Prolonged abuse of methylphenidate (MPH) often causes neuronal damage. Topiramate (TPM) has neuroprotective properties, but its mechanism of action remains unclear. The current study evaluates in vivo role of various doses of TPM (10, 30, 50, 70 and 100 mg/kg) and its possible mechanisms against MPH-induced hippocampal oxidative stress, inflammation and apoptosis, in absence and presence of different receptor agonists and antagonists. Domoic acid (DOM) as AMPA/kainate receptor agonist, bicuculline (BIC) as GABAA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as σ2 adrenergic receptor antagonist and haloperidole (HAL) as D2 dopamine receptor antagonist was used. Open Field Test (OFT) was used to investigate the disturbances in motor activity. Hippocampal oxidative, anti-oxidant and inflammatory parameters and apoptotic factors were studied. Expressions of BDNF at gene and protein levels were also evaluated. Crystal violet staining was performed to determine neuronal cell density. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased BDNF gene and protein expressions, Bcl-2 expression, the level of reduced form of glutathione (GSH) and activities of enzymes superoxide dismutase, glutathione peroxidase and glutathione reductase.TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing BDNF expressions. Thus, TPM by interacting with AMPA/kainate, GABAA, NMDA and σ2-adrenergic receptors improves BDNF expression and acts as a neuroprotective agent against MPH-induced neurodegeneration.