Methamphetamine (METH) is a highly addictive
CNS stimulant that its long-term use is associated with the loss of neurons in substantia nigra and development of
Parkinson's disease later in life. Common form of METH is Ya-Ba
tablet, in which, large portion of
caffeine is added to the mass to enhance the stimulatory effect. Previous study demonstrated that
caffeine potentiates the toxic effect of METH in association with the production of
reactive oxygen species and the induction of apoptosis. Since METH causes induction of autophagy, the question was raised whether this pathway participates in the potentiating effect of
caffeine on METH neurotoxicity. We used SH-SY5Y, a
neuroblastoma cell line, as an in vitro model to study the effect of METH and
caffeine. Co-treatment of non-toxic concentrations of METH, at 0.5 mM, and
caffeine, at 1 mM, caused reduction of the cell viability. Reduction of the cell viability was associated with attenuation of autophagy, demonstrated by reduction of LC3-II levels and the number of autophagosome puncta, together with increase of
caspase-3 activation. Similar effect was produced by treatment with autophagy inhibitors, 3-MA and wortmanin. Our results suggested that
caffeine potentiates METH toxicity through inhibition of autophagy and that autophagy serves as a protective mechanism. In conclusion, we proposed the augmented hazard associated with
caffeine and METH combination in Ya-Ba abusers.