Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
Neuroimage. 2011 Oct 1;58(3):885-94. doi: 10.1016/j.neuroimage.2011.06.089. Epub 2011 Jul 8.
We recently suggested that serotonin 7 (5-Ht7) receptors may play a role in ADHD-like symptoms, at least in animal models. A mixed 5-Ht(1a/7) agonist, 8-OH-DPAT, counteracted the augmented levels of basal impulsivity, observed after treatment with a selective 5-Ht7 antagonist, SB269970 (Leo et al., 2009). In the present study, these serotonergic compounds were investigated by pharmacological magnetic resonance imaging (phMRI) at 4.7 T in adult isoflurane-anaesthetized rats. Axial echo-planar images were collected from the prefrontal cortex (PFC), ventral (nucleus accumbens, NAcc) and dorsal (dStr) striata, the hippocampus and the thalamus. After consecutive image collection for 30 min (50 baseline images), adult rats received either SB269970 (3mg/kg), 8-OH-DPAT (0.06 mg/kg) or saline intra-peritoneally (i.p.) via a remote cannula; the images were then collected for further 30 min (50 post-treatment images). Data were analysed 1) through an activation map generated on brain templates, obtained by using animals from each experimental group; 2) by a two-way ANOVA for the evaluation of temporal profiles, extracted within selected ROIs of each animal. Both compounds increased the BOLD signal in the areas of interest: SB269970, the selective 5-Ht7 antagonist, induced a significant effect in the PFC, particularly the orbital (oPFC) region, and in the NAcc. This effect started 6 to 12 min after drug administration, reached a maximum (+2.8%/+2.3%) at 12 to 18 min, and then moved to the dorsal thalamic nuclei. In contrast, the effects of 8-OH-DPAT were first observed in midline thalamic nuclei, and later appeared in forebrain regions: its effects were modest and transient within the NAcc and oPFC (+1.7% at 18 to 24 min after injection), whereas they were higher and long-lasting in the dStr and PFC, specifically the medial (mPFC) region (+3.1%/+4.0% from 15 min after drug administration onwards). The brain BOLD changes, reported as a consequence of selective 5-Ht7 antagonist administration, seemed restricted to the oPFC, NAcc and dorso-thalamic circuits, whereas the non-selective blockade of serotonergic receptors affected the mPFC, dStr and mid(line)-thalamic circuitry. The present findings revealed two differential serotonergic sub-pathways, as evidenced by the detection of physiological vascular feedback and/or neuronal activation.
我们最近提出，5-羟色胺 7（5-HT7）受体可能在 ADHD 样症状中发挥作用，至少在动物模型中是这样。混合 5-HT（1a/7）激动剂 8-OH-DPAT 对抗了选择性 5-HT7 拮抗剂 SB269970 治疗后观察到的基础冲动性水平升高（Leo 等人，2009 年）。在本研究中，这些血清素化合物在成年异氟烷麻醉大鼠的 4.7T 下通过药理学磁共振成像（phMRI）进行了研究。从前额皮质（PFC）、腹侧（伏隔核，NAcc）和背侧（dStr）纹状体、海马体和丘脑采集轴向回波平面图像。在连续采集 30 分钟（50 个基线图像）后，成年大鼠通过远程套管分别腹膜内（i.p.）给予 SB269970（3mg/kg）、8-OH-DPAT（0.06mg/kg）或生理盐水；然后再采集 30 分钟（50 个治疗后图像）。数据通过 1）使用来自每个实验组的动物生成的大脑模板上的激活图进行分析；2）通过评估每个动物的选定 ROI 内提取的时间曲线的双向 ANOVA 进行分析。两种化合物均增加了感兴趣区域的 BOLD 信号：选择性 5-HT7 拮抗剂 SB269970 在前额皮质（特别是眶额皮质区域）和 NAcc 中诱导了显著的效应。这种作用在给药后 6 到 12 分钟开始，在 12 到 18 分钟达到最大值（+2.8%/+2.3%），然后转移到背侧丘脑核。相比之下，8-OH-DPAT 的作用首先在中线丘脑核中观察到，然后出现在前脑区域：其作用在 NAcc 和 oPFC 中短暂而温和（注射后 18 至 24 分钟为+1.7%），而在 dStr 和 PFC 中更高且持久，特别是在中前额皮质（mPFC）区域（从药物给药后 15 分钟开始增加 3.1%/+4.0%）。作为选择性 5-HT7 拮抗剂给药的结果报告的大脑 BOLD 变化似乎仅限于 oPFC、NAcc 和背侧丘脑回路，而 5-羟色胺能受体的非选择性阻断影响 mPFC、dStr 和中线-丘脑回路。本研究结果揭示了两种不同的 5-羟色胺能亚途径，这是通过检测生理血管反馈和/或神经元激活来证明的。
