Reviewing the role of the orexinergic system and stressors in modulating mood and reward-related behaviors

•Orexins increase reward-related and anxiety-like behaviors, and stress responses.•Orexinergic antagonists induce anti-reward effects.•Orexinergic antagonists improve stress- or anxiety-induced psychiatric disorders.•Orexinergic system plays inconsistent roles in modulating depression.•Orexins have no stable pattern in modulating stress-induced reward-seeking behavior. In this review study, we aimed to introduce the orexinergic system as an important signaling pathway involved in a variety of cognitive functions such as memory, motivation, and reward-related behaviors. This study focused on the role of orexinergic system in modulating reward-related behavior, with or without the presence of stressors. Cross-talk between the reward system and orexinergic signaling was also investigated, especially orexinergic signaling in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the hippocampus. Furthermore, we discussed the role of the orexinergic system in modulating mood states and mental illnesses such as depression, anxiety, panic, and posttraumatic stress disorder (PTSD). Here, we narrowed down our focus on the orexinergic signaling in three brain regions: the VTA, NAc, and the hippocampus (CA1 region and dentate gyrus) for their prominent role in reward-related behaviors and memory. It was concluded that the orexinergic system is critically involved in reward-related behavior and significantly alters stress responses and stress-related psychiatric and mood disorders.