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Portland, OR, United States

Ford M.M.,University of Oregon | Nickel J.D.,University of Oregon | Kaufman M.N.,University of Oregon | Finn D.A.,University of Oregon | Finn D.A.,Portland Alcohol Research Center
Behavior Genetics | Year: 2015

The neuroactive steroid allopregnanolone (ALLO) is a positive modulator of GABAA receptors, and manipulation of neuroactive steroid levels via injection of ALLO or the 5α-reductase inhibitor finasteride alters ethanol self-administration patterns in male, but not female, mice. The Srd5a1 gene encodes the enzyme 5α-reductase-1, which is required for the synthesis of ALLO. The current studies investigated the influence of Srd5a1 deletion on voluntary ethanol consumption in male and female wildtype (WT) and knockout (KO) mice. Under a continuous access condition, 6 and 10 % ethanol intake was significantly greater in KO versus WT females, but significantly lower in KO versus WT males. In 2-h limited access sessions, Srd5a1 deletion retarded acquisition of 10 % ethanol intake in female mice, but facilitated it in males, versus respective WT mice. The present findings demonstrate that the Srd5a1 gene modulates ethanol consumption in a sex-dependent manner that is also contingent upon ethanol access condition and concentration. © 2014, Springer Science+Business Media New York.

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
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.

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
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.

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