water (2.3 ml, i.g.) in a three-lever, food reinforced task. Substitution tests were conducted following administration of GABAA-positive modulators, noncompetitive N-methyl-D-aspartate (NMDA) antagonists, 5-HT1B agonists and isopropanol. Among the GABAA-positive modulators, diazepam was the only drug that completely substituted for midazolam; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution. The NMDA antagonist dizocilpine substituted for ethanol, while phencyclidine showed no substitution for either ethanol or midazolam. The serotonin agonists tested also showed no substitution for either ethanol or midazolam. Isopropanol was the only other drug that completely substituted for ethanol. These data extend previous findings from an ethanol-pentobarbital-water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol-like effect.     

The effects of restraint stress on voluntary ethanol consumption in rats

Sixty Wistar rats (Rattus norvegicus) were assigned to 4 groups of 15 rats each: ethanol stress (ES), ethanol no-stress (EN), isocaloric stress (IS) and isocaloric no-stress (IN). The effect of restraint stress on daily intake of ethanol and a 0.72% solution of glucose was examined in an ABA design (stress-no stress-stress). During the stress phases, 2 groups were subjected to daily 15-min restraint stress, whereas 2 groups were placed in different cages for 15 min as a control. All 4 groups were then given 6-hr access to their assigned liquid alone for 4 days followed by a choice between their assigned liquid and water on the 5th day. The ES group significantly increased their ethanol intake (g/kg) compared to the EN group on choice days but not on forced days. Percentage preference for ethanol was significantly greater and increased at a faster rate over the 75-day testing period compared with the EN group. However, total ethanol consumption (g/kg) and percentage preference did not vary as a function of phase. It is notable that the effects of restraint stress on ethanol self-administration persisted even after the stress schedule was removed.     

Attention,impulsivity, and cognitive flexibility in adult male rats exposed to ethanol binge during adolescence as measured in the five-choice serial reaction time task: the effects of task and ethanol challenges

Rationale  

Alcohol abuse is prevalent in adolescent humans, but the long-term behavioral consequences of binge alcohol drinking are unknown.     

Haloperidol and apomorphine effects on ethanol reinforcement in free feeding rats

Free feeding male Long Evans rats were trained to lever press on a Fixed Ratio 8 schedule for 10% ethanol reinforcement. Mean ethanol intake in 30-minute sessions was 0.38 g/kg. Subcutaneous apomorphine (APO: 0.025 to 0.5 mg/kg) and haloperidol (HAL: 0.005 to 0.0625 mg/kg) administered 15 minutes before sessions dose-dependently reduced responding, but only APO reduced momentary response rates. Low doses of HAL reduced the effect of 0.3 but not 0.05 mg/kg APO. When the rats were food-restricted, control response rates decreased, and APO (0.025 and 0.05 mg/kg) had no further effect. Results were discussed in terms of dopamine involvement in the mechanism of ethanol reinforcement.     

Hepatotoxic effects of ethanol and phenformin association in rats

• 1.1. The association of ethanol and phenformin during 6 months in the Sprague-Dawley rat produces an alteration in lactate homeostasis. A basal blood lactate value of 54.13 ± 15.43 mg/dl was found compared to 23.65 ± 7.4 mg/dl in control rats.
• 2.2. Lactic acid levels increased to 28.8 ± 7.42 mg/dl and 22.01 ± 8.08 mg/dl after chronic administration of ethanol or phenformin in Sprague-Dawley rats, respectively. Nevertheless, these were not statistically significant with respect to those of control group.
• 3.3. The total hepatic collagen content after chronic administration of phenformin and ethanol was moderately elevated 7.12 ± 1.85 mg/g of wet tissue, and statistically significant with respect to the control group, 4.77 ± 1.17 mg/g. Collagen content values in phenformin and ethanol rats did not reveal statistically significant differences.
• 4.4. Liver showed histological degenerative changes but not any sign of fibrosis after chronic administration of ethanol and phenformin together.

     

Deficits on a spatial navigation task following prenatal exposure to ethanol

Performance on a Morris water task was examined in young rats whose mothers consumed a liquid diet consisting of 35% ethanol-derived calories (EDC) during pregnancy. Offspring of pair-fed (0% EDC) and ad lib lab chow (LC) dams served as controls. Rats were required to find a platform submerged below the surface in a pool of opaque water. A trial ended when the rat remained on the platform for 15 sec, or had been in the tank for 180 sec without reaching the platform. Subjects received 5 trials daily for 3 consecutive days, followed by reversal training on Day 4. Groups did not differ in swimming ability. On Day 1 there were no group differences among females in latency to reach the platform or in distance traveled, but male 35% EDC and 0% EDC animals had shorter latencies than LC controls. On Day 2, latencies and distance traveled of LC and 0% EDC controls decreased while 35% EDC animals showed no change from Day 1, so that alcohol-exposed rats took longer to reach the platform and traveled a greater distance than controls. On Day 3, 35% EDC females took longer than controls to reach the platform, and 35% EDC animals of both sexes traveled a greater distance than controls. Search patterns on the first reversal trial on Day 4 suggest the differences are in spatial processing and not learning per se, but more so in alcohol-exposed males than females. The impaired performance on this task suggests that prenatal alcohol exposure alters the ability to process spatial information.     

