Acute and chronic continuous methamphetamine have different long-term behavioral and neurochemical consequences

We compared two different methamphetamine dosing regimens and found distinct long-term behavioral and neurochemical changes. Adult rats were treated with 1-day methamphetamine injection (3x5 mg/kg s.c., 3 h apart) or 7-day methamphetamine minipump (20 mg/kg/day s.c.). The minipump regimen models the sustained methamphetamine plasma levels in some human bingers whereas the 1-day regimen models a naive user overdose. On withdrawal days 7 and 28, rats were acutely challenged with cocaine to test for behavioral sensitization and subsequently sacrificed for caudate and accumbens dopamine tissue content. Other rats were analyzed on withdrawal days 3, 7 or 28 using voltammetry in caudate slices. On withdrawal days 7 and 28, the methamphetamine injection but not the minipump rats showed behavioral cross-sensitization to cocaine. There was no change in baseline dopamine release, reuptake or sensitivity to quinpirole in any treatment group on either withdrawal day. However, consistent with the behavioral sensitization, cocaine had a greater effect in potentiating dopamine release and in blocking dopamine reuptake in methamphetamine injection versus saline irrespective of withdrawal day. The minipump group showed tolerance to the dopamine releasing effect of cocaine on withdrawal day 28 and had lower dopamine tissue content in the caudate versus the methamphetamine injection group. Dopamine turnover as measured by the DOPAC/dopamine ratio tended to be higher in the minipump-treated rats. These data suggest that the behavioral cross-sensitization seen in the methamphetamine injection rats could be in part due to the increased potency of cocaine in blocking dopamine reuptake and in increasing dopamine release. The decreased potency of cocaine in the caudate slices from the minipump-treated group may be related to decreased dopamine tissue content.