Bdair Hussein, Sato-Fitoussi Marie, Planche Stéphane, Moquin Luc, Kang Min Su, Aliaga Arturo, Nagano-Saito Atsuko, Smart Kelly, Cox Sylvia M L, Near Jamie, Aguilar-Valles Argel, Massarweh Gassan, Rosa-Neto Pedro, Benkelfat Chawki, Soucy Jean-Paul, Kostikov Alexey, Gratton Alain, Leyton Marco
Department of Psychiatry, McGill University, Montreal, Canada.
Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, Montreal, Canada.
Imaging Neurosci (Camb). 2024 Apr 5;2. doi: 10.1162/imag_a_00126. eCollection 2024.
The excitatory neurotransmitter glutamate plays a critical role inexperience-dependent neuroplasticity, including addiction-related processes. Todate, however, it is not possible to measure glutamate release in the livinghuman brain. Positron emission tomography (PET) with [C]ABP688, aselective allosteric antagonist of metabotropic type 5 glutamate (mGlu5)receptors, could offer an effective strategy. To test this proposition, weconducted a series of studies in rats using microdialysis and[C]ABP688 microPET imaging, and in humans using PET and magneticresonance spectroscopy (MRS). Significant calcium-dependent glutamate releasewas identified in the ventral striatum of awake rats (190.5 ± 34.7%,< 0.05;= 7) followingadministration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacologicalchallenge readily translatable to human research. Simultaneous microdialysis andmicroPET studies in anesthetized rats yielded concurrent increases in glutamaterelease (126.9 ± 5.3%, < 0.001;= 11) and decreases in striatal[C]ABP688 binding (6.8 ± 9.6%,0.05). These latter two effects, however, were not significantlycorrelated (= 0.25,= 0.46).In humans, a laboratory stressor yielded significant changes in self-reportedmood (s < 0.041), sympathetic system activations(s < 0.042), and the MRS index of striatalglutamate reuptake following excitatory neurotransmission, Glx/Cr levels(= 0.048). These effects, however, were notaccompanied by significant changes in [C]ABP688 BP(s > 0.21,= 9) orcorrelated with each other (s > 0.074). Together, thesestudies document EtOH-induced glutamate release from neurons, EtOH-induceddecreases in [C]ABP688 binding, and stress-induced changes inglutamate turnover, yet fail to provide evidence that the PET[C]ABP688 method can be exploited to quantify moderate changes inglutamate release. The results underscore the need for highly controlled testingconditions during PET measures of mGlu5 receptors.
兴奋性神经递质谷氨酸在包括成瘾相关过程在内的经验依赖性神经可塑性中起关键作用。然而，迄今为止，尚无法在活体人脑中测量谷氨酸释放。使用代谢型5谷氨酸（mGlu5）受体的选择性变构拮抗剂[C]ABP688进行正电子发射断层扫描（PET），可能提供一种有效的策略。为了验证这一命题，我们在大鼠中使用微透析和[C]ABP688微PET成像进行了一系列研究，并在人类中使用PET和磁共振波谱（MRS）进行了研究。在清醒大鼠的腹侧纹状体中，在给予低剂量乙醇（EtOH；20%，0.5 g/kg）后，发现了显著的钙依赖性谷氨酸释放（190.5±34.7%，<0.05；=7），这是一种很容易转化为人体研究的药理学刺激。在麻醉大鼠中同时进行微透析和微PET研究，结果显示谷氨酸释放同时增加（126.9±5.3%，<0.001；=11），纹状体[C]ABP688结合减少（6.8±9.6%，0.05）。然而，后两种效应并没有显著相关性（=0.25，=0.46）。在人类中，一种实验室应激源导致自我报告情绪（<0.041）、交感神经系统激活（<0.042）以及兴奋性神经传递后纹状体谷氨酸再摄取的MRS指标Glx/Cr水平（=0.048）发生显著变化。然而，这些效应并没有伴随着[C]ABP688 BP（>0.21，=9）的显著变化，也没有相互关联（>0.074）。总之，这些研究记录了乙醇诱导的神经元谷氨酸释放、乙醇诱导的[C]ABP688结合减少以及应激诱导的谷氨酸代谢变化，但未能提供证据表明PET[C]ABP688方法可用于量化谷氨酸释放的适度变化。结果强调了在PET测量mGlu5受体期间需要高度受控的测试条件。
