Rate-dependent drug effects: History and contemporary implications.

The present review provides a history and current significance of the rate-dependency concept describing the behavioral effects of drugs. The concept was originally formulated by P. B. Dews from observations of methamphetamine effects on behavior controlled by schedules of reinforcement. Dews suggested that the drug increased low rates and decreased high rates of responding, and subsequent studies reported an inverse linear relation between change in response rate and its rate under control conditions. Several hypotheses purported to explain rate-dependent drug effects and challenges to the interpretations of those effects are discussed. Evidence for the widespread presence of rate dependencies indicates that to make coherent experiments addressing questions involving environmental factors purportedly influencing drug effects, response rate needs to be controlled. Several examples from the literature in which different conditions are examined on a wide range of control response rates show those conditions to alter rate-dependency relations. Given those differing rate dependencies, examples are discussed of how comparisons of drug effects under different environmental conditions at a single response rate can lead to flawed conclusions. It is suggested that by examining how any environmental factor influences the behavioral effects of drugs over a wide range of control response rates leads to more powerful and generalizable findings that can better advance the field of behavioral pharmacology. SIGNIFICANCE STATEMENT: Studies of drug effects on behavior in laboratory settings often use schedules of reinforcement to maintain rates and temporal patterns of responding, with drug effects often inversely related to control response rates. Because of response-rate dependencies, unambiguous assessments of the environmental factors influencing drug effects require coincident assessments of response rates. The most powerful experiments examine the effects of those factors over a wide range of control response rates.