en Behavioral Neuroscience Behavioral Neuroscience Original Original <strong>Introduction</strong>: Methamphetamine (MA) acts as a powerful oxidant agent, while Rosmarinic Acid (RA) is an effective herbal antioxidant. Oxidative stress-mediated by MA results in apoptosis, and caspase-3 is one of the critical enzymes in the apoptosis process. MA can epigenetically alter gene regulation. In this paper, to investigate the effects of RA on MA-mediated oxidative stress, changes in the level of casp3a mRNA were demonstrated in zebrafish.<br> <strong>Methods</strong>: The animals were grouped in 3 treatment conditions for the behavioral test: control, MA, MA pretreated by RA, and 6 treatment conditions for the molecular test: control, RA, MA, MA co-treated with RA, MA co-treated with RA/ZnO/chitosan nanoparticle, and ZnO/chitosan nanoparticle. Then molecular and behavioral investigations were carried out, and critical comparisons were made between the groups.&nbsp;<br> MA solution was prepared with a concentration of 25 mg/L, and RA solution was prepared by DPPH test with the antioxidant power of about 97%. Each solution was administered by immersing 20 zebrafish for 20 minutes, once per day for 7 days. The level of casp3a mRNA was quantified by using qRT-PCR. One-sided trapezoidal tank diving test was applied to study behavioral alterations.<br> <strong>Results</strong>: The qPCR analysis demonstrated the high potential of RA/ZnO/chitosan in counteracting the MA-mediated elevation in casp3a mRNA level. Based on the diving test results of MA-treated fish, MA was found to be anxiolytic compared to the control. While the resulted diving pattern of the MA-treated animals pretreated by RA was novel and different from both the control and MA-treated groups.<br> <strong>Conclusion</strong>: The potential of RA combined with a suitable nanoparticle against MA-induced oxidative stress was supported. The high efficiency of ZnO/chitosan in increasing RA penetration to the brain cells was evident. MA at a dose of 25 mg/L is anxiolytic for zebrafish. However, the molecular mechanisms involved in these processes should be studied. Methamphetamine, Casp3a, Rosmarinic acid, Zinc oxide, Chitosan nanoparticle, Zebrafish, Behavioral test 243 254 http://bcn.iums.ac.ir/browse.php?a_code=A-10-1777-1&slc_lang=en&sid=1 Vida Nikshenas Shahrestani v.nickshenas.sh@gmail.com 13700319475328460034908 13700319475328460034908 No Department of Biology, Faculty of Basic Sciences, University of Zabol, Zabol, Iran. Mohammad Haddadi hadadimohamad@gmail.com 13700319475328460034909 13700319475328460034909 Yes Department of Biology, Faculty of Basic Sciences, University of Zabol, Zabol, Iran. Ali Reza Samzadeh Kermani arsamzadeh@yahoo.com 13700319475328460034910 13700319475328460034910 No Department of Chemistry, Faculty of Basic Sciences, University of Zabol, Zabol, Iran.