Human Methamphetamine Pharmacokinetics Simulated in the Rat: Single Daily Intravenous Administration Reveals Elements of Sensitization and Tolerance

Abstract

We developed a computer-controlled intravenous methamphetamine (METH) administration procedure (dynamic infusion), which enables us to compensate for an important pharmacokinetic difference between rats and humans by imposing a 12-h half-life for the drug in rats. Dynamic infusion of 0.5 mg/kg METH produced a pharmacokinetic profile that closely simulates the METH exposure pattern in humans, including an apparent half-life of 11.6+/-1.3 h, and an area under the concentration vs time curve of 9.4 microM h, about 20-fold larger than results obtained with typical rat pharmacokinetics. Using this procedure, METH produced a prolonged behavioral stimulation and elevation in caudate extracellular dopamine (DA). Both the behavioral and the DA effects exhibited tolerance to the sustained plasma METH exposure. Single daily dynamic infusion of 0.5 mg/kg METH for 15 days resulted in a progressive enhancement of the behavioral response until about Day 10. On subsequent days, in addition to continued evidence of sensitization, tolerance in the form of a marked decrease in the duration of the behavioral activation became a prominent feature of the response. Qualitative changes in the behavior also emerged. Resumption of METH treatment following 4 days of withdrawal revealed that sensitization was apparent during the first dynamic infusion, and that tolerance re-emerged within two additional days of drug administration. These results showed that a human-like METH exposure pattern produced behavioral and striatal DA response profiles that are both quantitatively and qualitatively different from the effects typically observed with single daily METH injections in rats. Thus, simulation of human METH exposure patterns may be a critical prerequisite to identifying mechanisms relevant to the chronic use of this drug in humans.