Department of Neuroscience, Pharmacology and Psychiatry, CIBER of Mental Health, CIBERSAM, Instituto de Salud Carlos III, University of Cdiz, Cdiz, Spain.
CNS Drugs. 2012 Aug 1;26(8):637-48. doi: 10.2165/11634510-000000000-00000.
This review provides a brief summary of what is known about the anxiolytic mechanism of action of pregabalin, a highly selective, high-affinity ligand of the P/Q type of voltage-gated calcium channel (CaV). Evidence from in vivo models of neuronal hyperexcitability suggests that pregabalin reduces synaptic release of neurotransmitters in selected CNS regions including the cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum and dorsal horn of the spinal cord. Release of neurotransmitters from the synaptic vesicle, and propagation of neurotransmission, requires the vesicle to fuse with the presynaptic membrane. Pregabalin binding to the α(2)δ type 1 protein of the P/Q type CaV reduces the availability of Ca2+ required for membrane fusion and exocytosis of neurotransmitters. Evidence that the anxiolytic mechanism of action of pregabalin is mediated by binding to the α(2)δ type 1 protein comes from animal models, which have demonstrated a structure-activity relationship between the affinity of ligands for the α(2)δ type 1 protein and their potency in models of anxiety such as the Vogel conflict test. Furthermore, the anxiolytic activity of pregabalin is lost in transgenic mice with specific point mutations in the CaV α(2)δ type 1 protein. Pregabalin-mediated reduction in calcium currents has also been shown to result in a significant inhibition of the release of neurotransmitters implicated in pathological anxiety such as glutamate and monoamine neurotransmitters. However, further research is needed to confirm that these effects contribute to the anxiolytic mechanism of action of pregabalin. Finally, pregabalin may also act by inhibiting synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of CaV to the plasma membrane.
这篇综述简要概述了普瑞巴林（一种高度选择性、高亲和力的 P/Q 型电压门控钙通道（CaV）配体）的抗焦虑作用机制。来自神经元过度兴奋的体内模型的证据表明，普瑞巴林可减少包括皮质、嗅球、下丘脑、杏仁核、海马、小脑和脊髓背角在内的特定中枢神经系统区域的神经递质释放。神经递质从突触小泡释放和神经传递的传播都需要囊泡与突触前膜融合。普瑞巴林与 P/Q 型 CaV 的α(2)δ 型 1 蛋白结合，可减少膜融合和神经递质胞吐所需的 Ca2+的可用性。普瑞巴林的抗焦虑作用机制通过与α(2)δ 型 1 蛋白结合来介导的证据来自动物模型，这些模型表明配体与α(2)δ 型 1 蛋白的亲和力与其在焦虑模型（如 Vogel 冲突测试）中的效力之间存在结构-活性关系。此外，在 CaVα(2)δ 型 1 蛋白中具有特定点突变的转基因小鼠中，普瑞巴林的抗焦虑活性丧失。还表明，普瑞巴林介导的钙电流减少可导致与病理性焦虑相关的神经递质（如谷氨酸和单胺神经递质）释放的显著抑制。然而，需要进一步的研究来证实这些作用有助于普瑞巴林的抗焦虑作用机制。最后，普瑞巴林还可能通过抑制慢性应激或焦虑反应中形成的兴奋性神经元的突触发生，或者更急性地抑制 CaV 向质膜的运输来发挥作用。
