Chronic ethanol exposure during adolescence alters the behavioral responsiveness to ethanol in adult mice

in Behavioural Brain Research (2012), 229

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present ... [more ▼]

Alcohol exposure during early adolescence is believed to durably alter the behavioral properties of ethanol, increasing the likelihood of later alcohol-related disorders. The aim of the present experiments was to characterize changes in the behavioral effects of ethanol in adult female Swiss mice after a chronic ethanol exposure during adolescence, extending from postnatal day 28 to postnatal day 42. After a chronic ethanol exposure during adolescence (daily injections of 0, 2.5 or 4 g/kg ethanol for 14 consecutive days), adult mice were tested at postnatal day 63. The locomotor stimulant effects of ethanol, together with ethanol sensitization were tested in experiment 1. In experiment 2, the sedative effects of ethanol were assessed with the loss of righting reflex procedure. Finally, in experiment 3, the anxiolytic effects of ethanol were tested with the light/dark box test. Adult mice chronically exposed to ethanol during adolescence showed a lower basal locomotor activity, but higher locomotor stimulant effects of ethanol than non-exposed mice. Additionally, these adult mice developed higher rates of ethanol sensitization after chronic re-exposure to ethanol in adulthood. Adult mice exposed to ethanol during adolescence also had a stronger tolerance to the sedative effects of high ethanol doses, although they showed no evidence of changes in the anxiolytic effects of ethanol. These results are in agreement with the thesis that chronic alcohol consumption during adolescence, especially in high amounts, increases the risk of later alcohol-related disorders. [less ▲]

Ontogeny of the stimulant and sedative effects of ethanol in male and female Swiss mice: gradual changes from weaning to adulthood

in Psychopharmacology (2010), 212(4), 501-512

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is ... [more ▼]

Rationale: The adolescent period is characterized by a specific sensitivity to the effects of alcohol, which is believed to contribute to the enhanced risks of alcohol dependence when drinking is initiated early during adolescence. In adolescent rodents, while the reduced sensitivity to the sedative effects of ethanol has been well characterized, its stimulant effects have not yet been extensively studied. Objectives: The present study characterized the development of the stimulant and sedative effects of acute ethanol in male and female Swiss mice from weaning to early adulthood and tested whether both effects are interrelated. Methods: In a first experiment, mice aged 21, 28, 35, 42 and 60 days were injected with various ethanol doses and tested for ethanol-induced locomotor activity. In an independent experiment, mice of the same groups of age were injected with 4 g/kg ethanol and ethanol-induced sedation was quantified with the loss of righting reflex procedure. Results: In male and female mice, the stimulant effects of ethanol gradually decreased, whereas its sedative effects increased with age. When the sedation was statistically controlled using a covariance analysis, the differences between adult and juvenile mice in the locomotor stimulation were significantly reduced. Conclusions: From weaning to early adulthood, the acute stimulant and sedative effects of ethanol show gradual changes that are similar in male and female mice. Although the initial tolerance to the sedative effects of ethanol contribute to the changes in ethanol-induced locomotor activity, young mice also show a higher sensitivity to the stimulant effects of ethanol. [less ▲]

Effects of histamine H3 receptor modulators on sedative effects induced by ethanol

in Alcoholism, Clinical & Experimental Research (2010), 34(8), 93-93

Acetaldehyde and the hypothermic effects of ethanol in mice.

in Alcoholism, Clinical & Experimental Research (2009), 33(11), 2005-14

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of ... [more ▼]