Effects of lysine on toxicity and depressant effects of ethanol in rats

When l-lysine was administered prior to toxic doses of ethanol, the LD50 for ethanol was slightly increased after both po and ip administration. The onset of ethanol-induced sleeping time was prolonged while the duration was reduced by pretreatment with l-lysine.     

The effects of peripherally administered monoaminergic drugs on ethanol diuresis in rats

The effect of peripherally administered drugs that modify monoaminergic function, on ethanol (2.0 g kg-1, intragastrically)-induced changes in urine output has been examined in rats. The alpha-noradrenoceptor agonist, clonidine (0.05-0.15 mg kg-1) produced marked urine output and potentiated slightly the diuretic effect of ethanol. The alpha-noradrenoceptor antagonist, phentolamine (1-5 mg kg-1) dose-dependently decreased ethanol-induced diuresis. p-Chloroamphetamine (0.8-2.0 mg kg-1) produced significant diuresis and potentiated the diuresis produced by ethanol. Methysergide (1.25, 2.5 mg kg-1), a 5-hydroxytryptamine receptor antagonist, had no effect on urine output while it depressed the ethanol-induced increase in urine output. Apomorphine (0.8, 1.5 mg kg-1), a dopamine receptor agonist, did not modify urine output in either control or ethanol-treated animals, while the dopamine receptor antagonist, pimozide (0.75-3.0 mg kg-1), dose-dependently decreased ethanol-induced diuresis, but had no effect on urine output in control animals. Since our previous research indicates that the intraventricular administration of drugs that alter dopaminergic and 5-HT function does not alter ethanol-induced diuresis, the interaction of these types of agents with ethanol-induced diuresis in the present study suggests that the interaction was mediated peripherally.     

Differential effects of ethanol on motor coordination in adolescent and adult rats

Recent evidence suggests that adolescence represents a unique period of sensitivity to the effects of ethanol. Adolescent animals are more sensitive than adults to many of the effects of ethanol, including ethanol-induced learning and memory impairments, while being less sensitive to others, including ethanol-induced sedation. It is well known that ethanol produces dramatic impairments in balance and motor coordination. While previous research suggests that adolescents and adults do not differ in their sensitivity to the effects of relatively low doses of ethanol on motor coordination, it is not known whether differences in performance would emerge at higher doses. The present study compared the impact of a range of ethanol doses (1.0, 2.0 and 3.0 g/kg) on motor coordination in adolescent [postnatal day (PD) 35-40] and adult (PD 70-75) rats. Motor coordination was assessed using the tilting plane test before ethanol administration (baseline) and at 15, 30, 60, 120 and 180 min after ethanol administration. Performance was not affected by 1.0 g/kg ethanol in either age group. However, adults were more impaired than adolescents at nearly every time point following administration of both 2.0 and 3.0 g/kg ethanol. The results provide further evidence that adolescents and adults are differentially sensitive to the behavioral effects of ethanol. Given the critical role of motor coordination in the ability to operate motor vehicles and the central role of balance and coordination in field sobriety tests, these data could have important implications if extended to human subjects.     

The effects of chronic administration of ethanol on startle thresholds in rats

The thresholds for startle responses to electric shock were measured in adult male Wistar strain rats given ethanol daily in doses rising from 3 to 7 g/kg over a 30-day period, and in controls receiving equicaloric doses of sucrose. Tests made 23, 36, or 47 h after ethanol (i.e., during partial or complete ethanol withdrawal) gave threshold values significantly lower than those obtained with sucrose-treated controls. The difference became greater after longer ethanol treatment and larger doses. However, when threshold measurements were made under the acute influence of ethanol in the experimental group, the mean values were virtually equal to those of the sucrose controls. This normalization, by ethanol, of a disturbance produced by absence of ethanol in a chronically treated animal is indicative of physical dependence. Following termination of ethanol treatment there was a gradual return of startle thresholds almost to control values over a relatively short period, indicating that the changes underlying the hyperexcitability are readily reversible.     

