Effects of varenicline on ethanol-induced conditioned place preference, locomotor stimulation, and sensitization.

BACKGROUND: Varenicline, a partial nicotinic acetylcholine receptor (nAChR) agonist, is a promising new drug for the treatment of alcohol (ethanol [EtOH]) dependence. Varenicline has been approved by the Food and Drug Administration as a smoking cessation therapeutic and has also been found to reduce EtOH consumption in humans and animal models of alcohol use. These studies examined the hypotheses that varenicline attenuates the stimulant and sensitizing effects of EtOH and reduces the motivational effects of EtOH-associated cues. The goal was to determine whether these effects of varenicline contribute to its pharmacotherapeutic effects for alcohol dependence. In addition, effects of varenicline on acute stimulation and/or on the acquisition of sensitization would suggest a role for nAChR involvement in these effects of EtOH. METHODS: Dose-dependent effects of varenicline on the expression of EtOH-induced conditioned place preference (CPP), locomotor activation, and behavioral sensitization were examined. These measures model motivational effects of EtOH-associated cues, euphoric or stimulatory effects of EtOH, and EtOH-induced neuroadaptation. All studies used DBA/2J mice, an inbred strain with high sensitivity to these EtOH-related effects. RESULTS: Varenicline did not significantly attenuate the expression of EtOH-induced CPP. Varenicline reduced locomotor activity and had the most pronounced effect in the presence of EtOH, with the largest effect on acute EtOH-induced locomotor stimulation and a trend for varenicline to attenuate the expression of EtOH-induced sensitization. CONCLUSIONS: Because varenicline did not attenuate the expression of EtOH-induced CPP, it may not be effective at reducing the motivational effects of EtOH-associated cues. This outcome suggests that reductions in the motivational effects of EtOH-associated cues may not be involved in how varenicline reduces EtOH consumption. However, varenicline did have effects on locomotor behavior and significantly attenuated acute EtOH-induced locomotor stimulation. In humans who drink while taking varenicline, it might similarly reduce stimulant responses and have an impact on continued drinking. General sedative effects in such individuals should be carefully considered.

Genetic factors involved in risk for methamphetamine intake and sensitization.

Lines of mice were created by selective breeding for the purpose of identifying genetic mechanisms that influence the magnitude of the selected trait and to explore genetic correlations for additional traits thought to be influenced by shared mechanisms. DNA samples from high and low methamphetamine-drinking (MADR) and high and low methamphetamine-sensitization lines were used for quantitative trait locus (QTL) mapping. Significant additive genetic correlations between the two traits indicated a common genetic influence, and a QTL on chromosome X was detected for both traits, suggesting one source of this commonality. For MADR mice, a QTL on chromosome 10 accounted for more than 50 % of the genetic variance in that trait. Microarray gene expression analyses were performed for three brain regions for methamphetamine-naïve MADR line mice: nucleus accumbens, prefrontal cortex, and ventral midbrain. Many of the genes that were differentially expressed between the high and low MADR lines were shared in common across the three brain regions. A gene network highly enriched in transcription factor genes was identified as being relevant to genetically determined differences in methamphetamine intake. When the mu opioid receptor gene (Oprm1), located on chromosome 10 in the QTL region, was added to this top-ranked transcription factor network, it became a hub in the network. These data are consistent with previously published findings of opioid response and intake differences between the MADR lines and suggest that Oprm1, or a gene that impacts activity of the opioid system, plays a role in genetically determined differences in methamphetamine intake.

Unique genetic factors influence sensitivity to the rewarding and aversive effects of methamphetamine versus cocaine.

