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Gubner N.R.,Oregon Health And Science University | Wilhelm C.J.,Oregon Health And Science University | Phillips T.J.,Oregon Health And Science University | Phillips T.J.,Portland Alcohol Research Center | And 3 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2010

Background: High levels of impulsivity have been associated with a number of substance abuse disorders including alcohol abuse. Research has not yet revealed whether these high levels predate the development of alcohol abuse. Methods: The current study examined impulsivity in 15 inbred strains of mice (A/HeJ, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57L/J, C58/J, CBA/J, DBA/1J, DBA/2J, NZB/B1NJ, PL/J, SJL/J, SWR/J, and 129P3/J) using a Go/No-go task, which was designed to measure a subject's ability to inhibit a behavior. Numerous aspects of response to ethanol and other drugs of abuse have been examined in these strains. Results: There were significant strain differences in the number of responses made during the No-go signal (false alarms) and the extent to which strains responded differentially during the Go and No-go signals (d'). The rate of responding prior to the cue did not differ among strains, although there was a statistically significant correlation between false alarms and precue responding that was not related to basal activity level. Interstrain correlations suggested that false alarms and rate of responding were associated with strain differences in ethanol-related traits from the published literature. Conclusions: The results of this study do support a link between innate level of impulsivity and response to ethanol and are consistent with a genetic basis for some measures of behavioral inhibition. Copyright © 2010 by the Research Society on Alcoholism.


Crabbe J.C.,Medical Center R and D12 | Crabbe J.C.,Portland Alcohol Research Center | Crabbe J.C.,Oregon Health And Science University
Genes, Brain and Behavior | Year: 2012

In biomedical research, one key stage of translating basic science knowledge to clinical practice is the reconciliation of phenotypes employed for laboratory animal studies with those important for the clinical condition. Alcohol dependence (AD) is a prototypic complex genetic trait. There is a long history of behaviour-genetic studies of AD in both human subjects and various genetic animal models. This review assesses the state of the art in our understanding of the genetic contributions to AD. In particular, it primarily focuses on the phenotypes studied in mouse genetic animal models, comparing them to the aspects of the human condition they are intended to target. It identifies several features of AD where genetic animal models have been particularly useful, and tries to identify understudied areas where there is good promise for further genetic animal model work. © 2012.


Barkley-Levenson A.M.,Oregon Health And Science University | Barkley-Levenson A.M.,Portland Alcohol Research Center | Crabbe J.C.,Oregon Health And Science University | Crabbe J.C.,Portland Alcohol Research Center
Alcoholism: Clinical and Experimental Research | Year: 2012

Background: The High Drinking in the Dark (HDID) selected mouse line was bred for high blood ethanol (EtOH) concentration (BEC) following the limited access drinking in the dark (DID) test and is a genetic animal model of binge-like drinking. This study examines the microstructure of EtOH drinking in these mice and their control line during 3 versions of the DID test to determine how drinking structure differences might relate to overall intake and BEC. Methods: Male mice from the HDID-1 replicate line and HS/Npt progenitor stock were tested in separate experiments on 2- and 4-day versions of the DID test, and on a 2-day 2-bottle choice DID test with 20% EtOH and water. Testing took place in home cages connected to a continuous fluid intake monitoring system, and drinking during the DID test was analyzed for drinking microstructure. Results: HDID-1 mice had more drinking bouts, shorter interbout interval, larger bout size, greater total EtOH intake, and higher BECs than HS/Npt mice on the second day of the 2-day DID test. The 4-day DID test showed greater bout size, total EtOH intake, and BEC in the HDID-1 mice than the HS/Npt mice. Total EtOH intake and BECs for the HDID-1 mice in the DID tests averaged 2.6 to 3.0 g/kg and 0.4 to 0.5 mg/ml, respectively. The 2-bottle choice test showed no genotype differences in drinking microstructure or total consumption but did show greater preference for the EtOH solution in HDID-1 mice than HS/Npt. Conclusions: These results suggest that inherent differences in EtOH drinking structure between the HDID-1 and HS/Npt mice, especially the larger bout size in the HDID-1 mice, contribute to the difference in intake during the standard DID test. © 2012 by the Research Society on Alcoholism.


