The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra

Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB1-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.

突触前大麻素1型受体（CB1-R）可结合内源性与外源性大麻素，从而调节神经递质释放。CB1-R广泛表达于基底神经节（basal ganglia）全脑区域，涵盖纹状体（striatum）与黑质（substantia nigra），在学习过程及动机性行为调控中发挥重要作用。然而，目前仍不明确CB1-R在不同纹状体亚区、微环路以及传出靶区的表达模式，以及表达CB1-R的各类神经元对该表达模式的具体贡献。
本研究结合传统实验技术与新型遗传模型，对纹状体的纹状体小体（striosome，又称patch）与基质（matrix）亚区，以及纹状体中型多棘投射神经元（medium spiny projection neurons, MSNs）的黑质靶区中的CB1-R表达情况进行了系统评估。
在尾侧纹状体中，CB1-R蛋白与mRNA的表达强度呈现从背外侧向腹内侧递减的梯度，且纹状体小体中的表达水平显著高于周围的基质亚区。纹状体小体CB1-R的外侧富集特征，与经典纹状体小体标记物μ阿片受体（mu opioid receptor, MOR）形成鲜明对比：μ阿片受体在吻内侧纹状体小体中表达最为显著。CB1-R的背外侧-腹内侧表达梯度与Drd2多巴胺受体免疫反应性的分布模式相似，而与P物质（Substance P）的分布模式完全相反。
CB1-R的这种拓扑表达模式在下游的苍白球（globus pallidus）与黑质中得以保留。密集表达CB1-R的纹状体-黑质投射纤维在黑质网状部（substantia nigra pars reticulata）内向背侧延伸，并与黑质致密部（substantia nigra pars compacta）多巴胺能神经元的腹侧延伸、靶向纹状体小体的树突束（即纹状体小体-树突束簇，striosome-dendron bouquets）发生共定位。
在纹状体内，CB1-R与纹状体小体内经荧光标记的MSN侧支存在共定位现象。通过Cre重组酶（Cre recombinase）介导的皮层投射神经元或MSNs中CB1-R敲除实验，以及在CB1-R敲除小鼠中进行MSN选择性CB1-R重表达实验，研究人员证实背外侧纹状体小体中CB1-R的主要来源为局部MSN侧支。
上述数据表明，CB1-R在尾侧背外侧纹状体小体侧支以及投射至外侧黑质的纹状体小体-树突束簇投射中发挥关键功能；从解剖结构层面而言，这些CB1-R具备介导内源性大麻素（endocannabinoids）与大麻素类似物（cannabinomimetics）作用下，纹状体小体MSNs与中脑多巴胺能神经元的突触前去抑制效应的结构基础。