What Aspects of Human Alcohol Use Disorders Can Be Modeled Using Selectively Bred Rat Lines?

Abstract

The use of selective breeding to produce animal models for the study of alcohol abuse and alcoholism represents one of the major advances in the field of alcohol research. Rats selectively bred for alcohol preference and alcohol nonpreference have been useful to both preclinical and clinical investigators in the alcohol research community for studying the behavioral, neurobiological, and molecular basis of alcohol drinking, for identifying the genes that may contribute to the development of alcohol abuse and alcoholism, and for evaluating the utility of drugs aimed at reducing alcohol intake and preventing alcohol relapse. Rats selectively bred for alcohol preference (alcohol preferring or "P" line) have enhanced responsiveness to the low dose reinforcing effects of alcohol, less aversion to moderate/high doses of alcohol, and are able to develop tolerance to the aversive effects of alcohol more rapidly and to maintain tolerance longer than rats selectively bred for alcohol nonpreference (alcohol nonpreferring or "NP" line). The increased potency of low-dose alcohol as a reinforcer for P rats might be expected to foster and maintain alcohol drinking. Weaker aversion to the pharmacological effects of moderate/high doses of alcohol in the P line would allow P rats to drink more alcohol than NP rats before the postingestional effects become aversive. Rapid induction of tolerance to the aversive effects of alcohol with repeated bouts of voluntary alcohol drinking, as well as persistence of alcohol tolerance in rats of the P line might serve to maintain alcohol drinking. These are powerful mechanisms that may serve to promote and maintain a high alcohol drinking behavior. Although these rat lines have been used to address several characteristics of excessive alcohol consumption in humans, they have not yet been used to model several aspects of human alcohol use disorders. New applications of these selectively bred rat lines are discussed which may further our understanding of the factors contributing to alcohol abuse and alcoholism.

Combining Naltrexone and Prazosin in a Single Oral Medication Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone

“…Rats selected for breeding in the NP line were those that consumed less than 1.5 g alcohol/kg BW/day and did not exceed an alcohol to water preference ration of 0.2:1.0. Rats of the P line have been extensively characterized both behaviorally and physiologically (Froehlich, 2010; Froehlich and Li, 1991; Li et al, 1988; 1993) and have been found to meet all of the criteria of an animal model of alcoholism (Cicero, 1979). P rats are selectively bred in the Indiana University Alcohol Research Resource Center using “intensive selection” where they are tested for alcohol preference in every generation or using “relaxed selection” where they are tested for alcohol preference every 3-4 generations.…”

Rodent models of alcoholic liver disease: Of mice and men

“…While intragastric models bypass the natural aversion that rodents exhibit toward alcohol consumption, questions remain as to whether LDLD or enteral feeding regimes that provide alcohol within a single liquid food source adequately mimic human consumption with the inherent changes in dietary intake. Another means developed to overcome resistance to alcohol feeding has evolved from the selective breeding of rodents that demonstrate a preference for alcohol (Froehlich, 2010; Li et al, 1993; Li et al, 1979). In this model, selective breeding was started from a foundation stock of Wistar rats, and lines were generated to exhibit a (relatively) high or low preference for alcohol (Li et al, 1979).…”

Effects of Prazosin, an α1‐Adrenergic Receptor Antagonist, on the Seeking and Intake of Alcohol and Sucrose in Alcohol‐Preferring (P) Rats

“…P rats consume more than 5 g/kg/day of alcohol and achieve pharmacologically relevant blood ethanol concentrations through voluntary drinking (Li et al, 1987). Additionally, P rats meet all of the criteria for an animal model of alcoholism and exhibit many alcohol drinking patterns seen in humans genetically predisposed toward developing alcoholism such as binge drinking, relapse drinking, and adolescent drinking (for review see Froehlich, 2010). Interestingly, evidence also suggests that animal models genetically bred for high alcohol consumption may exhibit a down-regulation of norepinephrine transporters in the locus coeruleus (Murphy et al, 2002), a brain region involved in the stress response and a major site of CNS norepinephrine synthesis.…”