Effect of pattern and number of chronic ethanol exposures on subsequent voluntary ethanol intake in C57BL/6J mice

Rationale We previously demonstrated that chronic ethanol exposure and withdrawal experience significantly increased subsequent voluntary ethanol intake in C57BL/6J mice. This study was conducted to examine chronic ethanol conditions that optimize this enhanced ethanol-drinking behavior. Objectives The purpose of this study was to examine whether the pattern and/or number of chronic ethanol exposures influence subsequent ethanol intake. Methods C57BL/6J mice were trained to drink ethanol (15% v/v) in a limited access situation (2 h/day) until stable intake was achieved. In experiment 1, mice received two cycles of chronic ethanol exposure delivered either in an intermittent [multiple withdrawal (MW)] or continuous [continuous exposure (CE)] pattern. One week of daily drinking sessions followed each exposure. In experiment 2, mice received either two or four cycles of chronic intermittent ethanol exposure (MW), each followed by a week of testing sessions. Three additional weeks of ethanol intake testing followed the last ethanol (or air) exposure. Results Experiment 1: Only the MW group evidenced a significant increase in ethanol intake compared to controls after the first chronic ethanol exposure. Both MW and CE groups consumed more ethanol than controls after the second ethanol-exposure period. Experiment 2: Ethanol intake in MW mice compared to controls significantly increased after two or four cycles of chronic ethanol exposure/withdrawal, and this heightened ethanol intake lasted longer in mice that received four cycles of chronic intermittent ethanol exposure. Conclusions Increased voluntary ethanol intake after chronic ethanol exposure and withdrawal experience may be accelerated by intermittent (as opposed to continuous) ethanol exposure, and the effect may last longer with increased number of such experiences.     

Voluntary ethanol drinking in C57BL/6J and DBA/2J mice before and after sensitization to the locomotor stimulant effects of ethanol

RATIONALE: Drug-induced sensitization has been associated with enhanced drug self-administration and may contribute to drug addiction. OBJECTIVES: We investigated the possible association between sensitization to the locomotor stimulant effects of ethanol (EtOH) and voluntary EtOH consumption. METHODS: Mice of the EtOH-avoiding DBA/2J (D2) and EtOH-preferring C57BL/6J (B6) inbred strains were offered the choice of an EtOH solution versus tap water (EtOH-experienced) or just water (Na), and voluntary consumption was measured. Mice from each condition then received repeated EtOH or saline injections, and locomotor responses were measured. Subsequently, all mice were offered the choice of EtOH versus water, and voluntary consumption was again measured. A subsequent study examined relative susceptibility of D2 and B6 mice to EtOH-induced locomotor sensitization. RESULTS: Voluntary EtOH consumption induced locomotor sensitization to an EtOH challenge in B6 mice. D2 mice consumed little EtOH, but developed sensitization with repeated EtOH treatments as expected. EtOH consumption was not altered in EtOH-sensitized D2 mice. Unexpectedly, B6 mice developed significant sensitization, and following sensitization, the EtOH-experienced EtOH-sensitized group consumed more EtOH than their EtOH-experienced salinetreated (non-sensitized) counterparts. In an independent study, B6 mice required between three and five EtOH injections to express sensitization, whereas for D2 mice, between one and three EtOH exposures were sufficient. CONCLUSIONS: Development of sensitization to the locomotor stimulant effects of EtOH may be associated with increased EtOH consumption in mice with high initial avidity for EtOH. In the same mice, voluntary EtOH consumption can also produce behavioral sensitization to the effects of EtOH.     

