de Boer S F, Lesourd M, Mocaër E, Koolhaas J M
Department of Animal Physiology, University of, Groningen, The Netherlands.
Neuropsychopharmacology. 2000 Jul;23(1):20-33. doi: 10.1016/S0893-133X(00)00092-0.
To elucidate the relative contribution of somatodendritic 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors in the specific anti-aggressive properties of 5-HT(1A) receptor agonists, the influence of the novel benzodioxopiperazine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT(1A) receptors and as an agonist at 5-HT(1A) autoreceptors, upon offensive and defensive aggression was investigated in wild-type rats using a resident-intruder paradigm. S-15535 exerted a potent dose-dependent decrease in offensive, but not defensive, aggressive behavior (inhibitory dose (ID)(50) = 1.11 mg/kg). This anti-aggressive profile was roughly similar to that of the potent pre- and postsynaptic 5-HT(1A) full agonist alnespirone (ID(50) = 1. 24). The drug's profound anti-aggressive actions were not accompanied by sedative side effects or signs of the "5-HT(1A) receptor-mediated behavioral syndrome," which are characteristically induced by prototypical 5-HT(1A) receptor agonists like 8-OH-DPAT and buspirone. The selective pre- and postsynaptic 5-HT(1A) antagonist WAY-100635, which was inactive given alone, abolished the anti-aggressive effects of S-15535 and alnespirone, thereby confirming the involvement of 5-HT(1A) receptors. Furthermore, combined administration of S-15535 and alnespirone elicited an additive anti-aggressive effect, providing further support for somatodendritic 5-HT(1A) receptor involvement. Finally, the postsynaptic 5-HT(1A) antagonistic properties of S-15535 were confirmed by showing blockade of the alnespirone-induced hypothermia, a postsynaptic 5-HT(1A) mediated response in the rat. These data provide extensive evidence that the anti-aggressive effects of 5-HT(1A) receptor agonists are expressed via their action on somatodendritic 5-HT(1A) autoreceptors, thereby most likely attenuating intruder-activated serotonergic neurotransmission.
为阐明躯体树突状5-羟色胺（5-HT）1A自身受体和突触后5-HT1A受体在5-HT1A受体激动剂特定的抗攻击特性中的相对作用，我们使用定居者-入侵者范式，研究了新型苯并二氧哌嗪化合物S-15535对野生型大鼠攻击和防御性攻击行为的影响。S-15535在体内对突触后5-HT1A受体表现为竞争性拮抗剂，对5-HT1A自身受体表现为激动剂。S-15535对攻击性攻击行为产生了显著的剂量依赖性降低，但对防御性攻击行为没有影响（抑制剂量（ID）50 = 1.11毫克/千克）。这种抗攻击特征与强效的突触前和突触后5-HT1A完全激动剂阿奈螺酮大致相似（ID50 = 1.24）。该药物的强效抗攻击作用并未伴有镇静副作用或“5-HT1A受体介导的行为综合征”的迹象，而这些是由典型的5-HT1A受体激动剂如8-羟基二丙胺基四氢萘（8-OH-DPAT）和丁螺环酮典型诱导的。选择性突触前和突触后5-HT1A拮抗剂WAY-100635单独给药时无活性，它消除了S-15535和阿奈螺酮的抗攻击作用，从而证实了5-HT1A受体的参与。此外，S-15535和阿奈螺酮联合给药产生了相加的抗攻击作用，为躯体树突状5-HT1A受体的参与提供了进一步支持。最后，通过显示对阿奈螺酮诱导的体温过低的阻断，证实了S-15535的突触后5-HT1A拮抗特性，这是大鼠中突触后5-HT1A介导的反应。这些数据提供了广泛的证据，表明5-HT1A受体激动剂的抗攻击作用是通过其对躯体树突状5-HT1A自身受体的作用来表达的，从而最有可能减弱入侵者激活的5-羟色胺能神经传递。
