As complexities of addictive behaviors cannot be fully captured in laboratory studies, scientists use simple addiction‐associated phenotypes and measure them in laboratory animals. Locomotor sensitization, characterized by an increased behavioral response to the same dose of the drug, has been extensively used to elucidate the genetic basis and molecular mechanisms of neuronal plasticity. However, to what extent it contributes to the development of addiction is not completely clear. We tested if the development of locomotor sensitization to methamphetamine affects voluntary self‐administration, and vice versa, in order to investigate how two drug‐associated phenotypes influence one another. In our study, we used the genetically tractable model organism, Drosophila melanogaster, and quantified locomotor sensitization and voluntary self‐administration to methamphetamine using behavioral tests that were developed and adapted in our laboratory. We show that flies express robust locomotor sensitization to the second dose of volatilized methamphetamine, which significantly lowers preferential self‐administration of methamphetamine. Naive flies preferentially self‐administer food with methamphetamine over plain food. Exposing flies to volatilized methamphetamine after voluntary self‐administration abolishes locomotor sensitization. We tested period null (per01) mutant flies and showed that they do not develop locomotor sensitization, nor do they show preferential self‐administration of methamphetamine. Our results suggest that there may be partially overlapping neural circuitry that regulates the expression of locomotor sensitization and preferential self‐administration to methamphetamine and that this circuitry requires a functional per gene.

Non-enzymatic glycation and covalent modification of proteins leads to Advanced Glycation End products (AGEs). AGEs are biomarkers of aging and neurodegenerative disease, and can be induced by impaired neuronal signaling. The objective of this study was to investigate if manipulation of dopamine (DA) in vitro using the model protein, bovine serum albumin (BSA), and in vivo using the model organism Drosophila melanogaster, influences fluorescent AGEs (fAGEs) formation as an indicator of dopamine-induced oxidation events. DA inhibited fAGEs-BSA synthesis in vitro, suggesting an anti-oxidative effect, which was not observed when flies were fed DA. Feeding flies cocaine and methamphetamine led to increased fAGEs formation. Mutants lacking the dopaminergic transporter or the D1-type showed further elevation of fAGEs accumulation, indicating that the long-term perturbation in DA function leads to higher production of fAGEs. To confirm that DA has oxidative properties in vivo, we fed flies antioxidant quercetin (QUE) together with methamphetamine. QUE significantly decreased methamphetamine-induced fAGEs formation suggesting that the perturbation of DA function in vivo leads to increased oxidation. These findings present arguments for the use of fAGEs as a biomarker of DA-associated neurodegenerative changes and for assessment of antioxidant interventions such as QUE treatment.