Evidence against an essential role of endogenous brain dopamine in methamphetamine-induced dopaminergic neurotoxicity

The present studies examined the role of endogenous dopamine (DA) in metham phetamine (METH)-induced dopaminergic neurotoxicity while controlling for t emperature-related neuroprotective effects of the test compounds, reserpine and alpha -methyl-p-tyrosine (AMPT). To determine if the vesicular pool of DA was essential for the expression of METH-induced DA neurotoxicity, rese rpine (3 mg/kg, given iintraperitoneally 24-26 h prior to METH) was given p rior to a toxic dose regimen of METH. Despite severe striatal DA deficits d uring the period of METH exposure, mice treated with reserpine prior to MET H developed long-term reductions in striatal DA axonal markers, suggesting that vesicular DA stores were not crucial for the development of METH neuro toxicity, but leaving open the possibility that cytoplasmic DA might be inv olved. To evaluate this possibility, cytoplasmic DA stores were depleted wi th AMPT prior to METH administration. When this study was carried out at 28 degreesC, complete neuroprotection was observed, likely due to lingering e ffects on core temperature because when the same study was repeated at 33 d egreesC (to eliminate AMPT's hypothermic effect in METH-treated animals), t he previously observed neuroprotection was no longer evident. In the third and final set of experiments, mice were pretreated with a combination of re serpine and AMPT, to deplete both vesicular and cytoplasmic DA pools, and t o reduce striatal DA levels to negligible values during the period of METH administration (< 0.05%). When core temperature differences were eliminated by raising ambient temperature, METH-induced DA neurotoxic changes were ev ident in mice pretreated with reserpine and AMPT. Collectively, these findi ngs bring into question the view that endogenous DA plays an essential role in METH-induced DA neurotoxicity.