The objective of this project is to characterize a colony of rats which have been bred selectively and bidirectionally for the propensity to orally self-administer opioids. These lines of rats seek or avoid the high-potency opioid etonitazene (ETZ), in a situation in which it is presented continuously as a choice with water. Over generations, preferences are measured and selection pressure imposed: three lines (Preference, Aversion, and a Random control) now diverge significantly. Second litters in each generation will be produced so that these genetically selected rats may be tested for line differences in a variety of behavioral tests without the confounding effects of prior exposure to ETZ. For the lines to be useful in an investigation of the genetic bases of opioid reward, it is critical that ETZ be a positive reinforcer to the Preference line but not to the Aversion line, and that this be demonstrated by measures in addition to the extent of oral self- administration of ETZ used in the selection process. Our primary experiments to test whether the lines have been selected for this trait are 1) to measure the animals' willingness to work for ETZ in an operant situation by increasing the number of lever presses necessary to obtain ETZ, and 2) to assess the ability of ETZ to produce a conditioned place preference or aversion, as a measure of reward independent of opioid ingestion. It is also necessary to determine whether altered sensitivity to the major non-reward effects of ETZ has accompanied selection. In our primary experiments we will measure the acute dose-related effects of ETZ on catalepsy, body temperature, and analgesia. Should the primary experiments substantiate the value of the selected lines, we describe other studies which would be the topic of a renewal application, in order to present our overall research plan. By bringing the propensity to voluntarily ingest opioids under genetic control, one can address questions which are fundamental to an analysis of drug self-administration behavior. This is the only currently active selective breeding program for opioid preference, and its long-range objective is that these animals will contribute to our understanding of why only some people self-administer opioids.
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