Persistence of tolerance to effects of cocaine on schedule-controlled behavior in pigeons.

Keypecking by seven pigeons, maintained by a fixed-ratio 30 schedule of food presentation, was decreased in rate by acute pre-session administration of cocaine. In Part 1 (four pigeons), tolerance to the rate-suppressing effects of cocaine developed during daily administration conditions. Tolerance persisted (1) when daily cocaine injections were replaced by conditions in which cocaine was administered every other day, then every fourth day, then every eighth day, then every 16th day, with all intervening sessions preceded by saline injections and (2) when daily cocaine administration was replaced abruptly by a condition in which cocaine injections were spaced 16 days apart, with all intervening sessions preceded by saline. In Part 2 (three pigeons), tolerance developed during intermittent administration conditions (e.g. cocaine injected every eighth day) for two subjects, and during daily administration for the third subject. As in Part 1, tolerance persisted when cocaine was administered only once every 16 days. These results are consistent with an interpretation of tolerance based upon operant compensatory reactions to drug-induced behavioral disruptions and suggest that a simple associationist model of tolerance to cocaine-induced response-rate suppression may be inadequate. The data also have practical implications regarding tolerance development during intermittent administration conditions similar to conventional acute dose-effect determination procedures.