Dept. of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil.
Dept. of Pharmacology, Federal University of Parana, Curitiba, PR, Brazil.
Neuropharmacology. 2017 Oct;125:220-230. doi: 10.1016/j.neuropharm.2017.07.024. Epub 2017 Jul 25.
Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB) and type-2 (CB) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB receptor antagonist/inverse agonist AM251 or the CB receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB and CB receptors.
药理学干预能够调节巩固中的恐惧记忆，这可能具有调节过度巩固的适应性不良恐惧记忆的治疗价值。动物和人类研究表明，在恐惧条件作用期间给予的非条件刺激的强度会影响要建立的记忆的质量和数量方面。通过改变用于大鼠情境配对的电击强度，我们在这里诱导了特定和更广泛的长期恐惧记忆，以研究大麻二酚 (CBD；3.0-30mg/kg 腹腔内注射) 是否以及如何在大脑中干扰它们的巩固及其相关结果。当在获得后立即给予时，它分别减少了条件性恐惧表达、恐惧泛化、22-kHz 超声发声以及相对的抗灭绝能力。CBD 对短期恐惧记忆没有影响，其延迟治疗不再影响巩固过程。由于背侧海马体 (DH) 调节恐惧记忆的特异性和泛化，并且大麻素 1 型 (CB) 和 2 型 (CB) 受体有助于巩固，我们研究了它们在 CBD 作用中的参与。全身和 intra-DH 给予 CB 受体拮抗剂/反向激动剂 AM251 或 CB 受体拮抗剂/反向激动剂 AM630 均可阻止 CBD 对巩固的破坏作用。由于 CBD 对内源性大麻素传递的作用可能是间接的，因此我们研究并证明了 FAAH 抑制剂 URB597 具有与 CBD 相似的全身或 intra-DH 给药时的作用。总之，目前的结果表明，CBD 通过 DH CB 和 CB 受体的 anandamide 介导激活来干扰不同恐惧记忆的巩固。
