Dekeyne A, Brocco M, Adhumeau A, Gobert A, Millan M J
Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Paris, France.
Psychopharmacology (Berl). 2000 Sep;152(1):55-66. doi: 10.1007/s002130000449.
The benzodioxane, S15535, possesses low intrinsic activity and marked selectivity at 5-HT1A receptors, hippocampal populations of which are implicated in anxious states.
Herein, we examined its potential anxiolytic actions in relation to its influence upon extracellular levels of 5-HT in the dorsal hippocampus of freely-moving rats. Its effects were compared with those of other anxiolytic agents: the 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n-propylamino)-tetralin HBr (8-OH-DPAT), the 5-HT2C antagonist, SB206,553 and the benzodiazepine, diazepam.
Potential anxiolytic actions were evaluated in the Vogel conflict paradigm (increase in punished responses) and the social interaction (SI) test (increase in active SI) in rats. Extracellular levels of 5-HT were determined by microdialysis.
In analogy to diazepam. S15535 increased punished responses in the Vogel test. This action was dose dependently expressed over a broad (16-fold) dose range. Buspirone and 8-OH-DPAT were likewise active, but yielded highly biphasic dose-response curves. SB206,553 was dose dependently active in this model. In the SI test, S15535 similarly mimicked the anxiolytic-like effect of diazepam and was active over a broad dose range. Buspirone and 8-OH-DPAT again showed biphasic dose-response curves, as did SB206,553. In both the Vogel and SI tests, the anxiolytic-like effects of S15535 were abolished by the selective 5-HT1A receptor antagonist, WAY100,635, which was inactive alone. S15535 exerted its anxiolytic-like effects with a more pronounced separation to motor-disruptive doses than the other drugs. Finally, S15535 suppressed dialysate levels of 5-HT in the dorsal hippocampus, an action abolished by WAY100,635. Buspirone, 8-OH-DPAT and diazepam, but not SB206,553, also reduced 5-HT levels.
Likely reflecting its distinctive ability to selectively and preferentially activate pre- versus postsynaptic 5-HT1A receptors, S15535 suppresses hippocampal 5-HT release and displays marked anxiolytic-like effects over a broad dose range in the relative absence of motor perturbation.
苯并二恶烷S15535在5-HT1A受体处具有低内在活性和显著选择性，海马体中的5-HT1A受体与焦虑状态有关。
在此，我们研究了其对自由活动大鼠背侧海马体中5-HT细胞外水平的影响，并考察了其潜在的抗焦虑作用。将其作用与其他抗焦虑药物进行了比较：5-HT1A激动剂丁螺环酮和8-羟基-2-（二正丙基氨基）四氢萘溴化物（8-OH-DPAT）、5-HT2C拮抗剂SB206553以及苯二氮䓬类药物地西泮。
在大鼠的Vogel冲突范式（惩罚反应增加）和社交互动（SI）试验（主动社交互动增加）中评估潜在的抗焦虑作用。通过微透析测定5-HT的细胞外水平。
与地西泮类似，S15535在Vogel试验中增加了惩罚反应。这种作用在较宽（16倍）的剂量范围内呈剂量依赖性表达。丁螺环酮和8-OH-DPAT同样具有活性，但产生高度双相的剂量反应曲线。SB206553在此模型中呈剂量依赖性活性。在SI试验中，S15535同样模拟了地西泮的抗焦虑样作用，并且在较宽的剂量范围内具有活性。丁螺环酮和8-OH-DPAT再次显示出双相剂量反应曲线，SB206553也是如此。在Vogel试验和SI试验中，选择性5-HT1A受体拮抗剂WAY100635消除了S15535的抗焦虑样作用，而WAY100635单独使用时无活性。与其他药物相比，S15535发挥其抗焦虑样作用时，与运动干扰剂量的分离更为明显。最后，S15535抑制了背侧海马体中5-HT的透析液水平，这一作用被WAY100635消除。丁螺环酮、8-OH-DPAT和地西泮也降低了5-HT水平，但SB206553没有。
S15535可能反映了其选择性和优先激活突触前与突触后5-HT1A受体的独特能力，它抑制海马体5-HT释放，并在相对无运动干扰的情况下，在较宽的剂量范围内显示出显著的抗焦虑样作用。
