Numerous studies have demonstrated the correspondence between orexin transmission and reward-related behaviors. Orexin receptors are expressed in the hippocampus regions such as CA1, CA2, and CA3, as well as the DG region. The hippocampus is essential in learning and memory, and there is a correlation between reward and learning and memory processing. The dentate gyrus (DG) is the main gateway of the hippocampal formation, receives and integrates inputs from the rest of the hippocampus formation and regulates addiction-related behaviors. Methamphetamine and other psychostimulants can produce a marked elevation in mood, alertness, arousal, and reward.These experiments used male Wistar rats weighing 200–220 g. Animals were anesthetized with an intraperitoneal injection of ketamine (100 mg/kg) and xylazine (10 mg/kg) to implant bilateral stainless-steel guide cannulae (23 gauge) targeting the DG region of the hippocampus. Following the five days Meth injections (1 mg/kg; sc), animals received intra-DG microinjection of TCS OX2 29, as orexin 2 (OX2) receptor antagonists, without Meth administration during extinction phase. The extinguished rats received TCS OX2 29 before injecting a priming dose of Meth (0.25 mg/kg; sc). The CPP paradigm was used to evaluate the rewarding effects of addictive drugs in laboratory animals.The present findings indicated that TCS OX2 29 attenuated the extinction latency.On the whole, understanding the neural circuit involved in drug-seeking behavior may guide more efficient pharmacotherapeutic intervention to treat addiction to Meth and other drugs of abuse.