Effects of social housing conditions on ethanol-induced behavioral sensitization in Swiss mice.

RATIONALE: In previous animal model studies, it was shown that drug sensitization is dependent upon physical environmental conditions. However, the effects of social housing conditions on drug sensitization is much less known. OBJECTIVE: The aim of the present study was to investigate the effects of social conditions, through the size of housing groups, on ethanol stimulant effects and ethanol-induced behavioral sensitization in mice. MATERIALS AND METHODS: Male and female Swiss mice were housed in groups of different sizes (isolated mice, two mice per cage, four mice per cage and eight mice per cage) during a six-week period. A standard paradigm of ethanol-induced locomotor sensitization was then started with one daily injection of 2.5 g/kg ethanol for 8 consecutive days. RESULTS: The results show that social housing conditions affect the acute stimulant effects of ethanol. The highest stimulant effects were observed in socially isolated mice and then gradually decreased as the size of the group increased. Although the rate of ethanol sensitization did not differ between groups, the ultimate sensitized levels of ethanol-induced stimulant effects were significantly reduced in mice housed in groups of eight. CONCLUSIONS: These results are consistent with the idea that higher levels of acute and sensitized ethanol stimulant effects are observed in mice housed in stressful housing conditions, such as social isolation.

What Information Do Neuropsychologists Use to Guide their Clinical Decisions? A Survey on Knowledge and Application of Evidence-Based Practice in a French-Speaking Population.

OBJECTIVE: Evidence-based practice (EBP) is an approach that encourages clinicians to base their practice on evidence to improve the quality of patient care and reduce uncertainty in their clinical decisions. However, the state of knowledge and practice of neuropsychologists in French-speaking countries is still unknown. This study aimed to find out what these neuropsychologists know about EBP and whether they use it. METHOD: A questionnaire with 39 questions for French-speaking neuropsychologists was distributed. The questions focused on neuropsychologists' knowledge and use of EBP and information that guide their clinical decisions. RESULTS: A total of 392 respondents started the survey. The data show that only 35% correctly defined EBP and there was confusion between this practice and the strict use of research data. In practice, their decisions are influenced by multiple factors, including the patient's difficulties and advice from peers. Regarding the research, a significant proportion of the sample stated that they did not search the scientific literature frequently. Barriers to accessing scientific information and ineffective article-reading behavior were highlighted. CONCLUSION: A lack of knowledge of EBP among French-speaking neuropsychologists was observed. Furthermore, the factors influencing their decision-making do not clearly fit the definitions of EBP. Information-seeking behaviors show several weaknesses and barriers to the integration of scientific evidence into practice. These results are like those of other studies conducted among psychologists or in other health professions. We will discuss possible courses of action that could be implemented to improve the knowledge and use of EBP.

COVCOG: Immediate and long-term cognitive improvement after cognitive versus emotion management psychoeducation programs - a randomized trial in covid patients with neuropsychological difficulties.

BACKGROUND: Cognitive difficulties are a frequent complaint in long COVID and persist for more than a year post- infection. There is a lack of evidence-based data on effective intervention strategies. Non-pharmacological intervention programs that are used with other neurological populations have not yet been the subject of controlled trials. COVCOG is a multicentric, randomized trial comparing cognitive intervention and a cognitive-behavioural counselling. METHODS/DESIGN: Patients with long covid are selected and recruited at least three months post-infection. Patients are randomised in a 1:1 ratio into the cognitive (neuropsychological psychoeducation) and affective (emotion management with cognitive-behavioural counselling) intervention arms. The inclusion of 130 patients is planned. The cognitive intervention includes psycho-educational modules on fatigue and sleep, attention and working memory, executive functions and long-term memory. The affective intervention includes modules on emotion recognition and communication, uncertainty management and behavioral activation. The main objective is to reduce cognitive complaints 2 months after the intervention. A Follow-up is also planned at 8 months. DISCUSSION: Given the long-term effects of Covid on cognition and the negative effects of cognitive impairment on quality of life and social participation, it is important to determine whether low-dose, non-pharmacological interventions can be effective. The trial will determine which of the usual types of intervention is the most effective. TRIAL REGISTRATION: Clinicaltrials.gov Number: NCT05167266 (21/12/ 2021).

Voluntary alcohol binge-drinking in adolescent C57Bl6 mice induces delayed appearance of behavioural defects in both males and females.

Adolescence is a developmental period characterized by significant changes in brain architecture and behaviour. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure may interfere with the maturation of frontal brain regions and lead to long-lasting behavioural consequences. In this study, by using a slightly modified version of the Drinking in the Dark paradigm, adolescent C57Bl6 mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of adolescent alcohol exposure (AAE), a battery of behavioural tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behaviour but rather increased anxiety- and depressive-like behaviours, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioural flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex. Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioural impairments in adulthood.

Long-term exposure to daily ethanol injections in DBA/2J and Swiss mice: Lessons for the interpretation of ethanol sensitization.

Most mice ethanol sensitization studies focused on neurobiology at the expense of its behavioral characterization. Furthermore, relatively short ethanol exposures (10 to 20 injections) were used in these studies. The first aim of the present study is to better characterize the development and expression of ethanol sensitization after an extended exposure of 45 daily injections. In some previous studies, mice were classified as "respondent" and "resistant" to ethanol sensitization. The second aim of the present study is to test the long-term reliability of such categorizations and the consequences of their use on the interpretation of the ethanol sensitization results. Swiss and DBA/2J female mice received 45 consecutive daily ethanol administrations (respectively 2.5 and 2.0 g/kg) and their locomotor activity was daily recorded to test the development of ethanol sensitization. At the end of the procedure, a challenge test assessed the inter-group ethanol sensitization.The results of the present study show that ethanol sensitization continues to develop beyond 20 days to reach maximal levels after about 25 injections in DBA/2J mice and 40 injections in Swiss mice, although the core phase of the development of ethanol sensitization occurred in both strains during the first 20 days. Remarkably, ethanol sensitization after such a long daily ethanol treatment resulted in both an upward shift of the magnitude of ethanol stimulant effects and a prolongation of these effects in time (up to 30 minutes). Mice classified as "resistant to ethanol sensitization" according to previous studies developed very significant levels of ethanol sensitization when tested after 45 ethanol injections and are best described as showing a delayed development of ethanol sensitization. Furthermore, mice classified as respondent or resistant to ethanol sensitization also differ in their acute response to ethanol, such that it is difficult to ascertain whether these classifications are specifically related to the sensitization process.

Investigating the reciprocal relationships between locomotor sensitization to ethanol and PTSD-like clusters in DBA/2J mice.

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal of this study was twofold. First to investigate whether PTSD reduces the threshold for the acquisition of ethanol sensitization in an animal model of PTSD. Then to investigate whether ethanol sensitization modulates the expression of PTSD. METHODS: 152 female inbred DBA/2 J mice were submitted to an inescapable footshock paradigm to induce a PTSD-like condition (PTSDLC) and to a paradigm of locomotor sensitization to ethanol. In a first experiment, mice were submitted to the PTSDLC and then repeatedly injected with either saline, 1 g/kg ethanol or 2 g/kg ethanol. Their sensitization to the locomotor stimulant effects of ethanol was then tested in an open field. In a second experiment, mice were first sensitized to the locomotor stimulant effects of ethanol and then tested for their behavioral response to PTSDLC. RESULTS: In the first experiment, PTSDLC failed to induce a significant locomotor sensitization at the subthreshold dose of 1 g/kg ethanol. However, with 2 g/kg ethanol, a stronger ethanol sensitization was observed in mice submitted to the footshock relative to the control group. In the second experiment, ethanol sensitization increased only some of the behavioral clusters of PTSDLC, namely the fear generalization in a new context. CONCLUSION: PTSDLC did not reduce the dose threshold for the acquisition of ethanol sensitization but strengthened the development of ethanol sensitization with effective doses. This suggests that PTSD might interact with one of the mechanisms underlying the development of alcohol sensitization. When the relationship between ethanol sensitization and PTSDLC is tested in the reverse direction, the present study only shows a significant effect of ethanol administration on the "sensitized fear" PTSD cluster.

