SCHOOL OF MEDICINE

Department of Medicine

Indiana Alcohol Research Center

Animal Production Core


 
  • Rats available from the Indiana University Alcohol Research Center (IARC):
     
    • Selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats

    • Selectively bred high alcohol-drinking (HAD-1) and low alcohol-drinking (LAD-1) rats

    • Selectively bred high alcohol-drinking (HAD-2) and low alcohol-drinking (LAD-2) rats

    • N/NIH stock rats, which served as the progenitors of the HAD-1/LAD-1 and HAD-2/LAD-2 replicate rat lines

    • Inbred P (iP10A) and inbred NP (iNPXX)
       
  • Mice available from the Indiana University Alcohol Research Center (IARC):
     
    • Selectively bred high alcohol-preferring (HAP-1) mice

    • Selectively bred high alcohol-preferring (HAP-2) and low alcohol-preferring (LAP-2) mice

    • Selectively bred high alcohol-preferring (HAP-3) and low alcohol-preferring (LAP-3) mice

    • Cross between HAP-1 and HAP-2 (cHAP) mice
       
  • Process for obtaining rats from the Indiana University Alcohol Research Center (IARC):
     
    • Please e-mail iarc@iupui.edu.

    • Please note that the process of obtaining rats from our selective breeding and inbred rat colonies takes a substantial amount of time. After steps (c)(i) through (c)(iv) (below) have been completed, breeders have to be reserved to fill your request, these breeders must be mated, there is a subsequent 3 week gestation and 3 week weaning period, and we try to ship 3 weeks after this when the rats have reached 42 days old. In total, it may take 75 to 90 days after all of the paperwork and logistics have been established before you receive the rats.

      In addition, please keep in mind that air freight carriers have a moratorium on live animal shipments during extreme temperatures of the winter and summer months.

    • To process a request for Indiana high and/or low alcohol-consuming rats:
      • We will need you to provide a brief summary statement of your specific aims. This will be evaluated by Investigators associated with the IARC to prevent unnecessary duplication of research with the P/NP and HAD/LAD lines of rats. If there are similarities between your proposed research and ongoing research, then dialogue between yourself and the investigators carrying out the ongoing research will be initiated. Every effort is made to accommodate all parties, and we have never had to turn down a request for this reason. Therefore, in the vast majority of cases, it is essentially a formality for our records. We cannot proceed with processing the Memorandum of Understanding, below, until the specific aims have been evaluated by the IARC review board.

      • We will need you, or whoever has clearance on your Institution's IACUC for this study, to fill out and sign a rat request Memorandum of Understanding and return this to us as a .PDF attachment. We cannot proceed with communicating vivarium health reports, below, to your vivarium veterinarian/administrator until we receive your signed Memorandum of understanding.

      • We will need you to have your Institution or vivarium attending veterinarian request vivarium health reports. We cannot proceed with the business details, below, until communication has been established between your vivarium's attending veterinarian and our breeding colony's administrator and veterinarian, and the latter individuals have given our breeding colony administrator the approval to ship rats.

      • We will need you to have your business office complete a Billing Information Form. We cannot ship rats until we have received the requested billing information.

      • Please note 3(a), above, regarding a timeline for receiving your rats.
         
  • Background information:
     
    • Use of animal models — Animal models have been successfully used in developing treatments for a number of medical and psychiatric disorders. An animal model has the advantage of allowing the experimenter to control factors such as the animal's genetic background, environmental factors and prior drug exposure. In addition, an animal model allows for the examination of neurobehavioral, neurochemical and neurophysiological correlates with the behavioral, physiological or neurological state that is modeled, which cannot be systematically examined in humans. These correlates, in turn, can facilitate the development of pharmacological and/or behavioral treatments for the disorder in question.

    • Genetics of alcoholism — The observation that people with very similar environmental backgrounds often differ considerably in ethanol consumption and the well-documented familial incidence of alcoholism indicate that heredity contributes to excessive ethanol consumption in some individuals. Similarly, it is clear that outbred rats exhibit a wide-range of ethanol-consumption levels, and, as with humans, the propensity to ingest ethanol is genetically influenced. In the late 1940's, a genetic influence on ethanol self-administration by rodents was proposed. This was followed by reports that C57BL substrains of inbred mice display high ethanol-preference, while DBA/2 inbred mice display low ethanol-preference (aversion). However, it has been argued that inbred strains are not the best models to examine "correlated traits and responses." This is because inbreeding results in fortuitous (chance) fixation of genes associated with the phenotype being examined. It was recognized that selective bi-directional breeding, for ethanol preference versus nonpreference, should provide a more powerful research tool for examining factors affecting excessive ethanol intake.

