Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2012;64(6):1305-15. doi: 10.1016/s1734-1140(12)70928-3.
This paper summarizes a series of electrophysiological studies aimed at finding the effects of the activation of 5-HT(7) receptors on neuronal excitability as well as on excitatory and inhibitory synaptic transmission in the hippocampus and in the frontal cortex of the rat. These studies demonstrated that 5-HT(7) receptors play an important role in the modulation of the activity of the hippocampal network by regulating the excitability of pyramidal cells of the CA1 area, as well as via their effect on GABA and glutamatergic transmission. The reactivity of 5-HT(7) receptors in the hippocampus is decreased by repeated administration of antidepressant drugs and increased by a prolonged high level of corticosterone. More importantly, administration of antidepressant drug, imipramine, prevents the occurrence of corticosterone-induced changes in the function of hippocampal 5-HT(7) receptors. It has also been found that the blockade of 5-HT(7) receptors by the selective antagonist SB 269970, lasting for a few days, causes similar changes to those observed after long-term administration of antidepressants. Thus, it seems that the pharmacological blockade of 5-HT(7) receptors produces faster effects compared to classic antidepressant drugs. A similarity between the changes in the glutamatergic transmission induced by the blockade of 5 HT7 receptors and those caused by repeated administration of the antidepressant drug, imipramine, has also been found in the frontal cortex. It has also been shown that the changes in glutamatergic transmission and the impairment of long-term synaptic plasticity in the frontal cortex of animals subjected to repeated restraint stress are reversed by the blockade of 5-HT(7) receptors. Overall, these studies, together with the data provided by other investigators, support the hypothesis that 5-HT(7) receptor antagonists may become a prototype of a new class of antidepressant drugs. Such compounds will not function by blocking 5-HT reuptake, as many of the currently used drugs, but through a direct interaction with the 5-HT(7) receptor. This type of action is highly selective and usually does not require the occurrence of adaptive changes in neuronal functions, thus allowing for a much quicker therapeutic effect.
本文总结了一系列旨在寻找 5-HT(7) 受体激活对大鼠海马和前额皮质神经元兴奋性以及兴奋性和抑制性突触传递影响的电生理学研究。这些研究表明，5-HT(7) 受体通过调节 CA1 区锥体细胞的兴奋性，以及通过其对 GABA 和谷氨酸能传递的影响，在调节海马网络活动方面发挥重要作用。反复给予抗抑郁药可降低海马中 5-HT(7) 受体的反应性，而长期高水平皮质酮则可增加其反应性。更重要的是，给予抗抑郁药丙咪嗪可防止皮质酮引起的海马 5-HT(7) 受体功能变化的发生。研究还发现，选择性拮抗剂 SB 269970 阻断 5-HT(7) 受体数天，会引起类似于长期给予抗抑郁药后观察到的变化。因此，5-HT(7) 受体的药理学阻断似乎比经典抗抑郁药产生更快的效果。在阻断 5-HT7 受体诱导的谷氨酸能传递变化与反复给予抗抑郁药丙咪嗪引起的变化之间也存在相似性。还表明，反复束缚应激动物前额皮质中的谷氨酸能传递变化和长时程突触可塑性损伤可通过阻断 5-HT(7) 受体得到逆转。总之，这些研究与其他研究者提供的数据一起，支持了 5-HT(7) 受体拮抗剂可能成为新型抗抑郁药原型的假说。这类化合物不会像许多现有的药物那样通过阻断 5-HT 再摄取起作用，而是通过与 5-HT(7) 受体直接相互作用起作用。这种作用类型高度特异，通常不需要神经元功能发生适应性变化，从而可以更快地产生治疗效果。
