Role of dose interval in the acquisition of tolerance to methylphenidate

Two experiments were performed to test the role of dose interval in the development of tolerance to methylphenidate. Rats were trained to consume sweetened milk and then were given methylphenidate in a dose that decreased milk intake by approx. 50%. For the next 23 sessions they received either saline; methylphenidate daily, immediately post-session; or pre-session methylphenidate, either daily, every-other-day, or every-four-days. The next session, all groups received methylphenidate pre-session. The 3 groups treated on a chronic basis with methylphenidate pre-session returned to baseline levels of milk intake and differed significantly from the daily saline and daily post-session methylphenidate groups, which did not become tolerant. In a second experiment, rats injected presession daily or every fourth day with 15mg/kg methylphenidate developed tolerance to the disruption of milk consumption. As compared to rats treated chronically with saline, the 2 groups given methylphenidate showed a shift of their dose-effect curves to the right and cross-tolerance to d-amphetamine. These results demonstrate that tolerance can occur to the disruptive effects of amphetamine-type drugs even when three drug-free days intervene between administrations. This tolerance is characterized by a shift in the dose-effect curve as well as cross-tolerance to a drug with similar pharmacological properties.