Phenotypic and Genotypic Characterization of the Indiana University Rat Lines Selectively Bred for High and Low Alcohol Preference (original) (raw)
Related papers
A Quantitative Trait Locus for Alcohol Consumption in Selectively Bred Rat Lines
Alcoholism-clinical and Experimental Research, 1998
Selective breeding for high and low alcohol consumption led to the establishment of alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines that differ greatly in their alcohol consumption. These lines were inbred and F2 intercross progenies were generated to detect quantitative trait loci (QTLs) influencing alcohol consumption. A QTL on chromosome 4 was identified with a maximum lod score of 8.6. This QTL acts in an additive fashion and accounts for 11 YO of the total phenotypic variability and approximately one-third of the genetic variability. Neuropeptide Y, an endogenous anxiolytic and neuromodulator, has been mapped to this same region of chromosome 4. This study is an advance in genome analyses, demonstrating that crosses between divergent, selectively bred rat lines can be used to identify QTLs. Localization of a gene influencing alcohol consumption may have important implications for the etiology of alcohol abuse and alcoholism in humans.
The alcohol-preferring P rat and animal models of excessive alcohol drinking
Addiction Biology, 2006
The alcohol-preferring, P, rat was developed by selective breeding to study ethanol drinking behavior and its consequences. Characterization of this line indicates the P rat meets all of the criteria put forth for a valid animal model of alcoholism, and displays, relative to their alcohol-non-preferring, NP, counterparts, a number of phenotypic traits associated with alcohol abuse and alcoholism. Behaviorally, compared with NP rats, P rats are less sensitive to the sedative and aversive effects of ethanol and more sensitive to the stimulatory effects of ethanol. Neurochemically, research with the P line indicates the endogenous dopaminergic, serotonergic, GABAergic, opiodergic, and peptidergic systems may be involved in a predisposition for alcohol abuse and alcoholism. Paralleling the clinical literature, genetically selected P rats display levels of ethanol intake during adolescence comparable to that seen during adulthood. Binge drinking has been associated with an increased risk for health and other problems associated with ethanol abuse. A model of binge-like drinking during the dark cycle indicates that P rats will consume 6 g/kg/day of ethanol in as little as three 1-hour access periods/day, which approximates the 24-hour intake of P rats with free-choice access to a single concentration of ethanol. The alcohol deprivation effect (ADE) is a transient increase in ethanol intake above baseline values upon re-exposure to ethanol access after an extended period of deprivation. The ADE has been proposed to be an animal model of relapse behavior, with the adult P rat displaying a robust ADE after prolonged abstinence. Overall, these findings indicate that the P rat can be effectively used in models assessing alcohol-preference, a genetic predisposition for alcohol abuse and/or alcoholism, and excessive drinking using protocols of binge-like or relapse-like drinking.
Behavioural Features of Alcohol-Preferring Rats: Focus on Inbred Strains
Alcohol and Alcoholism, 1999
A recent study conducted a factor analysis on 18 behavioural measures obtained from four alcohol-preferring and five alcohol-non-preferring rat lines/strains. It was concluded that variables such as saccharin intake, ultrasonic vocalizations following an air puff, and defaecation in an open field were associated with voluntary and forced alcohol consumption. In contrast, measures such as time immobile in the forced swim test and time spent in the open arms of the elevated plus maze were not consistently associated with voluntary alcohol intake. The present study focuses on alcohol intake and related measures in four inbred strains of Fawn-Hooded (FH) rats that differ in voluntary alcohol intake and the ACI/N inbred rat strain, which voluntarily consumes very little alcohol. FH rats inbred by Jean Dodds (FH/Wjd) drank significantly more alcohol than FH rats inbred by Gordon Harrington (FH/Har) or selectively inbred by Abraham Provoost (FHH/Eur and FHL/EUR). In contrast, only the FH/Har strain was active in the forced swim test, suggesting that immobility and voluntary alcohol intake may be influenced by different genetic factors. The FH/Wjd rats were also much more immobile than the ACI/N rats in the forced swim test and drank almost 10 times as much alcohol voluntarily. Comparing the two parental lines with reciprocal F1 crosses revealed that alcohol consumption was influenced largely by additive genetic factors (F1 progeny had intermediate scores), whereas immobility was also influenced by dominance genetic factors (F1 progeny resembled the FH/Wjd parent). Preliminary analysis of 43 F2 progeny indicated that alcohol intake and immobility were not correlated. Thus, immobility in the forced swim test and high voluntary consumption of alcohol, two prominent features of the FH/Wjd rat strain which may be related to its serotonergic dysfunction, appear to be mediated by different genetic factors.