Assessing appetitive and consummatory phases of ethanol self-administration in C57BL/6J mice under operant conditions: regulation by mGlu5 receptor antagonism

Rationale The development of mouse models of ethanol consumption and ethanol-seeking behavior is of particular importance in understanding the underlying mechanisms of drug abuse because these models can enable an analysis of an effect of specific genotype on drug-seeking behavior and the interaction of potential therapeutics with genotype. However, there are some limitations with present models, notably the inability to examine appetitive and consummatory behavior separately.Materials and methods In the present study, C57BL/6 mice were trained to self-administer 10% ethanol in a modified operant protocol that allowed a clear delineation of consummatory and appetitive phases. The utility of this procedure was confirmed with the use of the metabotropic glutamate 5 (mGlu5) receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP).Results Limited-access consumption during the dark phase of the light–dark cycle with intermittent access (every second or third day) led to a high level of consumption by the mice. MTEP caused a dose-dependent decrease in both the consumption of ethanol and the appetitive response for ethanol. Furthermore, this effect was unrelated to any effect of MTEP on locomotor activity.Conclusions The model provides a useful paradigm for examining both the appetitive and consummatory phases of ethanol consumption in mice; furthermore, the data indicate mGlu5 receptors are involved in both phases.     

PDE7A expression on alcohol consumption and alcohol withdrawal in striatum of C57BL/6J mice

OBJECTIVE To observe PDE7A expression on alcohol consumption and alcohol withdrawal in the striatum of C57BL/6J mice. METHODS Forty adult female C57BL/6J mice were randomly divided into 3 groups: water intake control, alcohol(10% v/v) drinking(18 h · d~(-1) for 7 d), and alcohol withdrawal(for 24 h).PDE7A expression was analyzed using Western blotting in striatal tissues from mice. RESULTS Compared to the control, alcohol drinking mice displayed increases in the expression of PDE7A in the striatum, which decreased to normal 24 h after withdrawal. CONCLUSION The results suggest that PDE7, in particular PDE7A, may play a unique role in the regulation of ethanol depdendence.     

戊巴比妥钠腹腔麻醉对C57BL/6J小鼠体表心电图的影响

目的 观察戊巴比妥钠腹腔内注射麻醉对小鼠体表心电图(ECG)指标,包括心率、PR间期、QRS波宽度和QT间期随麻醉时间延长的变化规律.方法 6只雄性C57BL/6J小鼠,腹腔内注射戊巴比妥钠75 mg·kg-1后,每10 min记录ECG一次,直至90 min,分析ECG各指标的变化规律.结果 所有6只小鼠均顺利完成实验.戊巴比妥钠腹腔内注射后10～60 min时随给药时间延长,测得的心率显著减慢[(353.0±31.3)、(287.5±34.8)、(234.9±38)、(207.9±37.3)、(190.8±32.9)和(175.8±25.5)次/分钟,P<0.01],QRS波宽度显著增宽[(11.3±0.5)、(12.3±0.5)、(13.3±0.7)、(13.9±0.8)、(14.1±0.9)和(14.3±1.0)ms,P<0.05],QT间期显著延长[(18.8±0.5)、(20.9±0.9)、(23.0±1.1)、(24.5±1.3)、(25.7±2.0)和(26.4±2.2)ms,P<0.05].给药后60～90 min内测得的心率、QRS波宽度及QT间期均随给药时间延长而改变轻微,趋于平稳.而PR间期在注射后10～90 min的相邻两个测量采集点比较,均随给药时间延长而显著延长.结论 戊巴比妥钠腹腔注射麻醉可致小鼠心率显著减慢,PR间期、QRS波宽度和QT间期等ECG指标随麻醉时间延长而明显延长,在研究心律失常模式动物心电学表型时应予以重视.     

The mGluR5 antagonist MPEP selectively inhibits the onset and maintenance of ethanol self-administration in C57BL/6J mice

Rationale Many of the biochemical, physiological, and behavioral effects of ethanol are known to be mediated by ionotropic glutamate receptors. Emerging evidence implicates metabotropic glutamate receptors (mGluRs) in the biobehavioral effects of ethanol and other drugs of abuse, but there is little information regarding the role of mGluRs in the reinforcing effects of ethanol. Materials and methods Male C57BL/6J mice were trained to lever-press on a concurrent fixed ratio 1 schedule of ethanol (10% v/v) vs water reinforcement during 16-h sessions. Effects of mGluR1, mGluR2/3, and mGluR5 antagonists were then tested on parameters of ethanol self-administration behavior. Results The mGluR5 antagonist MPEP (1–10 mg/kg, i.p.) dose-dependently reduced ethanol-reinforced responding but had no effect on concurrent water-reinforced responding. Analysis of the temporal pattern of responding showed that MPEP reduced ethanol-reinforced responding during peak periods of behavior occurring during the early hours of the dark cycle. Further analysis showed that MPEP reduced the number of ethanol response bouts and bout-response rate. MPEP also produced a 13-fold delay in ethanol response onset (i.e., latency to the first response) with no corresponding effect on water response latency or locomotor activity. The mGluR1 antagonist CPCCOEt (1–10 mg/kg, i.p.) or the mGluR2/3 antagonist LY 341495 (1–30 mg/kg, i.p.) failed to alter ethanol- or water-reinforced responding. Conclusions These data indicate that mGlu5 receptors selectively regulate the onset and maintenance of ethanol self-administration in a manner that is consistent with reduction in ethanol’s reinforcement function.     

Effects of ethanol and GABA<Subscript>B</Subscript> drugs on working memory in C57BL/6J and DBA/2J mice

Rationale It has been suggested that GABA_B receptors may be part of a neural substrate mediating some of the effects of ethanol.Objective The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA_B receptors.Methods Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice.Results Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance.Conclusions Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA_B drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Effects of intraperitoneal injections of saline on the alcohol and sucrose consumption of C57/BL10 mice

RATIONALE: To determine the effects of multiple saline injections on alcohol drinking by male and female C57/BL10 mice with low preference for alcohol. OBJECTIVE: An investigation of the effects of multiple saline injections on alcohol consumption, with a comparison of corresponding effects on sucrose consumption. METHODS: The effects of a range of injection schedules on preference for 8% alcohol, or 1% sucrose, compared with tap water, were measured in two-bottle choice tests. RESULTS: The multiple saline injection schedule significantly increased the alcohol preference, even when no alcohol was available during the injection period. The actual administration of fluid was not necessary for the increase in alcohol preference, since sham injections without fluid administration also increased alcohol preference. A single injection of saline did not alter the alcohol preference 3 weeks later. Daily saline injections for 3 weeks did not alter the consumption of the dilute sucrose solution. In the population of mice used, the preference for sucrose over water was found to follow a biphasic distribution, similar to that reported earlier in these mice for alcohol preference, but there was no correlation between alcohol preference and sucrose preference. CONCLUSIONS: The results suggest that lasting changes in the areas of the brain that specifically control alcohol intake are produced by repetition of a routine laboratory procedure.     

Electrolytic lesions of the medial nucleus accumbens shell selectively decrease ethanol consumption without altering preference in a limited access procedure in C57BL/6J mice

The central extended amygdala (cExtA) is a limbic region proposed to play a key role in drug and alcohol addiction and to contain the medial nucleus accumbens shell (MNAc shell). The aim of this study was to examine the involvement of the MNAc shell in ethanol and sucrose consumption in a limited and free access procedure in the C57BL/6J (B6) mouse. Separate groups of mice received bilateral electrolytic lesions of the MNAc shell or sham surgery, and following recovery from surgery, were allowed to voluntarily consume ethanol (15% v/v) in a 2 h limited access 2-bottle-choice procedure. Following 1 week of limited access ethanol consumption, mice were given 1 week of limited access sucrose consumption. A separate group of lesioned and sham mice were given free access (24 h) to ethanol in a 2-bottle choice procedure and were run in parallel to the mice receiving limited access consumption. Electrolytic lesions of the MNAc shell decreased ethanol (but not sucrose) consumption in a limited access procedure, but did not alter free access ethanol consumption. These results suggest that the MNAc shell is a component of the underlying neural circuitry contributing to limited access alcohol consumption in the B6 mouse.     