Genetic factors significantly influence addiction-related phenotypes. This is supported by the successful bidirectional selective breeding of two replicate sets of mouse lines for amount of methamphetamine consumed. Some of the same genetic factors that influence methamphetamine consumption have been previously found also to influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine. The goal of the current studies was to determine if some of the same genetic factors influence sensitivity to the conditioned rewarding and aversive effects of cocaine. Cocaine conditioned reward was examined in methamphetamine high drinking and low drinking line mice using a conditioned place preference procedure and cocaine conditioned aversion was measured using a conditioned taste aversion procedure. In addition, a general sensitivity measure, locomotor stimulant response to cocaine, was assessed in these lines; previous data indicated no difference between the selected lines in sensitivity to methamphetamine-induced stimulation. In contrast to robust differences for methamphetamine, the methamphetamine high and low drinking lines did not differ in sensitivity to either the rewarding or aversive effects of cocaine. They also exhibited comparable sensitivity to cocaine-induced locomotor stimulation. These data suggest that the genetic factors that influence sensitivity to the conditioned rewarding and aversive effects of methamphetamine in these lines of mice do not influence sensitivity to these effects of cocaine. Thus, different genetic factors may influence risk for methamphetamine versus cocaine use.

Role of corticotropin-releasing factor and corticosterone in behavioral sensitization to ethanol.

Neuroadaptations underlying sensitization to drugs of abuse seem to influence compulsive drug pursuit and relapse associated with addiction. Our previous data support a role for the corticotropin-releasing factor (CRF) type-1 receptor (CRF1) in ethanol (EtOH)-induced psychomotor sensitization. CRF1 is endogenously activated by CRF and urocortin-1. Because genetic deletion of urocortin-1 did not affect EtOH sensitization, we hypothesized that CRF is the important ligand underlying EtOH sensitization. To test this hypothesis, we used heterozygous and homozygous knockout (KO) mice, which lack one or both copies of the gene coding for CRF, and their respective wild-type controls. EtOH sensitization was normal in heterozygous, but absent in homozygous, CRF KO mice. Corticosterone (CORT) levels were drastically reduced only in CRF KO mice. Because CRF/CRF1 initiate EtOH-induced activation of the hypothalamic-pituitary-adrenal axis, we investigated CORT effects on EtOH sensitization. The CORT synthesis inhibitor metyrapone prevented the acquisition, but not the expression, of EtOH sensitization. Exogenous CORT administration sensitized the locomotor response to a subsequent EtOH challenge; we observed, however, that the exogenous CORT levels necessary to induce sensitization to EtOH were significantly higher than those produced by EtOH treatment. Therefore, participation of CORT seems to be necessary, but not sufficient, to explain the role of CRF/CRF1 in the acquisition of sensitization to EtOH. Extra-hypothalamic CRF/CRF1 mechanisms are suggested to be involved in the expression of EtOH sensitization. The present results are consistent with current theories proposing a key role for CRF and CRF1 in drug-induced neuroplasticity, dependence, and addictive behavior.

Profound reduction in sensitivity to the aversive effects of methamphetamine in mice bred for high methamphetamine intake.

Reduced sensitivity to aversive effects of methamphetamine (MA) may increase risk for MA abuse. Studies in two replicate sets of mouse lines that were selectively bred for high and low levels of MA intake support this view. Current studies examined the extent of insensitivity to aversive MA effects of mice bred for high levels of MA drinking. Conditioning procedures in which drugs are delivered shortly after cue exposure have been used to detect aversive drug effects and, in some cases, are more sensitive to such effects. Aversive effects induced by MA injected immediately after exposure to cues from two different sensory modalities were examined. In addition, effects of higher MA doses than those used previously were examined. MA-associated place conditioning utilized tactile cues, whereas MA-induced taste conditioning utilized a novel tastant. Second replicate, MA high drinking (MAHDR-2) and low drinking (MALDR-2) mice were treated with doses of MA up to 4 mg/kg. MAHDR-2 mice were insensitive to aversive effects of MA, except after place conditioning with the 4 mg/kg dose; MALDR-2 mice exhibited sensitivity to aversive effects of MA at doses as low as 1 mg/kg. These studies show that the expression of aversion is dependent upon procedure and MA dose, and that MAHDR-2 mice have markedly reduced sensitivity to the aversive effects of MA. The current and previous results support a strong genetic relationship between level of MA intake and level of sensitivity to aversive effects of MA, a factor that could impact risk for MA use in humans. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption.

