Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose...

A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.1-4.0 mg/kg over 14 days) attenuated the toxicity of a subsequently administered high-dose METH binge (4 x 6 mg/kg at 2 h interval) that itself produced behavioral stereotypy, increases in core temperature, and decreases in DA system phenotypic markers in caudate-putamen (CP). Using those ED-METH and binge protocols in the present studies, pharmacokinetic and pharmacodynamic parameters that may have contributed to the apparent neuroprotection afforded by ED-METH were assessed. The ED-METH regimen itself reduced [(3)H]WIN35,428 (WIN) binding to the dopamine transporter (DAT) by 15% in CP, but did not affect DA content. During the METH binge, ED-METH pretreated animals showed attenuated increases in core temperature while concurrent microdialysis studies in CP showed a reduced DA response despite unaltered extracellular levels of METH. At 1 h after the binge, concentrations of METH and its metabolite amphetamine in brain and plasma were unaffected by the ED-METH. The results show that ED-METH pretreatment produces reductions in DAT binding and the DA response during a subsequent METH binge by altering pharmacodynamic and not pharmacokinetic parameters.