Ontogeny of ethanol intake in alcohol preferring (P) and alcohol nonpreferring (NP) rats
Developmental Psychobiology, 2011
There is a scarcity of research on ethanol affinity in alcohol-preferring (P) rats before weaning and it is unknown if neonate P rats exhibit ethanol intake preferences comparable to those observed in adult P rats. This study examined ethanol intake in alcohol-preferring and non-preferring (NP) rats 3 hours after birth (Experiment 1, surrogate nipple test), at postnatal days (PD) 8, 12 and 18 (Experiment 2, consumption off the floor procedure) and at adolescence (Experiment 3, two-bottle choice test at PD32). The high-preference genotype was readily expressed three hours after birth. P neonates drank twice as much ethanol as their NP counterparts. This heightened ethanol preference transiently reversed at P8, reemerged as weaning approached (P18) and was fully expressed during adolescence. These results help clarify the ontogeny of genetic predisposition for ethanol. Genetic predisposition for higher ethanol intake in P than in NP rats seems to be present immediately following birth.
Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines
Mammalian Genome, 1998
Selective breeding for voluntary alcohol consumption was utilized to establish the alcohol-preferring (P) and alcoholnonpreferring (NP) rat lines. Inbreeding was initiated after 30 generations of selection and, after 19 generations of inbreeding, 384 F 2 intercross progeny were created to identify quantitative trait loci (QTLs) influencing alcohol consumption. We had reported previously a QTL on Chromosome (Chr) 4; additional markers genotyped on Chr 4 have increased the maximum lod score from 8.6 to 9.2. This QTL acts in an additive fashion and continues to account for approximately 11% of the phenotypic variability. The 95% confidence interval is 12.5 cM and includes the candidate gene, neuropeptide Y. Subsequent to the identification of the QTL on Chr 4, a genome scan was completed to identify additional QTLs influencing alcohol consumption. A lod score of 2.5 was obtained on Chr 3, syntenic to a region previously reported for alcohol preference in mice. Analysis of Chr 8 produced a lod score of 2.2 near the dopamine D2 and serotonin 1b receptors, which have been previously reported as candidate genes for alcohol preference. Evidence for linkage to alcohol consumption was not found on any other chromosome. It therefore appears likely that, in addition to the QTL on Chr 4, multiple loci of small to moderate effect, such as those on Chrs 3 and 8, underlie the difference in alcohol consumption in the P/NP lines.
A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction
International Review of Neurobiology, 2016
The purpose of this review is to present up-to-date pharmacological, genetic and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this paper discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general.
A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction HHS Public Access
The purpose of this review is to present up-to-date pharmacological, genetic and behavioral findings from the alcohol-preferring P rat and summarize similar past work. Behaviorally, the focus will be on how the P rat meets criteria put forth for a valid animal model of alcoholism with a highlight on its use as an animal model of polysubstance abuse, including alcohol, nicotine and psychostimulants. Pharmacologically and genetically, the focus will be on the neurotransmitter and neuropeptide systems that have received the most attention: cholinergic, dopaminergic, GABAergic, glutamatergic, serotonergic, noradrenergic, corticotrophin releasing hormone, opioid, and neuropeptide Y. Herein we sought to place the P rat's behavioral and neurochemical phenotypes, and to some extent its genotype, in the context of the clinical literature. After reviewing the findings thus far, this paper discusses future directions for expanding the use of this genetic animal model of alcoholism to identify molecular targets for treating drug addiction in general.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence.