Inter-injection intervals during maintained cocaine self-administration behavior in male rats is regular and increases with higher unit doses due to the longer time required for the higher cocaine concentrations to decline to the minimum maintained concentration, the satiety threshold. In addition, lever pressing behavior is induced by cocaine when it is below the satiety threshold and above the priming threshold, termed the compulsion zone. This paradigm provides a framework for the development of medications to treat cocaine use disorder. However, this paradigm has never been tested in female rats. It is a regulatory requirement to test potential medications in both males and females. Female Sprague-Dawley rats also acquired iv cocaine self-administration behavior. The inter-injection intervals were regular and increased as a function of unit dose, indicating the underlying pharmacokinetic/pharmacodynamic cocaine induced behavior in female rats is consistent with the observed self-administration behavior in male rats. However, compared to age-matched male rats the inter-injection intervals in females were shorter across all unit doses. It is not yet clear whether this is due to a higher satiety threshold, faster cocaine elimination, or both in female rats. Interestingly, there was no detectable cyclicity of inter-injection intervals over several estrous cycles, implying that the faster rate of self-administration was not related to estrous hormone levels. The compulsion zone theory applies to female rats and females should be included in pre-clinical medication screening protocols.