Tanchuck M.A.,Oregon Health And Science University | Yoneyama N.,Oregon Health And Science University | Ford M.M.,Oregon Health And Science University | Fretwell A.M.,Portland Alcohol Research Center | And 2 more authors.
Alcohol | Year: 2011

Drinking to intoxication or binge drinking is a hallmark characteristic of alcohol abuse. Although hard to model in rodents, the scheduled high alcohol consumption (SHAC) procedure generates high, stable ethanol intake and blood ethanol concentrations in mice to levels consistent with definitions of binge drinking. The purpose of the present studies was to determine the effects of pharmacological manipulation of the opioidergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic systems on binge drinking with the SHAC procedure. Parallel manipulations were conducted in mice trained in operant self-administration of either sucrose or ethanol. For the SHAC procedure, genetically heterogeneous Withdrawal Seizure Control mice were given varying periods of fluid access, with a 30-min ethanol session every third day (total of seven). Mice were pretreated intraperitoneally with naltrexone (0, 0.6, or 1.25. mg/kg), baclofen (0, 2.5, or 5.0. mg/kg), or 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 3.0, or 10.0. mg/kg) before each ethanol session. For the operant self-administration procedure, separate groups of C57BL/6 mice were trained to complete a single response requirement (16 presses on the active lever) to gain 30. min of access to an ethanol or a sucrose solution. Mice received pretreatments of the same doses of naltrexone, MPEP, or baclofen before the self-administration sessions, with saline injections on intervening days. Naltrexone produced a dose-dependent decrease in binge drinking, and the highest dose also significantly decreased operant self-administration of ethanol and sucrose. Both doses of baclofen significantly decreased binge alcohol consumption, but the higher dose also tended to decrease water intake. The highest dose of baclofen also significantly decreased operant self-administration of sucrose. MPEP (10. mg/kg) significantly decreased binge alcohol consumption and sucrose self-administration. These results indicate that manipulation of the opioidergic, glutamatergic, and GABAergic systems significantly decreased binge drinking. © 2011 Elsevier Inc.


Barkley-Levenson A.M.,Oregon Health And Science University | Barkley-Levenson A.M.,Portland Alcohol Research Center | Crabbe J.C.,Oregon Health And Science University | Crabbe J.C.,Portland Alcohol Research Center
Alcohol | Year: 2014

Drinking to intoxication is a critical component of risky drinking behaviors in humans, such as binge drinking. Previous rodent models of alcohol consumption largely failed to demonstrate that animals were patterning drinking in such a way as to experience intoxication. Therefore, few rodent models of binge-like drinking and no specifically genetic models were available to study possible predisposing genes. The High Drinking in the Dark (HDID) selective breeding project was started to help fill this void, with HDID mice selected for reaching high blood alcohol levels in a limited access procedure. HDID mice now represent a genetic model of drinking to intoxication and can be used to help answer questions regarding predisposition toward this trait as well as potential correlated responses. They should also prove useful for the eventual development of better therapeutic strategies. © 2014 Elsevier Inc.


Strong M.N.,Oregon Health And Science University | Yoneyama N.,Oregon Health And Science University | Fretwell A.M.,Portland Alcohol Research Center | Snelling C.,Oregon Health And Science University | And 3 more authors.
Hormones and Behavior | Year: 2010

Binge drinking, defined as achieving blood ethanol concentrations (BEC) of 80 mg%, has been increasing in adolescents and was reported to predispose later physical dependence. The present experiments utilized an animal model of binge drinking to compare the effect of ethanol "binge" experience during adolescence or adulthood on subsequent ethanol intake in male and female C57BL/6 mice. Adolescent and adult mice were initially exposed to the scheduled high alcohol consumption procedure, which produces BECs that exceed the levels for binge drinking following a 30-min ethanol session every third day. Ethanol intake and BECs were significantly higher in the adolescent (~3 g/kg, 199 mg%) versus adult (~2 g/kg, 135 mg%) mice during the first three ethanol sessions, but were more equivalent during the final two ethanol sessions (1.85-2.0 g/kg, 129-143 mg%). Then, separate groups of the ethanol-experienced mice were tested with ethanol naïve adolescent and adult mice for 2-h limited access (10% and 20% solutions) or 24-h (5%, 10% and 20% solutions) ethanol preference drinking. Limited access ethanol intake was significantly higher in female versus male mice, but was not altered by age or ethanol experience. In contrast, 24-h ethanol intake was significantly higher in the adolescent versus adult mice and in female versus male mice. Furthermore, binge drinking experience in the adolescent mice significantly increased subsequent ethanol intake, primarily due to intake in female mice. Thus, adolescent binge drinking significantly increased unlimited ethanol intake during adulthood, with female mice more susceptible to this effect. © 2009 Elsevier Inc.


