Many drugs of abuse such as morphine not only produce effects that maintain drug-seeking and drug-taking behaviors (i.e., reinforcing or euphoric effects), but also initially disrupt ongoing behavior. When these drugs are chronically administered, one common effect is the development of tolerance to these disruptive behavioral effects. That is, with repeated administration, larger doses of the drug are required to produce the same effect as that of the initial administration, and the dose-effect curve is shifted to the right. The rate at which and the degree to which tolerance to these disruptive effects develops, may reflect the potential abuse liability of the drug. Also, behavioral and pharmacological variables that alter the rate of tolerance acquisition are important in development of treatment for drug abuse. Therefore, it is important to understand environmental, behavioral, and pharmacological variables that may influence the development of tolerance to disruptive effects of drugs such as morphine. The first specific aim of the current proposal is to examine the influence of the relationship between the number of responses required to produce food reinforcement and the amount of food reinforcement produced on the rate at which and the degree to which tolerance develops to morphine's response-rate decreasing effects. Under some conditions, a larger relative proportion of the daily intake will be obtained by emitting a smaller number of responses than under other conditions. The influence of pharmacological variables will be examined by determining the degree of cross-tolerance conferred to another other mu opioid, l-methadone. and a non-opioid, cocaine. The second specific aim is to examine the influence of the dependency between responding and daily food intake on the rate at which and the degree to which tolerance develops to morphine's response-rate decreasing effects. Some subjects will produce all of their daily intake within the experimental session, whereas other subjects will be fed some of their daily intake outside of the experimental session. Tolerance to the disruptive effects may develop more rapidly and to a larger degree in the subjects whose behavior is essential for the production of their food. The degree of crosstolerance conferred to an other mu opioid, l-methadone, and a non-opioid, cocaine, will be examined.