Alcohol-induced locomotor activation in C57BL/6J, A/J, and AXB/BXA recombinant inbred mice: strain distribution patterns and quantitative trait loci analysis

RATIONALE: Quantitative trait loci (QTLs) for initial sensitivity to alcohol have been identified in a number of mouse strains (e.g. BXD); however, confirmation is required. OBJECTIVES: The present paper aimed to characterize the C57BL/6J, A/J, and AXB/BXA recombinant inbred (RI) strains of mice for basal and ethanol-induced locomotor activation as measured in an open field and to provide provisional location of QTLs for these phenotypes. METHODS: A/J and C57BL/6J mice were habituated to handling and then randomly assigned to receive one of four alcohol doses (0, 0.5, 1.0, 2.0 g/kg). Subsequently, all available strains of the AXB/BXA RI were tested with the 2 g/kg dose of ethanol or vehicle control. RESULTS: Simple regression and interval mapping were used initially to identify significant gene markers associated with ethanol-induced activation (calculated as total activity on alcohol day-total activity on saline day). Subsequently, composite interval mapping (CIM) was used to increase the accuracy in mapping individual loci. Genetic markers on chromosomes 2, 3, 8, 13, 16, 18 and 19 were associated with ethanol-induced activation. CONCLUSIONS: Three significant markers identified through CIM accounted for 86% of the genetic variance in the ethanol-induced activation. QTLs on chromosome 16 (45.6 cM) and 19 (24 cM) previously associated with alcohol consumption in the AXB/BXA RI mice were found to overlap with QTLs for ethanol-induced activation identified in the present study.     

Behavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects

Rationale Acetaldehyde, the first metabolite of ethanol, was recently suggested to contribute to many behavioral effects of ethanol, although few studies have directly investigated the behavioral effects of acetaldehyde itself.Objectives The aim of the present study was to characterize the locomotor, hypnotic, anxiolytic-like and amnesic effects of acetaldehyde in C57BL/6J mice.Methods Increasing doses of acetaldehyde (0–300 mg/kg) were injected intraperitoneally and their effects on a series of representative behaviors were investigated. The locomotor effects of acetaldehyde were measured in activity boxes. The duration of the loss of righting reflex was used as an index of the hypnotic effects of acetaldehyde. The anxiolytic-like effects of acetaldehyde were tested with an elevated plus-maze and the amnesic effects with the one-trial passive avoidance test. Finally, brain and blood acetaldehyde concentrations were assessed.Results Acetaldehyde induced a significant hypolocomotor effect at 170 mg/kg and higher doses. In addition, the hypnotic effects of acetaldehyde were demonstrated by a loss of righting reflex after the administration of 170 and 300 mg/kg acetaldehyde. The elevated plus-maze showed that acetaldehyde does not possess anxiolytic-like properties. Finally, acetaldehyde (100–300 mg/kg) dose-dependently altered memory consolidation as shown by a reduced performance in the passive avoidance test.Conclusions The present results show that acetaldehyde induces sedative, hypnotic and amnesic effects, whereas it is devoid of stimulant and anxiolytic-like properties in C57BL/6J mice. However, the behavioral effects of acetaldehyde after intraperitoneal administration were apparent at very high brain concentrations. The present results also indicate that acetaldehyde is unlikely to be involved in the anxiolytic properties of ethanol in mice.     

Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice

Rationale  Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed “drinking in the dark” (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown. Objectives  To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice. Materials and methods  Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-β-erythroidine, and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry. Results  Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol. Conclusions  Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol.     

Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice

Mice of the C56BL/6J strain were trained to discriminate between nicotine (1.2 mg/kg) and saline in a two-lever drug discrimination procedure under a tandem variable-interval 60 s fixed-ratio 10 schedule of food reinforcement. Mice of the same strain were trained in conditioned taste aversion (CTA) experiments where drinking a saccharin or saline solution was paired with injection of nicotine or vehicle. During testing with both flavours presented simultaneously, a reduction in the intake of the nicotine-paired solution indicated CTA. The nicotine discrimination was acquired successfully and nicotine yielded a steep dose–response curve. The competitive nicotinic antagonist dihydro-β-erythroidine (DHβE, 0.6–3.0 mg/kg) shifted the dose–response for the discriminative stimulus effect of nicotine to the right; the 7 nicotinic receptor antagonist methyllycaconitine (MLA, 1.0–10 mg/kg) had no effect. The mice showed strong CTA to 2.0 mg/kg of nicotine and marginally to 0.6 and 1.2 mg/kg of nicotine. DHβE (3.0–5.6 mg/kg) attenuated the CTA while MLA (1.0–10 mg/kg) had no effect. These studies show that nicotine has discriminative and aversive stimulus properties in C57BL/6J mice and that the effects are mediated primarily by receptors sensitive to DHβE; there was no evidence for the involvement of 7 nicotinic receptors.     

Effects of acute alcohol administration on object recognition learning in C57BL/6J mice.

The goal of the present study was to investigate effects of alcohol intoxication on the object recognition learning task. Male C57BL/6J mice habituated to saline injections and exploratory arena received different doses of ethanol (0, 1.6 or 2.4 g/kg) before or after a 10-min training session. During training, animals were exposed to a small object (a marble or a die). On the next day, during a 10-min testing session, animals were exposed to two objects: the familiar object from the previous day and a novel object. Analysis of behavior during testing showed that mice injected with 0 and 1.6 g/kg of ethanol before training spent more time exploring a novel than a familiar object during testing. In contrast, mice injected with 2.4 g/kg ethanol spent equal amounts of time exploring the novel and the familiar object. Mice injected with this dose of ethanol after training did not show a decreased ratio of object exploration during testing. Analysis of behavior during training showed that mice injected with this dose of ethanol spent less time exploring the object, although their locomotor activity was not decreased. Our results show that in C57BL/6J mice, ethanol intoxication interferes with exploratory activity during object exploration, but not with consolidation of memory.     

Cocaine self-administration under fixed and progressive ratio schedules of reinforcement: comparison of C57BL/6J, 129X1/SvJ, and 129S6/SvEvTac inbred mice

Rationale Combining strains to generate mutant mice may obscure conclusions regarding the targeted gene. Specifically, cocaine may have reduced reinforcing effects in 129 substrains compared to the C57BL/6 strain, commonly used for ES cells and breeding, respectively. Objectives We tested the hypothesis that reinforcing effects of cocaine differ between the C57BL/6J strain and two substrains of 129, 129X1/SvJ and 129S6/SvEvTac. Methods To assess and reduce performance differences, operant responding was established with liquid food as a reinforcer and evaluated under fixed and progressive ratio schedules. Dose–effect functions for intravenous cocaine self-administration were then determined under both schedules. Finally, reinforced and nonreinforced manipulanda were reversed to assess acquisition of self-administration using a previously nonreinforced response. Results Relative to C57BL/6J mice, 129X1/SvJ mice showed decreased reinforcing effects of low-magnitude food and cocaine reinforcers. Dose–effect functions for cocaine self-administration were comparable between C57BL/6J and 129S6/SvEvTac mice, despite delayed acquisition of operant behaviors and rightward shifts in the food concentration–effect functions in 129S6/SvEvTac mice. A high cocaine dose clearly served as a positive reinforcer in all three strains in a reversal procedure. Conclusions Relative to C57BL/6J mice, the reinforcing effects of cocaine were diminished in 129X1/SvJ mice, but only for low cocaine doses, and a similar profile was observed with food reinforcement. 129S6/SvEvTac mice required more extensive operant training than C57BL/6J mice did, but after acquisition, reinforcing effects of cocaine were similar in the two strains. We suggest that comparable phenotypes observed in gene-targeting studies may result from genetic background, whereas more profound or qualitatively different phenotypes may be more confidently attributed to targeted mutations.     

