Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses

We recently demonstrated that pretreatment with N-(2-chloroethyl)-N-ethyl-2 -bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine, The mechanism responsible for this effect remains to be el ucidated. In this study, we investigated whether the exacerbation of chroni c dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to a n increased efficacy of the effects induced by methamphetamine. We administ ered different doses of methamphetamine either to DSP-4-pretreated or to in tact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evalu ated the striatal pharmacokinetics of methamphetamine, together with its ea rly biochemical effects. We found that previous damage to norepinephrine te rminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine, By contrast, p retreatment with DSP-4 exacerbated early biochemical effects of methampheta mine, which were already detectable 1 h after methamphetamine administratio n. In addition, in norepinephrine-depleted animals, the clearance of striat al methamphetamine is prolonged, although the striatal concentration peak o bserved at 1 h is unmodified. These findings, together with the lack of a m ethamphetamine enhancement when DSP-4 was injected 12 h after methamphetami ne administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.