Intensity and memory characteristics of near-death experiences.

Memories of Near-Death Experiences (NDEs) seem to be very detailed and stable over time. At present, there is still no satisfactory explanation for the NDEs' rich phenomenology. Here we compared phenomenological characteristics of NDE memories with the reported experience's intensity. We included 152 individuals with a self-reported "classical" NDE (i.e. occurring in life-threatening conditions). All participants completed a mailed questionnaire that included a measure of phenomenological characteristics of memories (the Memory Characteristics Questionnaire; MCQ) and a measure of NDE's intensity (the Greyson NDE scale). Greyson NDE scale total score was positively correlated with MCQ total score, suggesting that participants who described more intense NDEs also reported more phenomenological memory characteristics of NDE. Using MCQ items, our study also showed that NDE's intensity is associated in particular with sensory details, personal importance and reactivation frequency variables.

Differential effects of context on psychomotor sensitization to ethanol and cocaine.

Repeated drug injections lead to sensitization of their stimulant effects in mice, a phenomenon sometimes referred to as drug psychomotor sensitization. Previous studies showed that sensitization to cocaine is context dependent as its expression is reduced in an environment that was not paired with cocaine administration. In contrast, the effects of the test context on ethanol sensitization remain unclear. In the present study, female OF1 mice were repeatedly injected with 1.5 g/kg ethanol to test for both the effects of context novelty/familiarity and association on ethanol sensitization. A first group of mice was extensively pre-exposed to the test context before ethanol sensitization and ethanol injections were paired with the test context (familiar and paired group). A second group was not pre-exposed to the test context, but ethanol injections were paired with the test context (nonfamiliar and paired group). Finally, a third group of mice was not pre-exposed to the test context and ethanol was repeatedly injected in the home cage (unpaired group). Control groups were similarly exposed to the test context, but were injected with saline. In a second experiment, cocaine was used as a positive control. The same behavioral procedure was used, except that mice were injected with 10 mg/kg cocaine instead of ethanol. The results show a differential involvement of the test context in the sensitization to ethanol and cocaine. Cocaine sensitization is strongly context dependent and is not expressed in the unpaired group. In contrast, the expression of ethanol sensitization is independent of the context in which it was administered, but is strongly affected by the relative novelty/familiarity of the environment. Extensive pre-exposure to the test context prevented the expression of ethanol sensitization. One possible explanation is that expression of ethanol sensitization requires an arousing environment.

Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol.

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol.

Response to novelty and cocaine stimulant effects: lack of stability across environments in female Swiss mice.

RATIONALE: In humans, novelty/sensation seeking is seen as a personality trait with a positive relationship with addiction vulnerability. In animal studies, one of the standard procedures to model novelty seeking is the "response to novelty," i.e., the levels of locomotor activity in a new environment. In rodents, a positive correlation was demonstrated between the response to novelty and several effects of drugs, especially the locomotor stimulant effects of cocaine. OBJECTIVES: The present study was designed to test in mice whether the response to novelty is stable across environments and whether its relationship with the stimulant effects of cocaine is altered by environmental changes. Experiment 1 assessed the responses to novelty of the same mice in two different novel environments. Experiment 2 tested the correlation between response to novelty and acute stimulant effects of cocaine recorded in two distinct environments. RESULTS: The results show a weak correlation only during the first 5 min of the session between the responses to novelty measured in two distinct environments. Experiment 2 demonstrates that novelty responses and stimulant effects of cocaine are positively correlated only when both behavioral responses are measured in the same environment. In contrast, the relationship between response to novelty and acute stimulant effects of cocaine is completely lost when the behavioral responses are recorded in two different environments. CONCLUSIONS: The present results question the usual interpretation of the correlation between the response to novelty and the stimulant effects of cocaine as reflecting a relationship between two underlying individual stable characteristics.

Higher long-lasting ethanol sensitization after adolescent ethanol exposure in mice.

