J. Neurochem. (2010) 115, 595–605. Abstract Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long‐term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH‐induced neurotoxicity, most likely as a substrate for non‐enzymatic oxidation by METH‐generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long‐term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5‐hydroxytryptophan do not change METH‐induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p‐chlorophenylalanine are without effect on METH toxicity, despite the fact that p‐chlorophenylalanine largely prevents METH‐induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild‐type controls, despite showing enhanced drug‐induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH‐induced damage to DA nerve endings of the striatum.

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