Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention
Interaction between the Cholecystokinin and Endogenous Cannabinoid Systems in Cued Fear Expression and Extinction Retention
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DOI：
10.1038/npp.2014.225
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发表时间：
2015-02-01
影响因子：
7.6
通讯作者：
Ressler, Kerry J.
中科院分区：
文献类型：
--
作者：
Bowers, Mallory E.;Ressler, Kerry J.
创伤后应激障碍（PTSD）被认为在一定程度上是由于对恐惧的抑制不当造成的。因此，创伤后应激障碍最有效的治疗策略之一是基于暴露的心理治疗。理想情况下，神经科学将为辅助疗法提供信息，以参与消退过程的神经递质系统为目标。单独的研究表明，恐惧与胆囊收缩素（CCK）和内源性大麻素系统有关；然而，大麻素1受体（Cnrl）和CCK在基底外侧杏仁核（BLA）中存在高度的解剖共定位，这是一个对情绪调节至关重要的大脑区域。尽管大多数研究都将GABA和GABA能可塑性作为Cnrl介导恐惧抑制的机制，但我们假设Cnrl和CCKB受体（CCKBR）之间的功能相互作用对恐惧消退过程至关重要。在本研究中，大麻素系统的系统性药理操作调节了C57BU6J小鼠听觉恐惧条件巩固后的恐惧表达。然而，敲除CCKBR对恐惧或焦虑样行为没有影响。尽管如此，使用Cnrl拮抗剂增加了野生型受试者在暗示恐惧表达测试中的冻结行为，但对CCKBR敲除幼崽的冻结行为没有影响。此外，我们发现在BLA中，Cnrl阳性纤维在cckbr阳性细胞体周围形成细胞周围簇。这些cckbr阳性细胞包括兴奋性和抑制性神经元的分子异质性群体。这些发现提供了新的证据，表明Cnrl通过与CCK系统的相互作用来促进线索恐惧的表达。功能失调的Cnrl - CCKBR相互作用可能有助于恐惧相关精神疾病的病因或结果。
Post-traumatic stress disorder (PTSD) is thought to develop, in part, from improper inhibition of fear. Accordingly, one of the most effective treatment strategies for PTSD is exposure-based psychotherapy. Ideally, neuroscience would inform adjunct therapies that target the neurotransmitter systems involved in extinction processes. Separate studies have implicated the cholecystokinin (CCK) and endocannabinoid systems in fear; however, there is a high degree of anatomical colocalization between the cannabinoid 1 receptor (Cnrl) and CCK in the basolateral amygdala (BLA), a brain region critical for emotion regulation. Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnrl mediates fear inhibition, we hypothesize that a functional interaction between Cnrl and CCKB receptor (CCKBR) is critical for fear extinction processes. In this study, systemic pharmacological manipulation of the cannabinoid system modulated cued fear expression in C57BU6J mice after consolidation of auditory fear conditioning. Knockout of the CCKBR, however, had no effect on fear-or anxiety-like behaviors. Nonetheless, administration of a Cnrl antagonist increased freezing behavior during a cued fear expression test in wild-type subjects, but had no effect on freezing behavior in CCKBR knockout littermates. In addition, we found that Cnrl -positive fibers form perisomatic clusters around CCKBR-positive cell bodies in the BLA. These CCKBR-positive cells comprise a molecularly heterogenous population of excitatory and inhibitory neurons. These findings provide novel evidence that Cnrl contributes to cued fear expression via an interaction with the CCK system. Dysfunctional Cnrl CCKBR interactions might contribute to the etiology of, or result from, fear-related psychiatric disease.