RATIONALE: Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption. OBJECTIVES: Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA. METHODS: Beginning with the F2 cross of C57BL/6J and DBA/2J strains, mice were tested for locomotor sensitization to repeated injections of 1 mg/kg MA and bred based on magnitude of sensitization. Five selected offspring generations were tested. All generations were also tested for MA consumption, and some were tested for dose-dependent locomotor-stimulant responses to MA, consumption of saccharin, quinine, and potassium chloride as a measure of taste sensitivity, and MA clearance after acute and repeated MA. RESULTS: Selective breeding resulted in creation of two lines [MA high sensitization (MAHSENS) and MA low sensitization (MALSENS)] that differed in magnitude of MA-induced sensitization. Initially, greater MA consumption in MAHSENS mice reversed over the course of selection so that MALSENS mice consumed more MA. MAHSENS mice exhibited greater sensitivity to the acute stimulant effects of MA, but there were no significant differences between the lines in MA clearance from blood. CONCLUSIONS: Genetic factors influence magnitude of MA-induced locomotor sensitization and some of the genes involved in magnitude of this response also influence MA sensitivity and consumption. Genetic factors leading to greater MA-induced sensitization may serve a protective role against high levels of MA consumption.

Repeated ethanol administration modifies the temporal structure of sucrose intake patterns in mice: effects associated with behavioral sensitization.

Neuroadaptations supporting behavioral sensitization to abused drugs are suggested to underlie pathological, excessive motivation toward drugs and drug-associated stimuli. Drug-induced sensitization has also been linked to increased appetitive responses for non-drug, natural reinforcers. The present research investigated whether ethanol (EtOH)-induced neural changes, inferred from psychomotor sensitization, can modify consumption and intake dynamics for the natural reinforcer, sucrose. The effects of EtOH-induced sensitization in mice on the temporal structure of sucrose intake patterns were measured using a lickometer system. After sensitization, sucrose intake dynamics were measured for 1 hour daily for 7 days and indicated more rapid initial approach and consumption of sucrose in EtOH-sensitized groups; animals showed a shorter latency to the first intake bout and an increased number of sucrose bottle licks during the initial 15 minutes of the 1-hour sessions. This effect was associated with increased frequency and size of bouts. For the total 1-hour session, sucrose intake and bout dynamics were not different between groups, indicating a change in patterns of sucrose intake but not total consumption. When sensitization was prevented by the gamma-aminobutyric acid B receptor agonist, baclofen, the increased rate of approach and consumption of sucrose were also prevented. Thus, EtOH-induced sensitization, and not the mere exposure to EtOH, was associated with changes in sucrose intake patterns. These data are consistent with current literature suggesting an enhancing effect of drug-induced sensitization on motivational processes involved in reinforcement.

Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin1-independent mechanism.

A common expression of neuroadaptations induced by repeated exposure to addictive drugs is a persistent sensitized behavioral response to their stimulant properties. Neuroplasticity underlying drug-induced sensitization has been proposed to explain compulsive drug pursuit and consumption characteristic of addiction. The hypothalamic-pituitary-adrenal (HPA) axis-activating neuropeptide, corticotropin-releasing factor (CRF), may be the keystone in drug-induced neuroadaptation. Corticosterone-activated glucocorticoid receptors (GRs) mediate the development of sensitization to ethanol (EtOH), implicating the HPA axis in this process. EtOH-induced increases in corticosterone require CRF activation of CRF1 receptors. We posited that CRF1 signaling pathways are crucial for EtOH-induced sensitization. We demonstrate that mice lacking CRF1 receptors do not show psychomotor sensitization to EtOH, a phenomenon that was also absent in CRF1 + 2 receptor double-knockout mice. Deletion of CRF2 receptors alone did not prevent sensitization. A blunted endocrine response to EtOH was found only in the genotypes showing no sensitization. The CRF1 receptor antagonist CP-154,526 attenuated the acquisition and prevented the expression of EtOH-induced psychomotor sensitization. Because CRF1 receptors are also activated by urocortin-1 (Ucn1), we tested Ucn1 knockout mice for EtOH sensitization and found normal sensitization in this genotype. Finally, we show that the GR antagonist mifepristone does not block the expression of EtOH sensitization. CRF and CRF1 receptors, therefore, are involved in the neurobiological adaptations that underlie the development and expression of psychomotor sensitization to EtOH. A CRF/CRF1-mediated mechanism involving the HPA axis is proposed for acquisition, whereas an extrahypothalamic CRF/CRF1 participation is suggested for expression of sensitization to EtOH.

Ethanol-related traits in mice selectively bred for differential sensitivity to methamphetamine-induced activation.

Acute drug stimulation has been proposed to be an endophenotype for drug abuse. The authors previously reported the short-term selective breeding of lines of mice for low (LMACT) and high (HMACT) stimulation to methamphetamine (MA). These mice were used to examine whether common genes influence the locomotor response to MA and ethanol. Additionally, the authors tested these mice for ethanol drinking, locomotor sensitization, and clearance. LMACT mice were less stimulated by ethanol and consumed more ethanol than HMACT mice, but the lines did not differ in ethanol-induced sensitization. A small difference in ethanol clearance rate (0.1 mg/ml/h) likely had little impact on behavior. Some common genes may influence the locomotor response to MA and ethanol, as well as ethanol drinking.

Genetic correlational analyses of ethanol reward and aversion phenotypes in short-term selected mouse lines bred for ethanol drinking or ethanol-induced conditioned taste aversion.

Short-term selective breeding created mouse lines divergent for ethanol drinking (high drinking short-term selected line [STDRHI], low drinking [STDRLO]) or ethanol-induced conditioned taste aversion (CTA; high [HTA], low [LTA]). Compared with STDRLO, STDRHI mice consumed more saccharin and less quinine, exhibited greater ethanol-induced conditioned place preference (CPP), and showed reduced ethanol stimulation and sensitization under some conditions; a line difference in ethanol-induced CTA was not consistently found. Compared with LTA, HTA mice consumed less ethanol but were similar in saccharin consumption, sensitivity to ethanol-induced CPP, and ethanol-induced locomotor stimulation and sensitization. These data suggest that ethanol drinking is genetically associated with several reward-and aversion-related traits. The interpretation of ethanol-induced CTA as more genetically distinct must be tempered by the inability to test the CTA lines beyond Selection Generation 2.

Gene expression differences in mice divergently selected for methamphetamine sensitivity.

In an effort to identify genes that may be important for drug-abuse liability, we mapped behavioral quantitative trait loci (bQTL) for sensitivity to the locomotor stimulant effect of methamphetamine (MA) using two mouse lines that were selectively bred for high MA-induced activity (HMACT) or low MA-induced activity (LMACT). We then examined gene expression differences between these lines in the nucleus accumbens, using 20 U74Av2 Affymetrix microarrays and quantitative polymerase chain reaction (qPCR). Expression differences were detected for several genes, including Casein Kinase 1 Epsilon (Csnkle), glutamate receptor, ionotropic, AMPA1 (GluR1), GABA B1 receptor (Gabbr1), and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp-32). We used the www.WebQTL.org database to identify QTL that regulate the expression of the genes identified by the microarrays (expression QTL; eQTL). This approach identified an eQTL for Csnkle on Chromosome 15 (LOD = 3.8) that comapped with a bQTL for the MA stimulation phenotype (LOD = 4.5), suggesting that a single allele may cause both traits. The chromosomal region containing this QTL has previously been associated with sensitivity to the stimulant effects of cocaine. These results suggest that selection was associated with (and likely caused) altered gene expression that is partially attributable to different frequencies of gene expression polymorphisms. Combining classical genetics with analysis of whole-genome gene expression and bioinformatic resources provides a powerful method for provisionally identifying genes that influence complex traits. The identified genes provide excellent candidates for future hypothesis-driven studies, translational genetic studies, and pharmacological interventions.

Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol.

RATIONALE: Corticotropin-releasing factor (CRF) may play a significant role in drug and alcohol abuse. OBJECTIVE: To evaluate the role of CRF in these processes, we examined several ethanol (EtOH) related behaviors in mice that carry a transgene that causes overexpression of CRF. METHODS: We examined voluntary EtOH drinking, loss of the righting reflex (LORR), EtOH-induced conditioned taste aversion (CTA), and EtOH clearance in littermate transgenic (TG) and non-transgenic (non-TG) mice. In addition, because preliminary results indicated that age exacerbated differences in EtOH consumption between the two genotypes, we performed a cross-sectional and longitudinal evaluation of this trait at two ages ( approximately 100 and 200 days old). RESULTS: We found that TG mice consumed significantly less EtOH and had a lower preference for EtOH-containing solutions compared with their non-TG littermates. We also found that the older drug-naive TG mice drank less EtOH as compared with the younger mice of the same genotype; however, the same relationship did not exist for drug-naive non-TG mice. Prior experience in drinking EtOH when 100 days old led to decreased EtOH drinking when 200 days old in both genotypes. Duration of LORR was longer in the TG mice, EtOH-induced CTA was marginally greater in non-TG mice at the highest dose tested, and there were significant but small differences in EtOH clearance parameters. CONCLUSIONS: These data show that CRF overexpressing mice voluntarily consume less EtOH. This difference is associated with greater sensitivity to the sedative-hypnotic effects of EtOH, but not with increased sensitivity to the aversive effects of EtOH.

Reverse selection for differential response to the locomotor stimulant effects of ethanol provides evidence for pleiotropic genetic influence on locomotor response to other drugs of abuse.

BACKGROUND: Addictive drugs share the ability to induce euphoria, which may be associated with their potential for abuse. Replicate mouse lines with high (FAST-1, FAST-2) and low (SLOW-1, SLOW-2) sensitivity to ethanol-induced psychomotor stimulation (a possible animal model for the euphoria experienced by humans) have provided evidence for common genetic influences (pleiotropy) on sensitivity to the effects of ethanol and of GABA-A receptor acting compounds on locomotor activity. Differences between FAST and SLOW mice in locomotor response to certain other drugs were found later in selection. Reverse selection produced lines (r-FAST-1, r-FAST-2, r-SLOW-1, r-SLOW-2) with similar locomotor responses to ethanol. These lines are well suited for asking whether the same alleles that influence sensitivity to ethanol are also responsible for these later arising differences in drug sensitivity. METHODS: Two replicate sets of forward- and reverse-selected FAST and SLOW lines were tested for the effects of multiple doses of morphine, cocaine, methamphetamine, nicotine, and scopolamine on their locomotor behavior. We predicted that differences in drug sensitivity between the FAST and SLOW lines would be reduced or eliminated in the reverse-selected lines. RESULTS: Differences in sensitivity to morphine, cocaine, methamphetamine, and nicotine that arose in earlier generations of the FAST-1 and SLOW-1 lines ultimately also appeared in the FAST-2 and SLOW-2 lines. However, some differences between the FAST-2 and SLOW-2 lines (those in response to cocaine and methamphetamine) were not seen until several generations after selection had been relaxed. In lines reverse-selected for sensitivity to ethanol, differences in sensitivity to the other drugs were decreased, eliminated, or even reversed. No differences in scopolamine response were found in the replicate 1 forward- or reverse-selected lines. However, a small difference in scopolamine response in the replicate 2 lines was reversed. CONCLUSIONS: Genes that influence the locomotor response to ethanol also influence locomotor response to other drugs with stimulant effects in the FAST and SLOW mice. The current data most strongly support this conclusion for sensitivity to morphine and nicotine.