Comparative effects of ethanol administration on hepatic monooxygenases in rats and mice

The inducing effects of chronic ethanol ingestion on hepatic monooxygenases in Sprague-Dawley and Long-Evans rats, and A/J and C57BL/6J mice, were studied. Cytochrome P-450 content was significantly increased in livers of all animals receiving the experimental ethanol-containing liquid diet. The CO-difference spectra of microsomes from ethanol-treated animals showed a shift in the absorbance maximum to 451–452 nm, compared to the absorbance maximum of 450 nm observed with microsomes from control animals. Ethylmorphine N-demethylase and benzo[a]pyrene hydroxylase activities in livers of ethanol-treated animals were minimally affected. The shift in the absorbance maxima to longer wavelengths in the CO-difference spectrum and the minimal effects on the metabolism of ethylmorphine and benzo[a]pyrene demonstrate that ethanol differs in its inducing properties, when compared to the properties of the two widely used hepatic microsomal enzyme inducers, phenobarbital and 3-methylcholantrhene. In contrast to the minimal effects observed on the metabolism of ethylmorphine and benzo[a]pyrene, several fold increases were observed in hepatic 7-ethoxycoumarin 0-deethylase and aniline hydroxylase activities in the treated animals. Polyacrylamide gel electrophoresis of hepatic microsomes from those animals receiving ethanol revealed protein band(s) in the cytochrome P-450 molecular weight region, the intensities of which were markedly increased relative to that from control animals. The heme-associated peroxidase activity was also increased in the same molecular weight region. The results of the present spectral, catalytic, and electrophoretic studies demonstrate that in mice, as in rats, chronic ethanol treatment causes the induction of specific cytochrome(s) P-450 with preferential activity toward aniline and 7-ethoxycoumarin.     

Brain ethanol concentrations and ethanol discrimination in rats: effects of dose and time

Rationale In drug discrimination procedures, the substitution pattern for ethanol of various receptor ligands is dependent upon ethanol training dose, presumably reflecting functionally different concentrations of ethanol in the brain. The discriminative stimulus effects of ethanol are also time-dependent, although very few studies have investigated the time course of ethanol discriminations. Objectives The present study investigated the relationship between brain ethanol concentrations (BrEC), as measured by intracranial microdialysis of the nucleus accumbens, and the time course of ethanol discriminative effects. Methods Two groups of rats were trained to discriminate either 1.0 or 2.0 g/kg ethanol from water following a 30-min post-ethanol interval. Following training, the time course of the discriminative stimulus was assessed using a series of abbreviated testing trials at 20-min intervals for 5 h after the administration of various ethanol doses (0, 0.5, 1.0 and 2.0 g/kg). The rats were then fitted with microdialysis probes and the time course of BrECs were determined under conditions similar to the behavioral assessments. Results BrECs were significantly above zero at 4 min post-gavage and attained peak concentrations of 16 mmol/l, 24 mmol/l and 42 mmol/l at 9 min, 16 min and 95 min after IG administration of 0.5, 1.0 and 2.0 g/kg ethanol, respectively. BrECs were similar in ethanol-naive and ethanol-trained rats, indicating a lack of pharmacokinetic tolerance under these discrimination procedures. The discriminative stimulus effects of ethanol were dose- and time-dependent, with a threshold concentration of approximately 12 mmol/l achieved at 5 min after 1.0 g/kg ethanol gavage in rats trained to discriminate 1.0 g/kg ethanol. Acute tolerance to the discriminative stimulus effects of ethanol was evident from BrECs 2–5 h post-ethanol gavage. Conclusions Ethanol given intragastrically results in a rapid increase in BrEC, independent of ethanol exposure history. The discriminative stimulus effects of ethanol trained at 30 min post-gavage reflect a specific range of BrEC, and depend on the training dose. These data suggest that qualitatively different stimulus effects of ethanol reflect both different ranges of BrEC, as well as within dose acute tolerance to the discriminative stimulus effects.     

The rapid onset of ethanol tolerance in Wistar rats following intensive practice on the moving-belt task.

The influence of intensive practice on the onset of ethanol tolerance was studied in the Wistar rat. The moving-belt task was used to provide a graded measure of ethanol-induced ataxia by recording the percentage of time the animal stepped off a moving belt onto a shock-grid floor during a 100-sec trial (% TOB). Naive rats were sensitive to doses between 1.9 g/kg (< 1% TOB) and 3.1 g/kg (100% TOB); the ED50 was 2.5 g/kg. To study acute tolerance, rats were maintained at a constant blood ethanol concentration of 2.8–3.2 mg/ml for 6 to 8 hr. Rats which were tested hourly during this time developed tolerance, with error times decreasing from 90 to 12% TOB. Rats which remained in their cages with no opportunity to practice did not show improvement when tested at 6 to 8 hr, although they had received similar ethanol exposure. To study chronic tolerance, the dose-response curve was monitored on odd-numbered days for 1 week. On Days 2, 4, and 6, rats received intensive practice under the influence of ethanol for five hr. Rapid tolerance developed, indicated by an increase in the ED50 from 2.5 to 3.1 g/kg. The greatest increment occurred following the first intensive practice day. In contrast, rats given minimal practice over 4 days showed no detectable tolerance. These experiments demonstrate a rate of tolerance acquisition more rapid than previously reported, and indicate that practice while under the influence of ethanol plays a major role in the onset of tolerance measured on a behavioral task.