    • Criteria for an animal model of alcoholism — Certain criteria for a valid animal model of alcoholism have been put forth. Briefly, these criteria are as follows: (1) the animal should orally self-administer ethanol; (2) the amount of ethanol consumed should result in pharmacologically relevant blood ethanol levels; (3) ethanol should be consumed for its post-ingestive pharmacological effects, and not strictly for its caloric value or taste; (4) ethanol should be positively reinforcing, in other words, the animals must be willing to work for ethanol; (5) chronic ethanol consumption should lead to the expression of metabolic and functional tolerance; (6) chronic consumption of ethanol leads to dependence, as indicated by withdrawal symptoms after access to ethanol is terminated; and (7) an animal model of alcoholism should display characteristics associated with relapse, with a loss of controlled intake displayed when access to alcohol is reinstated following a period of alcohol abstinence/deprivation. This is generally modeled by an alcohol deprivation effect (ADE), which is a transient increase in ethanol consumption and/or preference over basal levels (average intake just prior to the deprivation interval) displayed by animals when given free-choice access to ethanol after a period of ethanol deprivation.

    • Criterion used for the selection of P vs. NP and HAD vs. LAD lines of rats — Bi-directional selection is accomplished through systematic mating of nonsiblings from the same extreme of the normal distribution over successive generations to obtain divergent lines that exhibit the extremes of ethanol preference—this results in selectively bred lines that display high (P and HAD) or low (NP and LAD) ethanol-drinking phenotypes based solely on selection history. The P and NP lines of rats were developed by mass selection from a Wistar foundational stock, in a closed colony, at Walter Reed Army Institute of Research and later transferred to Indiana University School of Medicine in Indianapolis, Indiana, USA. The general selection criteria have been that P rats, when given free access to food, water and a 10% (v/v) ethanol solution, should consume at least 5.0 g of ethanol/kg body weight/day with an ethanol to water ratio of at least 2:1, while NP rats should drink less than 1.5 g/kg/day with an ethanol to water ratio of less than 0.5:1. The HAD and LAD replicate lines were developed using a rotational breeding program (to limit the inbreeding coefficient) using N/NIH [The N/NIH heterogeneous stock was developed by crossing eight-inbred rat strains i.e., ACI, BN, BUF, F344, M520, MR, WKY and WN] rats from the National Institutes of Health at the Indiana University School of Medicine in Indianapolis, Indiana, USA. The general selection criteria (which are the same as those used in the P vs. NP selection) have been that HAD-1 and HAD-2 rats, when given free access to food, water and a 10% (v/v) ethanol solution, should consume at least 5.0 g of ethanol/kg body weight/day with an ethanol to water ratio of at least 2:1, while LAD-1 and LAD-2 rats should drink less than 1.5 g/kg/day with an ethanol to water ratio of less than 0.5:1. The HAD and LAD lines were selectively bred as replicates (i.e., with different parents in two different colonies), because a genotypic or phenotypic trait that is present in both replicate lines would convey greater confidence in the importance of that trait for the development of high or low alcohol drinking behavior than if the trait is identified in only one of the lines.

    • The alcohol-preferring (P) rat as an animal model of alcoholism — P rats drink greater than 5 g of ethanol/kg body weight/day; whereas NP rats will drink less than 1 g of ethanol/kg/day under these same conditions. P rats attain pharmacologically relevant blood alcohol concentrations (BACs, 50 to 200 mg%) under 24-hr and limited access conditions. P rats self-administer ethanol for its post-ingestive effects, as indicated by the self-administration of ethanol both intragastrically and directly into the ventral tegmental area (VTA). P rats will perform an operant response for access to ethanol, indicating P rats will work for access to ethanol and ethanol functions as a reinforcer. Whereas ethanol-naïve P and NP rats display similar levels of ethanol clearance, P rats, given chronic free-choice access to ethanol, drink sufficient amounts to develop metabolic tolerance and tolerance to the motor impairing/ataxic as well as aversive effects of ethanol. Furthermore, P rats develop dependence with 24-hr free-choice drinking, as indicated by physical signs upon ethanol withdrawal. Regarding relapse-like behavior, P rats will display an alcohol deprivation effect (ADE) after extended periods (2 to 8 weeks) of deprivation. Overall, the data indicate that the P line satisfies the criteria proposed for an animal model of alcoholism.

    • The high alcohol-drinking (HAD) rat as an animal model of alcoholism — HAD-1 and HAD-2 rats drink greater than 5 g of ethanol/kg body weight/day, whereas LAD-1 and LAD-2 rats drink less than 1.0 g of ethanol/kg/day. HAD rats attain pharmacologically relevant blood alcohol concentrations (BACs, 50 to 150 mg%) under 24-hr and limited access conditions. HAD-1 and HAD-2 rats will perform an operant response for access to ethanol indicating ethanol functions as a reinforcer for these rats. HAD-1 and HAD-2 rats, with access to a single concentration, will display an alcohol deprivation effect (ADE) but only after repeated cycles of deprivation, which is potentiated by access to multiple concentrations of ethanol. Overall, these findings indicate that the HAD lines satisfy most of the criteria proposed for an animal model of alcoholism. However, the HAD lines have not been characterized for the development and expression of tolerance and/or dependence following chronic free-choice drinking of ethanol.