Different data from different labs: lessons from studies of gene-environment interaction.

It is sometimes supposed that standardizing tests of mouse behavior will ensure similar results in different laboratories. We evaluated this supposition by conducting behavioral tests with identical apparatus and test protocols in independent laboratories. Eight genetic groups of mice, including equal numbers of males and females, were either bred locally or shipped from the supplier and then tested on six behaviors simultaneously in three laboratories (Albany, NY; Edmonton, AB; Portland, OR). The behaviors included locomotor activity in a small box, the elevated plus maze, accelerating rotarod, visible platform water escape, cocaine activation of locomotor activity, and ethanol preference in a two-bottle test. A preliminary report of this study presented a conventional analysis of conventional measures that revealed strong effects of both genotype and laboratory as well as noteworthy interactions between genotype and laboratory. We now report a more detailed analysis of additional measures and view the data for each test in different ways. Whether mice were shipped from a supplier or bred locally had negligible effects for almost every measure in the six tests, and sex differences were also absent or very small for most behaviors, whereas genetic effects were almost always large. For locomotor activity, cocaine activation, and elevated plus maze, the analysis demonstrated the strong dependence of genetic differences in behavior on the laboratory giving the tests. For ethanol preference and water escape learning, on the other hand, the three labs obtained essentially the same results for key indicators of behavior. Thus, it is clear that the strong dependence of results on the specific laboratory is itself dependent on the task in question. Our results suggest that there may be advantages of test standardization, but laboratory environments probably can never be made sufficiently similar to guarantee identical results on a wide range of tests in a wide range of labs. Interpretations of our results by colleagues in neuroscience as well as the mass media are reviewed. Pessimistic views, prevalent in the media but relatively uncommon among neuroscientists, of mouse behavioral tests as being highly unreliable are contradicted by our data. Despite the presence of noteworthy interactions between genotype and lab environment, most of the larger differences between inbred strains were replicated across the three labs. Strain differences of moderate effects size, on the other hand, often differed markedly among labs, especially those involving three 129-derived strains. Implications for behavioral screening of targeted and induced mutations in mice are discussed.

Locomotor activity responses to ethanol, other alcohols, and GABA-A acting compounds in forward- and reverse-selected FAST and SLOW mouse lines.

Mice selectively bred for high (FAST) or low (SLOW) locomotor stimulant response to ethanol have been found to differ in response to drugs with gamma-aminobutyric acid (GABA)-ergic actions. Reverse selection produced lines that are similar in sensitivity to ethanol stimulation (r-FAST and r-SLOW) and provided a unique model for testing hypotheses about shared genetic influence on sensitivity to ethanol and GABAergic drugs. FAST mice were more stimulated than SLOW mice by all drugs tested: ethanol, methanol, n-propanol, t-butanol, pentobarbital, diazepam, and allopregnanolone. In contrast, r-FAST and r-SLOW mice differed in sensitivity to only a few isolated drug doses. Locomotor responses of each reverse-selected line were significantly different from the responses of their respective forward-selected line for all drugs. Results support an effect of selection for ethanol sensitivity on allosteric modulation of the GABA-A receptor.

Forward, relaxed, and reverse selection for reduced and enhanced sensitivity to ethanol's locomotor stimulant effects in mice.

