Hampson A J, Bornheim L M, Scanziani M, Yost C S, Gray A T, Hansen B M, Leonoudakis D J, Bickler P E
Department of Cellular and Molecular Pharmacology, University of California San Francisco, USA.
J Neurochem. 1998 Feb;70(2):671-6. doi: 10.1046/j.1471-4159.1998.70020671.x.
Anandamide is an endogenous ligand of cannabinoid receptors that induces pharmacological responses in animals similar to those of cannabinoids such as delta9-tetrahydrocannabinol (THC). Typical pharmacological effects of cannabinoids include disruption of pain, memory formation, and motor coordination, systems that all depend on NMDA receptor mediated neurotransmission. We investigated whether anandamide can influence NMDA receptor activity by examining NMDA-induced calcium flux (deltaCa2+NMDA) in rat brain slices. The presence of anandamide reduced deltaCa2+NMDA and the inhibition was disrupted by cannabinoid receptor antagonist, pertussis toxin treatment, and agatoxin (a calcium channel inhibitor). Whereas these treatments prevented anandamide inhibiting deltaCa2+NMDA, they also revealed another, underlying mechanism by which anandamide influences deltaCa2+NMDA. In the presence of cannabinoid receptor antagonist, anandamide potentiated deltaCa2+NMDA in cortical, cerebellar, and hippocampal slices. Anandamide (but not THC) also augmented NMDA-stimulated currents in Xenopus oocytes expressing cloned NMDA receptors, suggesting a capacity to directly modulate NMDA receptor activity. In a similar manner, anandamide enhanced neurotransmission across NMDA receptor-dependent synapses in hippocampus in a manner that was not mimicked by THC and was unaffected by cannabinoid receptor antagonist. These data demonstrate that anandamide can modulate NMDA receptor activity in addition to its role as a cannabinoid receptor ligand.
花生四烯乙醇胺是大麻素受体的内源性配体，它能在动物体内诱导出与大麻素类似的药理反应，如δ9-四氢大麻酚（THC）。大麻素的典型药理作用包括扰乱疼痛、记忆形成和运动协调，而这些系统均依赖于N-甲基-D-天冬氨酸（NMDA）受体介导的神经传递。我们通过检测大鼠脑片中NMDA诱导的钙通量（δCa2+NMDA）来研究花生四烯乙醇胺是否能影响NMDA受体活性。花生四烯乙醇胺的存在降低了δCa2+NMDA，且大麻素受体拮抗剂、百日咳毒素处理和阿加毒素（一种钙通道抑制剂）可破坏这种抑制作用。虽然这些处理可阻止花生四烯乙醇胺抑制δCa2+NMDA，但它们也揭示了花生四烯乙醇胺影响δCa2+NMDA的另一种潜在机制。在存在大麻素受体拮抗剂的情况下，花生四烯乙醇胺可增强皮质、小脑和海马切片中的δCa2+NMDA。花生四烯乙醇胺（而非THC）还可增强表达克隆NMDA受体的非洲爪蟾卵母细胞中NMDA刺激的电流，这表明它有直接调节NMDA受体活性的能力。同样，花生四烯乙醇胺以一种THC无法模拟且不受大麻素受体拮抗剂影响的方式增强了海马中依赖NMDA受体的突触间的神经传递。这些数据表明，花生四烯乙醇胺除了作为大麻素受体配体发挥作用外，还可调节NMDA受体活性。
