Pre-clinical research from our laboratory suggests that LOB or its synthetic derivatives have potential as effective pharmacotherapies for METH abuse. Our previous research indicates that LOB reduces DA available for reverse transport by DAT, by redistribution of DA storage via a direct interaction at VMAT2. However, much of this research has focused on the acute in vivo presentation of LOB or in vitro assessment of the effects of LOB in rats that were never exposed to METH. Given the significant changes in DA neuron functioning with repeated METH treatment and the induction of drug craving, it is important to assess the effectiveness of LOB at VMAT2 and DAT in METH-sensitized animals. The present research will determine whether, contrasted to saline-treated animals, repeated METH administration alters LOB-induced DA utilization in vitro as indicated by an increase in DA and dihydroxyphenylacetic acid (DOPAC) overflow from superfused striatal slices. Concentrations of LOB that do not inherently increase DA or DOPAC overflow will then be used to determine whether LOB inhibits METH-evoked DA overflow from striatal slices from repeated METH and saline chronically pretreated rats. To ascertain potential repeated METH-induced alterations in LOB action, effects of LOB on VMAT2 and DAT following repeated METH administration will be determined. Thus, these repeated METH pre-exposure studies will provide the necessary basis for LOB to be considered as a novel therapeutic agent for the treatment of METH abuse.
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