Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats.
Sex-dependent effects of endocannabinoid modulation of conditioned fear extinction in rats.
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DOI：
10.1111/bph.15341
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发表时间：
2021-03
影响因子：
7.3
通讯作者：
Hill MN
中科院分区：
文献类型：
--
作者：
Morena M;Nastase AS;Santori A;Cravatt BF;Shansky RM;Hill MN
女性患创伤后应激障碍的可能性是男性的两倍，因此寻找这些性别差异背后的生物机制尤为重要。创伤后应激障碍的标志性症状之一是消除对创伤相关线索的恐惧反应的能力的改变。在雄性啮齿动物中，内源性大麻素系统可以调节恐惧消退，并已被建议作为PTSD的治疗靶点。然而，内源性大麻素系统是否以及如何调节女性的恐惧表达和灭绝仍然未知。为了回答这个问题，我们在听觉条件性恐惧消失之前，在雄性和雌性大鼠中操纵内源性大麻素信号，并测量被动（冻结）和主动（飞镖）条件反应。令人惊讶的是，我们发现，急性全身抑制内源性大麻素anandamide（AEA）或2-花生四烯酸甘油（2-AG）水解没有显着改变男性的恐惧表达或灭绝。然而，同样的操作在女性产生不同的影响。增加香草素TRPV 1受体的AEA信号转导损害恐惧记忆消退。相比之下，抑制2-AG水解通过激活大麻素1型受体急性促进主动而非被动的恐惧反应。测量AEA和2-AG水平后，灭绝训练显示性别和大脑区域的具体变化。我们提供的第一个证据表明，AEA和2-AG信号影响恐惧的表达和灭绝的女性在相反的方向。这些发现与未来关于恐惧消退机制的性别差异的研究有关，并可能有助于开发性别特异性疗法来治疗创伤相关疾病。
Women are twice as likely as men to develop post-traumatic stress disorder (PTSD) making the search for biological mechanisms underlying these gender disparities especially crucial. One of the hallmark symptoms of PTSD is an alteration in the ability to extinguish fear responses to trauma-associated cues. In male rodents, the endocannabinoid system can modulate fear extinction and has been suggested as a therapeutic target for PTSD. However, whether and how the endocannabinoid system may modulate fear expression and extinction in females remains unknown. To answer this question, we pharmacologically manipulated endocannabinoid signalling in male and female rats prior to extinction of auditory conditioned fear, and measured both passive (freezing) and active (darting) conditioned responses. Surprisingly, we found that acute systemic inhibition of the endocannabinoid anandamide (AEA) or 2-arachidonoyl glycerol (2-AG) hydrolysis did not significantly alter fear expression or extinction in males. However, the same manipulations in females produced diverging effects. Increased AEA signalling at vanilloid TRPV1 receptors impaired fear memory extinction. In contrast, inhibition of 2-AG hydrolysis promoted active over passive fear responses acutely via activation of cannabinoid type-1 receptors. Measurement of AEA and 2-AG levels after extinction training revealed sex- and brain region-specific changes. We provide the first evidence that AEA and 2-AG signalling affect fear expression and extinction in females in opposite directions. These findings are relevant to future research on sex differences in mechanisms of fear extinction and may help develop sex-specific therapeutics to treat trauma-related disorders.
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影响因子：
10.6
作者：
Gruene TM;Roberts E;Thomas V;Ronzio A;Shansky RM
通讯作者：
Shansky RM
影响因子：
4.6
作者：
Colangeli R;Pierucci M;Benigno A;Campiani G;Butini S;Di Giovanni G
通讯作者：
Di Giovanni G
DOI：
10.1006/bbrc.2000.2406
发表时间：
2000-04-02
影响因子：
3.1
作者：
González, S;Bisogno, T;Fernández-Ruiz, JJ
通讯作者：
Fernández-Ruiz, JJ
影响因子：
7.7
作者：
Gruene, Tina M.;Flick, Katelyn;Shansky, Rebecca M.
通讯作者：
Shansky, Rebecca M.
影响因子：
25
作者：
Chavez, Andres E.;Chiu, Chiayu Q.;Castillo, Pablo E.
通讯作者：
Castillo, Pablo E.