Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOH_D and SCM_D) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOH_ND and SCM_ND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOH_D/ND and SCM_D/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOH_D and SCM_D). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOH_D and SCM_D groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.

参与处理自然奖励和滥用药物的神经系统重叠和接触滥用药物会诱发神经适应，从而导致类似强迫行为的行为。例如，滥用药物对食欲素 (Orx) 系统的募集已被提议诱导神经适应，进而改变其功能，表现为适应不良、强迫性和成瘾行为。食欲素神经元投射到丘脑室旁核 (PVT)，尤其是后部 (pPVT)，该结构在压力调节中起关键作用。本研究调查了 pPVT 中的 Orx 传递是否在应激诱导的恢复对乙醇 (EtOH) 的奖励寻求行为和大鼠高度可口的食物奖励 [甜炼乳 (SCM)] 中起作用，以及这种作用是否随 EtOH 而改变依赖性。_D和 SCM _D ) 慢性间歇性乙醇蒸气暴露。对照非依赖性组（EtOH _ND和 SCM _ND）暴露于空气中。灭绝后，测试大鼠应激诱导的乙醇和 SCM 寻求行为的恢复。压力在所有组（EtOH _D/ND和 SCM _D/ND）中恢复了 EtOH 和 SCM 寻求行为。在 pPVT 中施用双 Orx 受体 (OrxR) 拮抗剂 TCS1102 (15 μg) 仅在依赖性大鼠（EtOH _D和 SCM _D）中防止应激诱导的恢复。同时，qPCR 分析表明，奥克斯 下丘脑中的 mRNA 表达和 OrxR1/R2在 EtOH _D和 SCM _D组中测试时 pPVT 中的 mRNA 表达增加。这些结果首次表明 pPVT 中的 Orx 传输与 EtOH 依赖大鼠的压力诱导的奖励寻求行为恢复有关，并表明 EtOH 依赖对 pPVT 中 Orx 传输的适应不良招募。