Iancu O.D.,Oregon Health And Science University | Oberbeck D.,Oregon Health And Science University | Darakjian P.,Oregon Health And Science University | Metten P.,Oregon Health And Science University | And 6 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2013

Background: Heterogeneous stock (HS/NPT) mice have been used to create lines selectively bred in replicate for elevated drinking in the dark (DID). Both selected lines routinely reach a blood ethanol (EtOH) concentration (BEC) of 1.00 mg/ml or greater at the end of the 4-hour period of access in Day 2. The mechanisms through which genetic differences influence DID are currently unclear. Therefore, the current study examines the transcriptome, the first stage at which genetic variability affects neurobiology. Rather than focusing solely on differential expression (DE), we also examine changes in the ways that gene transcripts collectively interact with each other, as revealed by changes in coexpression patterns. Methods: Naïve mice (N = 48/group) were genotyped using the Mouse Universal Genotyping Array, which provided 3,683 informative markers. Quantitative trait locus (QTL) analysis used a marker-by-marker strategy with the threshold for a significant logarithm of odds (LOD) set at 10.6. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene coexpression network analysis (WGCNA) were implemented largely as described elsewhere. Results: Significant QTLs for elevated BECs after DID were detected on chromosomes 4, 14, and 16; the latter 2 were associated with gene-poor regions. None of the QTLs overlapped with known QTLs for EtOH preference drinking. Ninety-four transcripts were detected as being differentially expressed in both selected lines versus HS controls; there was no overlap with known preference genes. The WGCNA revealed 2 modules as showing significant effects of both selections on intramodular connectivity. A number of genes known to be associated with EtOH phenotypes (e.g., Gabrg1, Glra2, Grik1, Npy2r, and Nts) showed significant changes in connectivity. Conclusions: We found marked and consistent effects of selection on coexpression patterns; DE changes were more modest and less concordant. The QTLs and differentially expressed genes detected here are distinct from the preference phenotype. This is consistent with behavioral data and suggests that the DID and preference phenotypes are markedly different genetically. © 2013 by the Research Society on Alcoholism.


Barkley-Levenson A.M.,Oregon Health And Science University | Barkley-Levenson A.M.,Portland Alcohol Research Center | Crabbe J.C.,Oregon Health And Science University | Crabbe J.C.,Portland Alcohol Research Center
Alcohol | Year: 2015

Alcohol use disorders and anxiety disorders are highly comorbid in humans. In rodent lines selected for alcohol drinking, differences in anxiety-like behavior are also seen. The High Drinking in the Dark (HDID) lines of mice are selectively bred for drinking to intoxication during limited access to alcohol, and these mice represent a genetic model of risk for binge-like drinking. The present studies investigated whether these selected lines differ from control (HS) mice in basal anxiety behavior or in anxiolytic response to alcohol. We also assessed the genetic correlation between alcohol drinking in the dark (DID) and basal anxiety-like behavior using existing inbred strain data. Mice of both sexes and HDID replicates (HDID-1 and HDID-2) were tested on an elevated zero maze immediately following a DID test. In general, HDID mice showed more time spent in the open arms after drinking alcohol than HS mice, and open-arm time was significantly correlated with blood alcohol concentration. HDID-1 male mice also showed less anxiety-like behavior at baseline (water-drinking controls). In a separate experiment, HDID-1 and HS mice were tested for anxiolytic dose-response to acute alcohol injections. Both genotypes showed increasing time spent in the open arms with increasing alcohol doses, and HDID-1 and female mice had greater open-arm time across all doses. HDID-1 control males showed lower anxiety-like behavior than the HS control males. Inbred strain data analysis also showed no significant genetic relationship between alcohol DID and anxiety. These findings suggest that HDID selection has not produced systematic changes in anxiety-like behavior or sensitivity to alcohol-induced anxiolysis, though there is a tendency in the male mice of the first replicate toward reduced basal anxiety-like behavior. Therefore, anxiety state and sensitivity to alcohol's anxiolytic effects do not appear to contribute significantly to the high drinking behavior of the HDID mice. © 2015 Elsevier Inc.


