Activation of an apomorphine behavior pattern by cocaine: a new behavioral test for drug substitution

In current tests for drug substitution using the 2-choice operant bar press paradigm, an animal can be trained to respond differentially between an interoceptive drug state stimulus vs. saline. Despite the long history and extensive number of investigations, the interpretation of such test results, nevertheless, is limited by number of potential sources of stimulus drug effects which can occur with repeated drug administration but which cannot be distinguished by this paradigm: (1) local effects at the injection site; (2) peripheral effects; (3) central activity effects; and/or (4) sensory-motor dysfunctional effects. By using a video-image analysis of behavior in an intact animal model and a pavlovian drug treatment protocol, new, spontaneous but environmentally contingent and stable behavior patterns emerge selectively in the paired treatment group with repeated drug administration which can be used as a behavioral marker to assess dose-response effects and drug substitution test results with a novel drug. A study with repeated administration of the DA agonist apomorphine and with a drug substitution assessment by a cocaine drug test is presented as a reference example to illustrate the new response-based methodological approach to the study of central mechanisms mediating the stimulus and response effects of drugs. Additionally, the observed efficacy of cocaine to activate a complex acquired behavioral pattern unique to repeated apomorphine treatment supports a critical role for dopaminergic mechanisms in the mediation of cocaine induced stereotypy.