Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC, 88049-900, Brazil.
Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Florianópolis, SC, 88049-900, Brazil.
Neuropharmacology. 2018 Jun;135:399-411. doi: 10.1016/j.neuropharm.2018.03.032. Epub 2018 Mar 26.
Stimulation of the midbrain periaqueductal gray matter (PAG) in humans elicits sensations of fear and impending terror, and mediates predator defensive responses in rodents. In rats, pharmacological stimulation of the dorsolateral portion of the PAG (dlPAG) with N-Methyl-d-Aspartate (NMDA) induces aversive conditioning that acts as an unconditioned stimulus (US). In the present work, we investigated the interplay between the vanilloid TRPV1 and cannabinoid CB1 receptors in the NMDA-dlPAG defensive response and in subsequent aversive learning. Rats were subjected to dlPAG NMDA infusion in an olfactory conditioned stimulus (CS) task allowing the evaluation of immediate and long-term defensive behavioral responses during CS presentation. The results indicated that an intermediate dose of NMDA (50 pmol) induced both immediate and long-term effects. A sub-effective dose of NMDA (25 pmol) was potentiated by the TRPV1 receptor agonist capsaicin (CAP, 1 nmol) and the CB1 receptor antagonist, AM251 (200 pmol). CAP (10 nmol) or the combination of CAP (1 nmol) and AM251 (200 pmol) induced long-term effects without increasing immediate defensive responses. The glutamate release inhibitor riluzole (2 or 4 nmol) and the AMPA/kainate receptor antagonist DNQX (2 or 4 nmol) potentiated the immediate effects but blocked the long-term effects. The results showed that immediate defensive responses rely on NMDA receptors, and aversive learning on the fine-tuning of TRPV1, CB1, metabotropic glutamate and AMPA receptors located in pre- and postsynaptic membranes. In conclusion, the activity of the dlPAG determines core affective aspects of aversive memory formation controlled by local TRPV1/CB1 balance.
刺激中脑导水管周围灰质（PAG）会在人类中引起恐惧和即将到来的恐惧的感觉，并介导啮齿动物的捕食者防御反应。在大鼠中，用 N-甲基-D-天冬氨酸（NMDA）刺激 PAG 的背外侧部分（dlPAG）会引起厌恶条件反射，作为无条件刺激（US）。在本工作中，我们研究了香草素 TRPV1 和大麻素 CB1 受体在 NMDA-dlPAG 防御反应和随后的厌恶学习中的相互作用。大鼠在嗅觉条件刺激（CS）任务中接受 dlPAG NMDA 输注，允许在 CS 呈现期间评估即时和长期防御行为反应。结果表明，中间剂量的 NMDA（50 pmol）诱导了即时和长期效应。NMDA 的亚有效剂量（25 pmol）被 TRPV1 受体激动剂辣椒素（CAP，1 nmol）和 CB1 受体拮抗剂 AM251（200 pmol）增强。CAP（10 nmol）或 CAP（1 nmol）和 AM251（200 pmol）的组合诱导了长期效应，而没有增加即时防御反应。谷氨酸释放抑制剂利鲁唑（2 或 4 nmol）和 AMPA/ kainate 受体拮抗剂 DNQX（2 或 4 nmol）增强了即时效应，但阻断了长期效应。结果表明，即时防御反应依赖于 NMDA 受体，而厌恶学习依赖于位于突触前和突触后膜上的 TRPV1、CB1、代谢型谷氨酸和 AMPA 受体的精细调节。总之，dlPAG 的活动决定了厌恶记忆形成的核心情感方面，由局部 TRPV1/CB1 平衡控制。
