Ase A R, Sénécal J, Reader T A, Hen R, Descarries L
Faculté de Médecine, Département de Physiologie, Université de Montréal, Succursale Centre-ville, Montréal, Quebec, Canada.
Neuropharmacology. 2002 Jun;42(7):941-9. doi: 10.1016/s0028-3908(02)00045-x.
The firing of central serotonin (5-hydroxytryptamine, 5-HT) neurons and their capacity to release 5-HT are subjected to a receptor-mediated auto-control via 5-HT(1A) and 5-HT(1B) receptors respectively located on the somata/dendrites (5-HT(1A) autoreceptors) and preterminal axon arborizations (5-HT(1B) autoreceptors) of these neurons. To further characterize mutual adaptations of these two receptor subtypes in the absence of one of them, activation of G-protein coupling by agonist was measured and compared to wild-type (WT) in 5-HT(1A) and 5-HT(1B) homozygous knockout (KO) mice. As expected, in WT, the non-selective 5-HT(1A/1B) receptor agonist 5-carboxyamidotryptamine (5-CT) stimulated guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTP(gamma)S) incorporation in many brain regions endowed with one and/or the other receptor. In the respective KOs, no stimulation was measured in regions known to express only or mainly the deleted receptor. In the 5-HT(1A) KOs, the amplitude of G-protein activation in regions endowed with 5-HT(1B) receptors was unchanged by comparison to WT. In the 5-HT(1B) KOs, the magnitude of the 5-CT stimulation was the same as WT in all regions containing 5-HT(1A) receptors, except in the amygdala, where it was significantly lower, even if this region was one of the most strongly activated in the WT. A similar result was obtained in the amygdala of 5-HT(1B) KOs after activation by the selective 5-HT(1A) receptor agonist R-(+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Under these conditions, however, there was in addition a significant lowering of the stimulated (but not basal) [(35)S]GTP(gamma)S incorporation by comparison to WT in all regions endowed with 5-HT(1A) receptors, including the dorsal raphe nucleus. Thus, eventhough agonist radioligand binding to either 5-HT(1A) or 5-HT(1B) receptors is unchanged in the reciprocal KOs, it appears that a compensatory decrease in the efficiency of G-protein coupling to 5-HT(1A) receptors has developed in the 5-HT(1B) mutant. This could represent the first indication of a cross-talk between these two 5-HT receptor subtypes, at least in brain regions where they are co localized in the same neurons.
中枢5-羟色胺（5-羟色氨酸，5-HT）能神经元的放电及其释放5-HT的能力分别通过位于这些神经元胞体/树突（5-HT(1A)自身受体）和终末前轴突分支（5-HT(1B)自身受体）上的5-HT(1A)和5-HT(1B)受体接受受体介导的自身调控。为了进一步明确这两种受体亚型在缺失其中一种时的相互适应性，我们在5-HT(1A)和5-HT(1B)纯合基因敲除（KO）小鼠中测量并比较了激动剂对G蛋白偶联的激活作用，并与野生型（WT）小鼠进行对比。正如预期的那样，在野生型小鼠中，非选择性的5-HT(1A/1B)受体激动剂5-羧基酰胺色胺（5-CT）刺激鸟苷5'-O-(γ-[(35)S]硫代)三磷酸（[(35)S]GTP(γ)S）掺入许多同时表达一种和/或另一种受体的脑区。在各自的基因敲除小鼠中，在已知仅表达或主要表达缺失受体的脑区未检测到刺激作用。在5-HT(1A)基因敲除小鼠中，与野生型相比，具有5-HT(1B)受体的脑区中G蛋白激活的幅度没有变化。在5-HT(1B)基因敲除小鼠中，除杏仁核外，在所有含有5-HT(1A)受体的脑区，5-CT刺激的强度与野生型相同，而在杏仁核中，即使该脑区在野生型小鼠中是激活最强的脑区之一，其刺激强度也显著降低。在用选择性5-HT(1A)受体激动剂R-(+)8-羟基-2-(二正丙基氨基)四氢萘（8-OH-DPAT）激活后，5-HT(1B)基因敲除小鼠的杏仁核也得到了类似的结果。然而，在这些条件下，与野生型相比，在所有含有5-HT(1A)受体的脑区，包括中缝背核，刺激（而非基础）[(35)S]GTP(γ)S掺入也显著降低。因此，尽管在相互的基因敲除小鼠中，激动剂与5-HT(1A)或5-HT(1B)受体的放射性配体结合没有变化，但似乎在5-HT(1B)突变体中已经出现了G蛋白与5-HT(1A)受体偶联效率的代偿性降低。这可能代表了这两种5-HT受体亚型之间相互作用的首个迹象，至少在它们共定位于同一神经元的脑区是如此。