RATIONALE: Due to their maturing brain, adolescents are suggested to be more vulnerable to the long-term consequences of chronic alcohol use. Increased sensitization to the stimulant effects of ethanol is a possible consequence of ethanol exposure during adolescence. OBJECTIVES: The aim of this study was to characterize the long-term alterations in the stimulant effects of ethanol and in the rate of ethanol sensitization in mice pre-exposed to ethanol during adolescence in comparison to mice pre-exposed to ethanol in adulthood. METHODS: Adolescent and adult female Swiss mice were injected with saline or ethanol (2.5 or 4 g/kg) during 14 consecutive days. After a 3-week period of ethanol abstinence, mice were tested as adults before and after a second exposure to daily repeated ethanol injections. RESULTS: All mice pre-exposed to ethanol as adults or adolescents showed higher stimulant effects when re-exposed to ethanol 3 weeks later. However, this enhanced sensitivity to the stimulant effects of ethanol was of significantly higher magnitude in mice repeatedly injected with high ethanol doses (4 g/kg) during adolescence. Furthermore, the increased expression of ethanol stimulant effects in these mice was maintained even after a second procedure of ethanol sensitization. CONCLUSIONS: Adolescence is a critical period for the development of a sensitization to ethanol stimulant properties providing that high intermittent ethanol doses are administered. These results might contribute to explain the relationship between age at first alcohol use and risks of later alcohol problems and highlight the dangers of repeated consumption of high alcohol amounts in young adolescents.

Chronic tolerance to ethanol-induced sedation: implication for age-related differences in locomotor sensitization.

The adolescent brain has been suggested to be particularly sensitive to ethanol-induced neuroadaptations, which in turn could increase the risk of youths for alcohol abuse and dependence. Sensitization to the locomotor stimulant effects of ethanol has often been used as an animal model of ethanol-induced neuroadaptations. Previously, we showed that young mice were more sensitive than adults to the locomotor sensitization induced by high ethanol doses. However, this effect could be due to age-related differences in chronic tolerance to the sedative effects of ethanol. The aim of the present study is to assess chronic tolerance to the sedative effects of ethanol in weaning 21-day-old (P21), adolescent 35-day-old (P35) and adult 63-day-old (P63) female Swiss mice. After a daily injection of saline or 4 g/kg ethanol during 6 consecutive days, all P21, P35 and P63 mice were injected with 4 g/kg ethanol and submitted to the loss of righting reflex procedure. Our results confirm that the sensitivity to the acute sedative effects of ethanol gradually increases with age. Although this schedule of ethanol injections induces significant age-related differences in ethanol sensitization, it did not reveal significant differences between P21, P35 and P63 mice in the development of a chronic ethanol tolerance to its sedative effects. The present results show that age-related differences in the development of ethanol sensitization cannot be explained by differences in chronic ethanol tolerance to its sedative effects. More broadly, they do not support the idea that ethanol-induced sensitization is a by-product of chronic ethanol tolerance.

Effects of L-histidine and histamine H3 receptor modulators on ethanol-induced sedation in mice.

Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol-induced behaviors. Part of this effect might be due to a modulation of ethanol-induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function.

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

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.

Developmental differences in ethanol-induced sensitization using postweanling, adolescent, and adult Swiss mice.

RATIONALE: The maturing adolescent brain has been suggested to be more sensitive than the adult brain to ethanol-induced neuroadaptations. In animal studies, sensitization to the stimulant effects of ethanol is used to study the vulnerability to chronic ethanol-induced neurobehavioral alterations. OBJECTIVES: The aim of the present study was to systematically characterize age-dependent changes in the development and expression of the sensitization to the stimulant effects of a range of ethanol doses in female Swiss mice. Three ages were studied: 21-day-old mice (postweanlings), 35-day-old mice (adolescents), and 63-day-old mice (adults). METHODS: Postweanling, adolescent, and adult mice were daily injected with saline or various ethanol doses (1.5 to 4 g/kg) for 7 days. They were then tested for acute and sensitized locomotor activity. RESULTS: Postweanling and adolescent mice were more sensitive than adult mice to the acute stimulant effects of ethanol. In adult mice, daily injections of ethanol at doses between 2.5 and 4 g/kg led to significant sensitization. Higher ethanol doses (3.5 and 4 g/kg) were required to induce sensitization in postweanling and adolescent mice. However, younger mice showed ethanol sensitization of higher magnitude. CONCLUSIONS: Young mice develop very strong ethanol sensitization at doses that mimic binge drinking in humans. These results might explain why early ethanol drinking during adolescence is related to a higher prevalence of subsequent alcohol disorders.