BACKGROUND: Acetaldehyde, the first metabolite of ethanol, has been suggested to be involved in many behavioral effects of ethanol. However, few studies have investigated the hypothermic effects of acetaldehyde or the contribution of acetaldehyde to ethanol-induced hypothermia. The aim of the present study is to better understand the hypothermic effects of acetaldehyde and the possible contribution of acetaldehyde in ethanol-induced hypothermia, especially under conditions leading to acetaldehyde accumulation. METHODS: Female Swiss mice were injected intraperitoneally with ethanol and acetaldehyde and their rectal temperatures were measured with a digital thermometer at various time points after the injections. Experiment 1 compared the hypothermic effects of various acetaldehyde doses (0 to 300 mg/kg) with a reference dose of ethanol (3 g/kg). Experiment 2 tested the effects of a pretreatment with the aldehyde dehydrogenase (ALDH) inhibitor cyanamide (25 mg/kg) on ethanol- and acetaldehyde-induced hypothermia. In experiments 3 and 4, mice received a combined pretreatment with cyanamide and the alcohol dehydrogenase (ADH) inhibitor 4-Methylpyrazole (10 mg/kg) before the injection of ethanol or acetaldehyde. RESULTS: Acetaldehyde at doses between 100 and 300 mg/kg induced significant hypothermic effects, but of shorter duration than ethanol-induced hypothermia. The inhibition of ALDH enzymes by cyanamide induced a strong potentiation of both ethanol- and acetaldehyde-induced hypothermia. The pretreatment with 4-MP prevented the potentiation of ethanol-induced hypothermia by cyanamide, but slightly increased the potentiation of acetaldehyde-induced hypothermia by cyanamide. CONCLUSIONS: The results of the present study clearly show that acetaldehyde has hypothermic properties in mice at least at relatively high concentrations. Furthermore, the accumulation of acetaldehyde following ALDH inhibition strongly enhanced the hypothermic effects of ethanol. These latter results confirm the hypothermic properties of acetaldehyde and show that acetate, the next step in ethanol metabolism, is not involved in these hypothermic effects. Finally, the experiment with 4-MP indicates that the potentiating effects of cyanamide are mediated by the peripheral accumulation of acetaldehyde, which then reaches the brain to induce a severe hypothermia. [less ▲]

Behavioral effects of acetaldehyde in mice and rats: From reinforcement to amnesia

in Alcoholism, Clinical & Experimental Research (2008), 32(6), 289-289

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In ... [more ▼]

Whereas human studies keep reporting evidence that acetaldehyde accumulation prevents alcohol drinking and alcoholism, animal studies support a rewarding rather than aversive role for acetaldehyde. In recent years, the reinforcing properties of acetaldehyde were demonstrated in various rodent strains and using different experimental methods. These results led to the hypothesis that acetaldehyde might be involved in the addictive properties of alcohol. In addition to its possible role in the reinforcing properties of alcohol, there is also evidence that acetaldehyde is involved in many other behavioral effects of ethanol. Using various behavioral procedures with both mice and rats, we have studied the behavioral effects of direct acetaldehyde injections. Additionally, in independent experiments we have compared the effects of ethanol in mice with or without a pre-treatment with the aldehyde dehydrogenase inhibitor cyanamide, which produces acetaldehyde accumulation. The results of these studies show that acetaldehyde produces a wide spectrum of behavioral effects, including reinforcement, aversion, sedation, ataxia and amnesia. These effects were mainly dependent upon acetaldehyde doses, with some of them showing an inverted U shape dose-response curve. These results also suggest that acetaldehyde might mediate or contribute to many of the behavioral effects of ethanol and especially to alcohol abuse and alcoholism. [less ▲]

Acute and chronic effects of acetaldehyde on learning and memory in mice

in Alcohol & Alcoholism (2007), 42 Suppl. 1

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of ... [more ▼]

Acetaldehyde has been postulated to mediate several of the behavioral effects of ethanol, including its reinforcing properties. At the highest doses, alcohol disrupts the acquisition and performance of memory tasks, culminating with the blackout experience at high blood alcohol concentrations. However, it remains unknown whether acetaldehyde is involved in such memory impairments induced by acute ethanol. Additionally, chronic alcohol consumption in humans sometimes leads to persistent memory impairments partly due to serious brain damages. The Wernicke-Korsakoff syndrome, characterized by severe anterograde amnesia, is the most serious memory disorder induced by chronic alcohol. The aim of the present study was to show whether acute and chronic treatments with acetaldehyde, the first metabolite of ethanol, lead to similar memory impairments as ethanol in mice. Memory performances of Swiss and C57BL/6J mice were tested in both the passive avoidance task and the fear conditioning procedure. In the first part of the experiments mice were injected with acute acetaldehyde (50 to 300 mg/kg) immediately after the training phase. In the second part of the experiment, mice were tested for memory performance after 10 daily acetaldehyde injections. The first part of the experiments shows that acute acetaldehyde administrations produce a strong amnesic effect in both experimental paradigms. Additionally, the amnesic effects of acetaldehyde were more consistent than those observed after ethanol administration. In the second part of the studies, we show that 10 daily acetaldehyde injections to mice led to a severe and persistent anterograde amnesia in both the pavlovian and the operant learning tasks. In conclusion, acute acetaldehyde produces strong amnesic effects trough yet unknown pharmacological mechanisms. In addition, chronic acetaldehyde administration leads to persistent memory impairments. These results suggest that acetaldehyde might be involved in both the acute amnesic effects of high ethanol doses and the neurotoxic effects of chronic alcohol consumption. [less ▲]

