The Effect of Methamphetamine and Sub-threshold Doses of Rotenone on Caudal Striatal Neuronal Nitric Oxide Synthas

The association of long-term methamphetamine (meth) abuse with an increased risk of Parkinson's disease (PD) later in life merits further elucidation of the neurotoxicity mechanisms of this drug. The mechanisms of meth neurotoxicity involve a complex interplay between myriad biochemical and intercellular pathways, and dopamineinduced oxidative stress. The associated excess nitric oxide (NO) synthesis in the striatum by neuronal nitric oxide synthase (n-NOS) are thought to be important in this process. However, prior studies using rodents have yielded conflicting results on the impact of meth on n-NOS levels in the striatum and it is relevant to note that most of these studies utilized high doses administered in a short-term "binge" protocol, which may not be translatable to human meth users. This study was the first to apply the paradigm of meth self-administration, along with "sub-threshold" doses of rotenone, to probe n-NOS levels in the caudal striatum (a region involved in motor symptoms of PD). Rotenone is a mitochondrial poison that was utilized in current studies to promote methinduced PD-like pathology from a subclinical to a clinical level. Contrary to the hypothesized increase, study outcomes indicated that meth exhibited no discernible impact on n-NOS levels while rotenone on its own actually decreased the level of this protein in the caudal striatum. These results imply that meth may have a ceiling effect considering that some prior studies observed similar results with high doses of meth.;The n-NOS decrease induced by rotenone is puzzling, as earlier studies have shown that higher doses of this reagent have the opposite effect on striatal n-NOS. Future studies using larger sample sizes and dose response comparisons will be necessary to definitively determine the involvement of n-NOS in the striatal effects of meth and rotenone.