Anxiety commonly co‐occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL– and not BLA– and vHipp–NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL–NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

焦虑症通常与强迫症（OCD）同时发生。两者都与压力密切相关。但是，共享的神经生物学底物和治疗目标仍不清楚。在这里，我们报告了谷氨酸能传入终端从前肢前额叶皮层（PrL）到伏隔核（NAc）核心（边缘环中的重要结节）上的组胺突触前H3异型受体对焦虑和强迫症的缓解作用。NAc核心接受直接的下丘脑组织胺能投射，并且下丘脑NAc核心组织胺能传入的光遗传学激活通过H3受体选择性抑制NAc核心中的谷氨酸能而不是GABA能突触传递，从而产生抗焦虑作用，并改善焦虑和强迫症。约束压力引起的行为。尽管H3受体在PrL，基底外侧杏仁核（BLA）和腹侧海马（vHipp）而不是丘脑的谷氨酸能传入末端表达，但只有PrL –而不是BLA –和vHipp –NAc核心谷氨酸能途径在谷氨酸能NAc核心的大量输入负责共同出现焦虑和强迫症样行为。此外，H3受体的激活改善了由PrL–NAc谷氨酸能传入者的光遗传激发引起的焦虑和强迫症样行为。这些结果证明了调节焦虑和强迫症样行为的共同机制，并通过靶向NAc核心中的组胺H3受体，为患有合并症的强迫症的OCD的临床治疗策略提供了见识。