BACKGROUND: Rarely have trait markers for alcoholism risk been identified. However, relative sensitivity to the arousing effects of ethanol and sensitivity to ethanol's sedative effects have been distinguished as potentially valuable behavioral risk factors. Both traits are genetically influenced and have been modeled in mice by measuring sensitivity to ethanol-induced locomotor stimulation and hypnosis. Reverse selection was performed to examine the hypothesis that forward selection for differential sensitivity to ethanol's locomotor stimulant effects resulted in homozygous fixation of selection trait-relevant alleles and to test the hypothesis that common genes influence ethanol's stimulant and sedative effects. METHODS: Bidirectional selective breeding was completed for enhanced (FAST mice) and reduced (SLOW mice) sensitivity to ethanol's locomotor stimulant effects. Selection was terminated (relaxed), and the lines were tested to detect genetic drift. Reverse selection for enhanced sensitivity to ethanol-induced stimulation in SLOW mice and reduced sensitivity in FAST mice was performed for 16 generations. Forward and reverse selected lines were tested for sensitivity to ethanol's sedative effects by measuring duration of ethanol-induced loss of righting reflex. RESULTS: Differential sensitivity to the sedative effects of ethanol emerged with selection for differential ethanol stimulation, indicating a common genetic influence on these traits. SLOW mice developed greater sensitivity to ethanol's sedative effects relative to FAST mice. Reverse selection, never before reported for a pharmacogenetic trait, was effective in eliminating most of the difference in stimulant sensitivity between the FAST and SLOW lines and also eliminated the difference in loss of righting reflex duration. CONCLUSIONS: Residual heterozygosity persisted at trait-relevant loci even at the selection plateau, possibly due to heterosis, natural selection favoring heterozygosity, or epistatic phenomena involving differences in the sets of genes regulating the high- versus low-sensitivity traits. They also suggest that some common genes influence sensitivity to ethanol's locomotor stimulant and sedative effects.

Shared genes influence sensitivity to the effects of ethanol on locomotor and anxiety-like behaviors, and the stress axis.

RATIONALE: In rodents, a common response to many drugs of abuse, including ethanol (EtOH), is locomotor stimulation. It has been proposed, although debated, that EtOH-induced locomotor stimulation may represent an animal model of EtOH's euphoric effects. Another possibility is that this behavioral phenotype may represent an altered state of anxiety, and/or stress axis activation. OBJECTIVES: Mouse lines selectively bred for sensitivity (FAST) or resistance (SLOW) to EtOH's low dose locomotor stimulant effects were tested for differential sensitivity to EtOH's anxiolytic and/or stress axis activating effects, with the goal of detecting genetic correlations. METHODS: Saline- and EtOH-treated FAST and SLOW mice were tested on the elevated plus maze and the light-dark box, two widely used measures of anxiety-related behavior in rodents. In addition, serum corticosterone (CORT) levels were measured at various time points following injection of saline or ethanol. RESULTS: Behavioral data from both anxiety tests showed that FAST mice were less sensitive to EtOH's anxiolytic effects than were SLOW mice. Moreover, late recovery of elevated serum CORT levels following mild saline injection stress, as well as reduced CORT release in response to EtOH, suggested that FAST mice may possess a less responsive stress axis. CONCLUSIONS: These results provide evidence that sensitivity to the effects of EtOH on locomotor behavior, anxiety-like behavior, and the stress axis share some genetic influence.

Sensitivity to the locomotor stimulant effects of ethanol and allopregnanolone is influenced by common genes.

Allopregnanolone is a neuroactive steroid that, like ethanol (EtOH), has stimulant, anxiolytic, ataxic, and depressant effects. Two experiments tested the hypothesis that sensitivity to the locomotor stimulant effects of these drugs is influenced by a common set of genes. Sensitivity to the locomotor stimulant effects of allopregnanolone was determined in 24 BXD recombinant inbred (RI) strains. Strain means were positively correlated with extant means for EtOH stimulation in 20 of the same strains. Quantitative trait locus (QTL) analysis provisionally identified many loci, including several known to influence sensitivity to EtOH. Sensitivity to allopregnanolone was also measured in FAST and SLOW mice, which were selectively bred for differential locomotor response to EtOH, to determine whether selection has also altered allopregnanolone sensitivity. FAST mice were more sensitive to the stimulant effects of allopregnanolone compared with SLOW mice. These data suggest that sensitivity to the locomotor stimulant effects of these drugs is influenced by common genes.