Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
Psychopharmacology (Berl). 2019 Jun;236(6):1863-1874. doi: 10.1007/s00213-019-5170-2. Epub 2019 Jan 29.
The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses.
We aimed to verify which mechanisms underlie anandamide-mediated responses in the DMH.
To test the hypothesis that the anandamide produces panicolytic-like effects, we treated mice with intra-DMH microinjections of vehicle or increasing doses of anandamide (0.5, 5, or 50 pmol) and then performed confrontation with the South American snake Epicrates cenchria assisi.
Intra-DMH anandamide treatment yielded a U-shaped dose-response curve with no effect of the lowest (0.5 pmol) or the highest (50 pmol) dose and significant inhibition of panic-like responses at the intermediate (5 pmol) dose. In addition, this panicolytic-like effect was prevented by pretreatment of the DMH with the CB1 receptor antagonist AM251 (100 pmol). However, pretreatment of the DMH with the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin (3 nmol) restored the panicolytic-like effect of the highest dose of anandamide. Immunohistochemistry revealed that CB1 receptors were present primarily on axonal fibers, while TRPV1 receptors were found almost exclusively surrounding the perikarya in DMH.
The present results suggest that anandamide exerts a panicolytic-like effect in the DMH by activation of CB1 receptors and that TRPV1 receptors are related to the lack of effect of the highest dose of anandamide.
内源性大麻素系统在惊恐样防御行为的组织中起着重要作用。威胁性的情况会刺激大脑区域，如背内侧下丘脑（DMH）。然而，目前缺乏研究探讨 DMH 内源性大麻素系统在惊恐样反应中的作用。
我们旨在验证大麻素介导的 DMH 反应的潜在机制。
为了检验内源性大麻素在 DMH 中产生惊恐样缓解作用的假设，我们用 vehicle 或递增剂量的内源性大麻素（0.5、5 或 50 pmol）对 DMH 进行微注射，然后让这些小鼠与南美蛇 Epicrates cenchria assisi 进行对抗。
DMH 内源性大麻素处理产生了一种 U 形剂量反应曲线，最低（0.5 pmol）或最高（50 pmol）剂量没有效果，而中间（5 pmol）剂量则显著抑制了惊恐样反应。此外，这种惊恐样缓解作用可通过在 DMH 预处理中使用 CB1 受体拮抗剂 AM251（100 pmol）来预防。然而，用 TRPV1 受体拮抗剂 6-碘-N-去氢辣椒素（3 nmol）预处理 DMH，则恢复了内源性大麻素最高剂量的惊恐样缓解作用。免疫组织化学显示 CB1 受体主要存在于轴突纤维上，而 TRPV1 受体几乎完全存在于 DMH 的神经元周围。
目前的结果表明，内源性大麻素通过激活 CB1 受体在 DMH 中发挥惊恐样缓解作用，而 TRPV1 受体与内源性大麻素最高剂量缺乏作用有关。
