Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors
Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors
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DOI：
10.1111/j.1476-5381.2010.00738.x
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发表时间：
2010-08-01
影响因子：
7.3
通讯作者：
Celada, P.
中科院分区：
文献类型：
--
作者：
Llado-Pelfort, L.;Assie, M-B;Celada, P.
背景和目的：F15599是一种新型的5-羟色胺(5-HT)(1A)受体激动剂，与其他单胺类受体相比具有1000倍的选择性，在动物模型中显示出极低剂量的抗抑郁和前认知活性。我们检测了F15599在体树突状自体受体和突触后5-HT1a异型受体上的活性。实验方法：在体单单位和局部场电位记录和微透析。关键结果：F15599增加了内侧前额叶皮质锥体神经元的放电频率，从0.2mU/kg·kg~(-1)静脉注射增加，并降低了中缝背侧5-羟色胺能神经元的放电频率(最小有效剂量8.2mU/kg)。这两种作用均被5-HT1A拮抗剂(+/-)WAY100635逆转。F15599不改变mPFC的低频振荡(类似于1赫兹)。在微透析研究中，F15599增加了mPFC的多巴胺输出(这种作用依赖于突触后5-HT1A受体的激活)，其ED50为30mU g中心点kg-1 ip，而它减少了海马5-HT的释放(该效应完全依赖于5-HT1A自身受体的激活)，其ED50为240 mu g中心点kg-1 ip。同样，在mPFC中应用反向透析的F15599以浓度依赖的方式增加多巴胺的产量。给予(+/-)WAY100635可阻止对F15599的所有神经化学反应。结论和意义：这些结果表明，全身应用F15599优先激活PFC的突触后5-HT1a受体，而不是躯体树突状5-HT1a自身受体。这种区域选择性使F15599有别于以前开发的5-HT1A受体激动剂，后者优先激活躯体树突状5-HT1A自体受体，这表明F15599可能在治疗抑郁症和精神分裂症的认知障碍方面特别有用。
Background and purpose:F15599, a novel 5-hydroxytryptamine (5-HT)(1A) receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors.Experimental approach:In vivo single unit and local field potential recordings and microdialysis in the rat.Key results:F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 mu g center dot kg-1 i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses > 10-fold higher (minimal effective dose 8.2 mu g center dot kg-1 i.v.). Both effects were reversed by the 5-HT1A antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (similar to 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 mu g center dot kg-1 i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 mu g center dot kg-1 i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635.Conclusions and implications:These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.