新型 5-HT（1A）受体激动剂 F15599 在后突触 5-HT（1A）受体中的优先体内作用。
Preferential in vivo action of F15599, a novel 5-HT(1A) receptor agonist, at postsynaptic 5-HT(1A) receptors.
机构信息
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), IDIBAPS, Barcelona, Spain.
出版信息
Br J Pharmacol. 2010 Aug;160(8):1929-40. doi: 10.1111/j.1476-5381.2010.00738.x.
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-HT(1A) 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 microg x kg(-1) i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 microg x kg(-1) i.v.). Both effects were reversed by the 5-HT(1A) antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (approximately 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT(1A) receptors) with an ED(50) of 30 microg x kg(-1) i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT(1A) autoreceptor activation) with an ED(50) of 240 microg x 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-HT(1A) receptors in PFC rather than somatodendritic 5-HT(1A) autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT(1A) receptor agonists, which preferentially activate somatodendritic 5-HT(1A) autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.
背景与目的
F15599 是一种新型的 5-羟色胺（5-HT）（1A）受体激动剂，与其他单胺受体相比，对 5-HT 的选择性高达 1000 倍，在动物模型中以非常低的剂量表现出抗抑郁和认知促进作用。我们研究了 F15599 在 somatodendritic 自身受体和突触后 5-HT（1A）异源受体中的体内活性。
实验方法
在大鼠的体内单细胞和局部场电位记录和微透析。
主要结果
F15599 从 0.2μg x kg(-1) 静脉内增加了内侧前额叶皮质（mPFC）中锥体神经元的放电率，而在高 10 倍以上的剂量下减少了背侧中缝核 5-羟色胺能神经元的放电率（最小有效剂量为 8.2μg x kg(-1) 静脉内）。两种作用都被 5-HT（1A）拮抗剂（+/-）WAY100635 逆转。F15599 没有改变 mPFC 中的低频振荡（约 1 Hz）。在微透析研究中，F15599 增加了 mPFC 中的多巴胺输出（一种依赖于突触后 5-HT（1A）受体激活的作用），其 ED（50）为 30μg x kg(-1) 腹腔内注射，而减少了海马体 5-HT 的释放（一种仅依赖于 5-HT（1A）自身受体激活的作用），其 ED（50）为 240μg x kg(-1) 腹腔内注射。同样，通过逆行透析在 mPFC 中应用 F15599 以浓度依赖的方式增加多巴胺的输出。所有对 F15599 的神经化学反应都被（+/-）WAY100635 给药所预防。
结论与意义
这些结果表明，全身给予 F15599 优先激活 PFC 中的突触后 5-HT（1A）受体，而不是 somatodendritic 5-HT（1A）自身受体。这种区域选择性将 F15599 与以前开发的 5-HT（1A）受体激动剂区分开来，后者优先激活 somatodendritic 5-HT（1A）自身受体，表明 F15599 在治疗抑郁症和精神分裂症的认知缺陷方面可能特别有用。
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