Acute effects of Naltrexone and GBR 12909 on ethanol drinking-in-the-dark in C57BL/6J mice

Rationale Recently, a simple procedure was described, drinking in the dark (DID), in which C57BL/6J mice self-administer ethanol to the point of intoxication. The test consists of replacing the water with 20% ethanol in the home cage for 2 or 4 h early during the dark phase of the light/dark cycle. Objectives To determine whether the model displays predictive validity with naltrexone, and whether opioid or dopaminergic mechanisms mediate excessive drinking in the model. Materials and methods Naltrexone or GBR 12909 were administered via intraperitoneal injections immediately before offering ethanol solutions, plain tap water, or 10% sugar water to male C57BL/6J mice, and consumption was monitored over a 2- or 4-h period using the DID procedure. Results Naltrexone (0.5, 1, or 2 mg/kg) dose dependently decreased ethanol drinking but these same doses had no significant effect on the consumption of plain water or 10% sugar water. GBR 12909 (5, 10, and 20 mg/kg) dose dependently reduced the consumption of ethanol and sugar water but had no effect on plain water drinking. Conclusions The DID model demonstrates predictive validity. Both opioid and dopamine signaling are involved in ethanol drinking to intoxication. Different physiological pathways mediate high ethanol drinking as compared to water or sugar water drinking in DID. DID may be a useful screening tool to find new alcoholism medications and to discover genetic and neurobiological mechanisms relevant to the human disorder.     

Phenobarbital during pregnancy alters operant behavior of offspring in C57BL/6J mice.

Offspring of C57BL/6J injected daily with phenobarbital for the last third of pregnancy responded less than control animals when maintained on various fixed ratio schedules of reinforcement. The response decrement became more pronounced as the schedule demands were increased and was noted in offspring of both sexes. The higest dose (80 mg/kg) was less effective than the 2 lower doses (20 mg and 40 mg/kg) in producing the decrement which may reflect a selection factor due to high neonatal mortality previously reported at this dose. The study provides no evidence of the mechanism mediating the long term behavioral abnormality but does clearly extend the finding of such changes to doses which do not produce increased neonatal mortality or noticeable morphological changes.     

Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6J mice

Psychological stress is a major risk factor for mood and anxiety disorders. However, the phenotypic manifestation of stress effects varies across individuals, likely due, in part, to genetic variation. Modeling the behavioral and neural consequences of stress across genetically diverse inbred mouse strains is a valuable approach to studying gene × stress interactions. Recent work has shown that C57BL/6J mice exposed to ten daily sessions of restraint stress exhibited increased exploration of the aversive light compartment in the light/dark exploration (LDE) test. Here we sought to clarify the nature of this stress-induced phenotype by testing the ability of treatment with various clinically efficacious drugs of different therapeutic classes to rescue it. Ten days of restraint increased light compartment exploration, reduced body weight and sensitized the corticosterone response to swim stress. Subchronic administration (during stress and LDE testing) of fluoxetine, and to a lesser extent, lithium chloride, rescued stress-induced LDE behavior. Chronic fluoxetine treatment prior to (plus during stress and testing) failed to block the LDE stress effect. Acute administration of antipsychotic haloperidol, anti-ADHD medication methylphenidate or anxiolytic drug chlordiazepoxide, prior to LDE testing, was also unable to normalize the LDE stress effect. Collectively, these data demonstrate a treatment-selective prophylactic rescue of a restraint stress-induced behavioral abnormality in the C57BL/6J inbred strain. Further work with this novel model could help elucidate genetic and neural mechanisms mediating stress-induced changes in mouse 'emotion-relevant' behaviors and, ultimately, further understanding of the pathophysiology of stress-related neuropsychiatric disorders. This article is part of a Special Issue entitled 'Anxiety and Depression'.