Chhatwal Jasmeer P, Gutman Alisa R, Maguschak Kimberly A, Bowser Michael E, Yang Yong, Davis Michael, Ressler Kerry J
Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
Neuropsychopharmacology. 2009 Jan;34(2):509-21. doi: 10.1038/npp.2008.97. Epub 2008 Jun 25.
The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.
内源性大麻素系统和1型大麻素受体（CB1R）对于条件性恐惧的消退是必需的。已表明，CB1拮抗剂在全身给药以及杏仁核内给药时均可阻止消退。解剖学研究表明，基底外侧杏仁核（BLA）中的CB1R表达于表达致焦虑肽胆囊收缩素（CCK）的GABA能中间神经元上。突触前CB1R抑制神经递质释放，这表明在消退过程中CB1R的激活可能会减少CCK肽的释放以及GABA的释放。因此，我们研究了消退是否涉及CB1R对CCK2受体激活的调节。我们发现，脑室内注射CCK2激动剂五肽胃泌素会剂量依赖性地损害条件性恐惧的消退。全身给予CB1拮抗剂利莫那班（SR141716）也能有效抑制消退学习。全身给予CCK2拮抗剂CR2945可改善这种作用。此外，全身给予SR141716所导致的消退阻断作用可被BLA内而非纹状体内注射CR2945所逆转。最后，由于消退通常会导致Akt磷酸化增加，而全身CB1拮抗剂治疗会拮抗这种生化效应，我们研究了联合给予CR2945是否会增加消退诱导的p-Akt水平。我们观察到，接受消退训练的动物在消退后Akt磷酸化增加，接受CB1拮抗剂治疗的动物的p-Akt水平与未接受消退训练的动物相似，而联合给予CR2945和SR141716导致的p-Akt水平与接受溶媒治疗、接受消退训练的对照组相似。总之，这些数据表明，内源性大麻素系统与CCK能递质系统之间的相互作用可能是条件性恐惧消退过程的基础。