Tipps M.E.,Portland Alcohol Research Center | Tipps M.E.,Oregon Health And Science University | Raybuck J.D.,Oregon Health And Science University | Buck K.J.,Portland Alcohol Research Center | And 2 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2015

Background: Alcohol affects many of the brain regions and neural processes that support learning and memory, and these effects are thought to underlie, at least in part, the development of addiction. Although much work has been done regarding the effects of alcohol intoxication on learning and memory, little is known about the effects of acute withdrawal from a single alcohol exposure. Methods: We assess the effects of acute ethanol withdrawal (6 hours postinjection with 4 g/kg ethanol) on 2 forms of fear conditioning (delay and trace fear conditioning) in C57BL/6J and DBA/2J mice. The influence of a number of experimental parameters (pre- and post training withdrawal exposure; foreground/background processing; training strength; and nonassociative effects) is also investigated. Results: Acute ethanol withdrawal during training had a bidirectional effect on fear-conditioned responses, decreasing contextual responses and increasing cued responses. These effects were apparent for both trace and delay conditioning in DBA/2J mice and for trace conditioning in C57BL/6J mice; however, C57BL/6J mice were selectively resistant to the effects of acute withdrawal on delay cued responses. Conclusions: Our results show that acute withdrawal from a single, initial ethanol exposure is sufficient to alter long-term learning in mice. In addition, the differences between the strains and conditioning paradigms used suggest that specific learning processes can be differentially affected by acute withdrawal in a manner that is distinct from the reported effects of both alcohol intoxication and withdrawal following chronic alcohol exposure. Thus, our results suggest a unique effect of acute alcohol withdrawal on learning and memory processes. © 2015 by the Research Society on Alcoholism.


Barkley-Levenson A.M.,Oregon Health And Science University | Barkley-Levenson A.M.,Portland Alcohol Research Center | Cunningham C.L.,Oregon Health And Science University | Smitasin P.J.,Oregon Health And Science University | And 2 more authors.
Addiction Biology | Year: 2015

Both rewarding and aversive effects contribute to alcohol consumption. Animals genetically predisposed to be high drinkers show reduced sensitivity to the aversive effects of alcohol, and in some instances, increased sensitivity to alcohol's rewarding effects. The present studies tested the high drinking in the dark (HDID) selected lines, a genetic model of drinking to intoxication, to determine whether intake in these mice was genetically related to sensitivity to alcohol aversion or reward. Male HDID mice from the first and second replicate lines (HDID-1 and HDID-2, respectively) and mice from the heterogeneous progenitor control population (HS/Npt, or HS) were conditioned for a taste aversion to a salt solution using two doses of alcohol, and lithium chloride (LiCl) and saline controls. In separate experiments, male and female HDID-1, HDID-2 and HS mice were conditioned for place preference using alcohol. HDID mice were found to have an attenuated sensitivity to alcohol at a moderate (2g/kg) dose compared to HS mice, but did not differ on conditioned taste aversion to a high (4g/kg) dose or LiCl or saline injections. HDID and HS mice showed comparable development of alcohol-induced conditioned place preference. These results indicate that high blood alcohol levels after drinking in the HDID mice is genetically related to attenuated aversion to alcohol, while sensitivity to alcohol reward is not altered in these mice. Thus, HDID mice may find a moderate dose of alcohol to be less aversive than control mice and consequently may drink more because of this reduced aversive sensitivity. © 2013 Society for the Study of Addiction.

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