Role of acetaldehyde in mediating the pharmacological and behavioral effects of alcohol

in Alcohol Research & Health : The Journal of the National Institute on Alcohol Abuse & Alcoholism (2006), 29(4), 258-265

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological ... [more ▼]

Acetaldehyde is the first active breakdown product (i.e., metabolite) generated during alcohol metabolism. It has toxic properties but also exerts other actions on the body (i.e., has pharmacological properties). Recent studies have shown that the direct administration of acetaldehyde, especially into the brain, induces several effects that mimic those of alcohol. High doses of acetaldehyde induce sedative as well as movement-and memory-impairing effects, whereas lower doses produce behavioral effects (e.g., stimulation and reinforcement) that are characteristic of addictive drugs. When acetaldehyde accumulates outside the brain (i.e., in the periphery), adverse effects predominate and prevent further alcohol drinking. To investigate the role of acetaldehyde in mediating alcohol's effects, investigators have pharmacologically manipulated alcohol metabolism and the production of acetaidehyde within the body (i.e., endogenous acetaldehyde production). Studies manipulating the activity of the enzyme catalase, which promotes acetaldehyde production in the brain, suggest that acetaldehyde contributes to many behavioral effects of alcohol, especially its stimulant properties. However, it remains controversial whether acetaldehyde concentrations obtained under normal physiological conditions are sufficient to induce significant pharmacological effects. Current evidence suggests that the contribution of acetaldehyde to alcohol's effects is best explained by a process in which acetaidehyde modulates, rather than mediates, some of alcohol's effects. [less ▲]

Effects of centrally versus peripherally administered ethanol in C57BL/6J and CD1 mice

in Behavioural Pharmacology (2005), 16

Locomotor activation is often reported to occur after a systemic administration of low doses of ethanol in most mouse strains, as for example outbred CD1 mice. However, in some strains of mice, such as ... [more ▼]

Locomotor activation is often reported to occur after a systemic administration of low doses of ethanol in most mouse strains, as for example outbred CD1 mice. However, in some strains of mice, such as the inbred C57BL/6J mice, and in rats, systemic injections of ethanol typically induce only a depression of the locomotor activity. Recently, Correa et al. (2003) showed that direct infusions of ethanol in the brain ventricles of rats induced locomotor stimulant effects. These authors suggested that some undefined peripheral effects of ethanol may mask its central stimulant effects when ethanol is administered intraperitoneally. The aim of the present study was to investigate the locomotor effects of either intraperitoneal and intracerebroventricular ethanol administrations in two strains of mice, outbred CD1 and inbred C57BL/6J, that are respectively characterized by the presence and absence of a locomotor stimulant response to ethanol. The results showed that ethanol at moderate and high doses induced locomotor depressant effects in C57BL/6J mice whatever the route of ethanol administration. In contrast, ethanol induced a biphasic effect on locomotor activity in CD1 mice with a stimulant response at low doses followed by a significant sedation. Such a response to ethanol was observed after both peripheral and central administrations of ethanol. The results of the present study demonstrate that the locomotor effects of ethanol in mice are not affected by the route of administration, i.e. peripheral or central. In these rodents, there is no evidence that unidentified peripheral effects of ethanol mask the stimulant ethanol effects. [less ▲]