Neurotoxic methamphetamine regimens produce long‐lasting changes in striatal G‐proteins

Animals repeatedly dosed with methamphetamine during a single day suffer damage to brain dopamine and serotonin terminals and show behavioral deficits. These methamphetamine regimens also produce long‐term reductions in dopamine agonist‐stimulated immediate‐early gene responses both in striatum and several cortical areas, but the mechanism(s) underlying these long‐lasting effects of methamphetamine remain uncertain. Six weeks after a neurotoxic regimen of methamphetamine (4 × 4 mg/kg) or saline, α subunit levels of striatal G‐proteins that couple dopamine receptors to second messenger systems were measured. Because the damage to striatal monoamine terminals produced by methamphetamine is regionally heterogeneous, we used radioimmunocytochemistry, which combines quantification with regional resolution. We found significant increases in G_iα and G_olfα expression in the ventral striatum (but not in the dorsolateral striatum or nucleus accumbens) of methamphetamine‐pretreated rats, a regional pattern similar to that reported for methamphetamine effects on dopamine terminal markers. By contrast, G_qα expression was unaffected in all striatal subregions. The central roles of G_i and G_olf in modulating the activity of a series of interlinked intracellular signaling pathways suggest that methamphetamine‐induced changes in G_i and G_olf can have lasting effects on striatal neuronal function. Synapse 64:839–844, 2010. © 2010 Wiley‐Liss, Inc.