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

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 the 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 contributes to the changes in ethanol-induced locomotor activity, young mice also show a higher sensitivity to the stimulant effects of ethanol.

Acetaldehyde and the hypothermic effects of ethanol in mice.

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.

Parametric analysis of the development and expression of ethanol-induced behavioral sensitization in female Swiss mice: effects of dose, injection schedule, and test context.

RATIONALE: Repeated administrations of ethanol induce a progressive and enduring increase in its locomotor stimulant effects, a phenomenon termed behavioral sensitization that has not been systematically characterized. OBJECTIVE: The aim of the present studies was to characterize the development and expression of ethanol sensitization in female Swiss mice by examining (1) the doses of ethanol that induce behavioral sensitization, (2) the doses of acute ethanol challenges that are necessary to express behavioral sensitization, (3) the effects of the intervals between administrations, and (4) the context dependency of ethanol sensitization. MATERIALS AND METHODS: Mice were i.p. injected for 8 days with various ethanol doses, and locomotion was recorded for 5 min. Two days after the last sensitization session, ethanol sensitization was tested in 30-min test sessions. RESULTS: Mice repeatedly injected with 2.5 g/kg ethanol showed a progressive (200-300%) increase in locomotor activity. In response to a 2.5 g/kg ethanol challenge, the mice repeatedly treated with doses above 1.5 g/kg showed a significant sensitization. Following the induction of sensitization with the maximally effective sensitizing dose (2.5 g/kg), mice showed greater activation after challenges with 1.5, 2.0, 2.5, and 3.0 g/kg ethanol. The intervals (24, 48, or 96 h) between ethanol injections did not affect the induction or expression of sensitization. Finally, sensitization to 2.5 g/kg ethanol was expressed regardless of the context in which it was induced. CONCLUSIONS: Female Swiss mice develop a robust context-independent sensitization after repeated ethanol injections at all doses above 1.5 g/kg, including highly sedative doses such as 4 g/kg.

Locomotor effects of ethanol and acetaldehyde after peripheral and intraventricular injections in Swiss and C57BL/6J mice.

Several studies have suggested that acetaldehyde, the first product of ethanol metabolism, is involved in the locomotor stimulant effects of ethanol in mice, although it has never been formally tested whether acetaldehyde injected directly into the brain of mice has stimulant properties. Recently, it was also shown in rats that both ethanol and acetaldehyde can induce opposite locomotor effects according to the route of administration. Whereas peripheral administrations of ethanol and acetaldehyde induced locomotor depressant effects, their infusions directly into the brain produced locomotor stimulation. The aim of the present study was to characterize in mice the locomotor effects of ethanol and acetaldehyde injected either peripherally by the intraperitoneal route or centrally into the brain ventricles. Additionally, the effects of ethanol and acetaldehyde were compared in two strains of mice known for their differential sensitivity to the locomotor effects of ethanol, namely Swiss and C57BL/6J mice. Ethanol induced a biphasic effect on locomotor activity in Swiss mice, with stimulant effects at low to moderate doses and depressant effects at higher doses. Such a profile of effects was observed whatever the route of administration, peripheral or central. In C57BL/6J mice, ethanol only induced monophasic depressant effects. In this mouse strain, no evidence of the stimulant effects of ethanol was found after either an i.p. or an i.c.v. administration of ethanol. In contrast to ethanol, acetaldehyde yielded only depressant effects in both strains of mice after both peripheral and central administrations. These results indicate that the route of administration does not alter the locomotor effects of ethanol and acetaldehyde in mice. Additionally, the present study shows that the stimulant properties of acetaldehyde, even after direct infusion into the brain, are not as obvious as previously speculated.