“…Multiple injections are administered within a day, typically at 2-h intervals, to simulate the prolonged elevation of drug associated with binge-pattern administration in humans. Although several variations in this procedure have been studied, most researchers have reported a 'neurotoxic' profile which, especially at the higher doses, includes regionally specific damage to DA terminals as well as profound, although less persistent, changes in other neurotransmitter systems (Seiden and Ricaurte, 1987;Eisch et al, 1992;Axt et al, 1994;Bowyer and Holson, 1995;Pu and Vorhees, 1995;Cass, 1997;Fleckenstein et al, 2000;O'Callaghan and Miller, 2000). The mechanisms underlying these changes have received considerable attention, with many studies suggesting important roles for temperature and accumulation of reactive oxidative species, as well as other factors, in the cascade of changes that appear to result from this high-dose 'binge' protocol (Farfel and Seiden, 1994;Seiden and Sabol, 1995;Stephans and Yamamoto, 1996;Wrona et al, 1997;Xie et al, 2000;Davidson et al, 2001;Yuan et al, 2001;Larsen et al, 2002).…”