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1570082 
Journal Article 
The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum 
Thomas, DM; Perez, MA; Francescutti-Verbeem, DM; Shah, MM; Kuhn, DM 
2010 
Yes 
Journal of Neurochemistry
ISSN: 0022-3042
EISSN: 1471-4159 
115 
3 
595-605 
20722968 
WOS:000282979400005 
P>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. 
5HTP; dopamine; methamphetamine; neurotoxicity; PCPA; serotonin; TPH2