Corticosteroids (CORT) have been widely used in anti-inflammatory medication. Chronic CORT treatment can cause mesocorticolimbic system dysfunctions, which are known to play a key role for the development of psychiatric disorders. The VTA is a critical site in the mesocorticolimbic pathway and is responsible for motivation and reward-seeking behaviors. However, the mechanism by which chronic CORT alters VTA dopamine neuronal activity is largely unknown. We treated periadolescent male mice with vehicle, 1 d, or 7 d CORT in the drinking water, examined behavioral impacts with light/dark box, elevated plus maze, operant chamber, and open field tests, measured the effects of CORT on VTA dopamine neuronal activity using patch-clamp electrophysiology and dopamine concentration using fast-scan cyclic voltammetry, and tested the effects of dopamine D2 receptor (D2R) blockade by intra-VTA infusion of a D2R antagonist. CORT treatment induced anxiety-like behavior as well as decreased food-seeking behaviors. We show that chronic CORT treatment decreased excitability and excitatory synaptic transmission onto VTA dopamine neurons. Furthermore, chronic CORT increased somatodendritic dopamine concentration. The D2R antagonist sulpiride restored decreased excitatory transmission and excitability of VTA dopamine neurons. Furthermore, sulpiride decreased anxiety-like behavior and rescued food-seeking behavior in mice with chronic CORT exposure. Together, 7 d CORT treatment induces anxiety-like behavior and impairs food-seeking in a mildly aversive environment. D2R signaling in the VTA might be a potential target to ameliorate chronic CORT-induced anxiety and reward-seeking deficits.

SIGNIFICANCE STATEMENT With widespread anti-inflammatory effects throughout the body, corticosteroids (CORT) have been used in a variety of therapeutic conditions. However, long-term CORT treatment causes cognitive impairments and neuropsychiatric disorders. The impact of chronic CORT on the mesolimbic system has not been elucidated. Here, we demonstrate that 7 d CORT treatment increases anxiety-like behavior and attenuates food-seeking behavior in a mildly aversive environment. By elevating local dopamine concentration in the VTA, a region important for driving motivated behavior, CORT treatment suppresses excitability and synaptic transmission onto VTA dopamine neurons. Intriguingly, blockade of D2 receptor signaling in the VTA restores neuronal excitability and food-seeking and alleviates anxiety-like behaviors. Our findings provide a potential therapeutic target for CORT-induced reward deficits.

皮质类固醇（CORT）已广泛用于抗炎药物。慢性CORT治疗可引起中皮层皮质功能障碍，这在精神疾病的发展中起关键作用。VTA是中皮层皮质障碍途径中的关键部位，并负责动机和寻求奖励的行为。但是，慢性CORT改变VTA多巴胺神经元活性的机制很大程度上未知。我们用媒介物，饮用水中的1 d或7 d CORT对青春期后的雄性小鼠进行了治疗，使用明/暗盒，高架迷宫，手术室和开放视野测试检查了行为影响，测量了CORT对VTA多巴胺神经元的影响使用膜片钳电生理学检测活性，使用快速扫描循环伏安法测定多巴胺浓度，并通过VTA内注入D2R拮抗剂测试了多巴胺D2受体（D2R）阻断作用。CORT治疗可诱发焦虑样行为，并减少觅食行为。我们显示，慢性CORT治疗可降低对VTA多巴胺神经元的兴奋性和兴奋性突触传递。此外，慢性CORT增加了树突状多巴胺的浓度。D2R拮抗剂舒必利恢复了VTA多巴胺神经元兴奋传递的减少和兴奋性。此外，舒必利降低了慢性CORT暴露小鼠的焦虑样行为并挽救了觅食行为。总之，在轻度厌恶的环境中，7 d CORT治疗会诱发类似焦虑的行为，并损害觅食。

重要性声明皮质类固醇（CORT）具有在全身广泛的抗炎作用，已被用于多种治疗条件。但是，长期CORT治疗会导致认知障碍和神经精神疾病。慢性CORT对中脑边缘系统的影响尚未阐明。在这里，我们证明了在轻度厌恶环境中7 d CORT治疗可增加焦虑样行为，并减弱觅食行为。通过提高VTA中的局部多巴胺浓度，该区域对驱动动机行为很重要，CORT治疗可抑制兴奋性和突触传递到VTA多巴胺神经元上。有趣的是，VTA中D2受体信号传导的阻滞恢复了神经元的兴奋性和觅食能力，并减轻了类似焦虑的行为。