Neuroprotective effects of melatonin on amphetamine‐induced dopaminergic fiber degeneration in the hippocampus of postnatal rats

AbstractChronic amphetamine (AMPH) abuse leads to damage of the hippocampus, the brain area associated with learning and memory process. Previous results have shown thatAMPH‐induced dopamine neurotransmitter release, reactive oxygen species formation, and degenerative protein aggregation lead to neuronal death. Melatonin, a powerful antioxidant, plays a role as a neuroprotective agent. The objective of this study was to investigate whether the protective effect of melatonin onAMPH‐induced hippocampal damage in the postnatal rat acts through the dopaminergic pathway. Four‐day‐old postnatal rats were subcutaneously injected with 5‐10 mg/kgAMPHand pretreated with 10 mg/kg melatonin prior toAMPHexposure for seven days. The results showed that melatonin decreased theAMPH‐induced hippocampal neuronal degeneration in the dentate gyrus,CA1, andCA3. Melatonin attenuated the reduction in the expression of hippocampal synaptophysin,PSD‐95, α‐synuclein, and N‐methyl‐D‐aspartate (NMDA) receptor protein andmRNAcaused byAMPH. Melatonin attenuated theAMPH‐induced reduction in dopamine transporter (DAT) protein expression in the hippocampus and the reduction inmRNAexpression in the ventral tegmental area (VTA). Immunofluorescence demonstrated that melatonin not only prevented theAMPH‐induced loss ofDATandNMDAreceptor but also preventedAMPH‐induced α‐synuclein overexpression in the dentate gyrus,CA1, andCA3. Melatonin decreased theAMPH‐induced reduction in the protein andmRNAof theNMDAreceptor downstream signaling molecule, calcium/calmodulin‐dependent protein kinaseII(CaMKII), and the melatonin receptors (MT1 andMT2). This study showed that melatonin preventedAMPH‐induced toxicity in the hippocampus of postnatal rats possibly via its antioxidative effect and mitochondrial protection.